Article

The effects of omega-3 polyunsaturated fatty acids and genetic variants on methylation levels of the interleukin-6 gene promoter

October 2015
Molecular Nutrition & Food Research 60(2)

October 2015
60(2)

DOI:10.1002/mnfr.201500436

Authors:

Yiyi Ma

Boston University

Caren E Smith

Tufts University

Chao-Qiang Lai

JM USDA Human Nutrition Research Center on Aging at Tufts University

Marguerite R Irvin

University of Alabama at Birmingham

Show all 15 authorsHide

Scope: Omega-3 polyunsaturated fatty acids (n-3 PUFA) reduce interleukin-6 (IL6) gene expression, but their effects on transcription regulatory mechanisms are unknown. We aimed to conduct an integrated analysis with both population and in vitro studies to systematically explore the relationships among n-3 PUFA, DNA methylation, single nucleotide polymorphisms (SNPs), gene expression, and protein concentration of IL6. Methods and results: Using data in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study and the Encyclopedia of DNA Elements (ENCODE) consortium, we found that higher methylation of IL6 promoter cg01770232 was associated with higher IL-6 plasma concentration (P = 0.03) and greater IL6 gene expression (P = 0.0005). Higher circulating total n-3 PUFA was associated with lower cg01770232 methylation (P = 0.007) and lower IL-6 concentration (P = 0.02). More A allele of IL6 rs2961298 was associated with higher cg01770232 methylation (P = 2.55×10(-7) ). The association between n-3 PUFA and cg01770232 methylation was dependent on rs2961298 genotype (P = 0.02), but higher total n-3 PUFA was associated with lower cg01770232 methylation in the heterozygotes (P = 0.04) not in the homozygotes. Conclusions: Higher n-3 PUFA is associated with lower methylation at IL6 promoter, which may be modified by IL6 SNPs. This article is protected by copyright. All rights reserved.

Impacts of Eccentric Resistance Exercise on DNA Methylation of Candidate Genes for Inflammatory Cytokines in Skeletal Muscle and Leukocytes of Healthy Males

Article

Full-text available

Feb 2023

Physical inactivity and a poor diet increase systemic inflammation, while chronic inflammation can be reduced through exercise and nutritional interventions. The mechanisms underlying the impacts of lifestyle interventions on inflammation remain to be fully explained; however, epigenetic modifications may be critical. The purpose of our study was to investigate the impacts of eccentric resistance exercise and fatty acid supplementation on DNA methylation and mRNA expression of TNF and IL6 in skeletal muscle and leukocytes. Eight non-resistance exercise-trained males completed three bouts of isokinetic eccentric contractions of the knee extensors. The first bout occurred at baseline, the second occurred following a three-week supplementation of either omega-3 polyunsaturated fatty acid or extra virgin olive oil and the final bout occurred after eight-weeks of eccentric resistance training and supplementation. Acute exercise decreased skeletal muscle TNF DNA methylation by 5% (p = 0.031), whereas IL6 DNA methylation increased by 3% (p = 0.01). Leukocyte DNA methylation was unchanged following exercise (p > 0.05); however, three hours post-exercise the TNF DNA methylation decreased by 2% (p = 0.004). In skeletal muscle, increased TNF and IL6 mRNA expression levels were identified immediately post-exercise (p < 0.027); however, the leukocyte mRNA expression was unchanged. Associations between DNA methylation and markers of exercise performance, inflammation and muscle damage were identified (p < 0.05). Acute eccentric resistance exercise is sufficient to induce tissue-specific DNA methylation modifications to TNF and IL6; however, neither eccentric training nor supplementation was sufficient to further modify the DNA methylation.

Impact of aerobic exercise and fatty acid supplementation on global and gene-specific DNA methylation

Article

Feb 2019

Lifestyle interventions, including exercise and dietary supplementation, can modify DNA methylation and exert health benefits; however, the underlying mechanisms are poorly understood. Here we investigated the impact of acute aerobic exercise and the supplementation of omega-3 polyunsaturated fatty acids (n-3 PUFA) and extra virgin olive oil (EVOO) on global and gene-specific (PPARGC1A, IL6 and TNF) DNA methylation, and DNMT mRNA expression in leukocytes of disease-free individuals. Eight trained male cyclists completed an exercise test before and after a four-week supplementation of n-3 PUFA and EVOO in a double-blind, randomised, repeated measures design. Exercise triggered global hypomethylation (Pre 79.2%; Post 78.7%; p = 0.008), alongside, hypomethylation (Pre 6.9%; Post 6.3%; p < 0.001) and increased mRNA expression of PPARGC1A (p < 0.001). Associations between PPARGC1A methylation and exercise performance were also detected. An interaction between supplement and trial was detected for a single CpG of IL6 indicating increased DNA methylation following n-3 PUFA and decreased methylation following EVOO (p = 0.038). Global and gene-specific DNA methylation associated with markers of inflammation and oxidative stress. The supplementation of EVOO reduced DNMT1 mRNA expression compared to n-3 PUFA supplementation (p = 0.048), whereas, DNMT3a (p=0.018) and DNMT3b (p=0.046) mRNA expression were decreased following exercise. In conclusion, we demonstrate that acute exercise and dietary supplementation of n-3 PUFAs and EVOO induce DNA methylation changes in leukocytes, potentially via the modulation of DNMT mRNA expression. Future studies are required to further elucidate the impact of lifestyle interventions on DNA methylation.

The integration of epigenetics and genetics in nutrition research for CVD risk factors

Article

Dec 2016
P NUTR SOC

There is increasing evidence documenting gene-by-environment (G × E) interactions for CVD related traits. However, the underlying mechanisms are still unclear. DNA methylation may represent one of such potential mechanisms. The objective of this review paper is to summarise the current evidence supporting the interplay among DNA methylation, genetic variants, and environmental factors, specifically (1) the association between SNP and DNA methylation; (2) the role that DNA methylation plays in G × E interactions. The current evidence supports the notion that genotype-dependent methylation may account, in part, for the mechanisms underlying observed G × E interactions in loci such as APOE, IL6 and ATP-binding cassette A1. However, these findings should be validated using intervention studies with high level of scientific evidence. The ultimate goal is to apply the knowledge and the technology generated by this research towards genetically based strategies for the development of personalised nutrition and medicine.

Evaluation of the Efficacy of Omega-3 Fatty Acids Formulations in the Lipopolysaccharide-Induced Acute Lung Inflammation Rat Model

Preprint

Full-text available

Nov 2021

Many current treatment options for lung inflammation and thrombosis come with unwanted side effects. The natural omega-3 fatty acids (O3FA) are generally anti-inflammatory and antithrombotic. The O3FA are always administered orally and occasionally by intravenous (IV) infusion. The main goal of this study is to determine if O3FA administered by inhalation of a nebulized formulation mitigates LPS-induced acute lung inflammation in male Wistar rats. Inflammation was triggered by intraperitoneal injection of LPS once a day for 14 days. One hour later, rats received nebulized treatments consisting of egg lecithin emulsified O3, budesonide and Montelukast, and blends of O3 and melatonin or Montelukast or Cannabidiol; O3 was in the form of free fatty acids for all groups except one group with ethyl esters. Lung histology and cytokines were determined in n=3 rats per group at day 8 and day 15. All groups had alveolar histiocytosis severity scores half or less than that of the disease control (Cd) treated with LPS and saline only inhalation. IL-6, TNF-α, TGF-β, and IL-10 were attenuated in all O3 groups. IL-1β was attenuated in most but not all O3 groups. O3 administered as ethyl ester was overall most effective in mitigating LPS effects. No evidence of lipid pneumonia or other chronic distress was observed. These preclinical data suggest that O3FA formulations should be further investigated as treatments in lung inflammation and thrombosis related lung disorders, including asthma, chronic obstructive pulmonary disease, lung cancer and acute respiratory distress like COVID-19.

Omega‑3 polyunsaturated fatty acids inhibit IL‑11/STAT3 signaling in hepatocytes during acetaminophen hepatotoxicity

Article

Full-text available

Aug 2021

Omega‑3 polyunsaturated fatty acids (n‑3 PUFAs) exert a negative effect on IL‑6 production in several liver disorders, including cirrhosis, acute liver failure and fatty liver disease. However, its effect on the production of IL‑11, another important IL‑6 family cytokine, remains unclear. IL‑11 was found to be significantly elevated in acetaminophen (APAP)‑induced liver damage. The aim of the present study was to investigate whether and how n‑3 PUFAs modulate IL‑11 production during APAP‑induced liver injury. For that purpose, wild‑type (WT) and fat‑1 transgenic mice were intraperitoneally injected with APAP to induce liver injury. Serum was collected for ELISA and alanine aminotransferase assay. The hepatocytes of APAP‑injected mice were isolated for reverse transcription‑quantitative PCR and western blot analyses. For the in vitro study, primary hepatocytes isolated from WT or fat‑1 mice were stimulated with APAP. The results revealed that both endogenous and exogenous n‑3 PUFAs significantly aggravated APAP‑induced liver damage via the downregulation of STAT3 signaling. Notably, n‑3 PUFAs inhibited IL‑11 expression, but not IL‑6 expression in hepatocytes during the APAP challenge. Furthermore, it was demonstrated that limited phosphorylation of ERK1/2 and Fos‑ like‑1 (Fra‑1) expression are responsible for the n‑3 PUFA‑mediated inhibitory effect on IL‑11 production in APAP‑treated hepatocytes. It was concluded that n‑3 PUFAs inhibit IL‑11 production and further STAT3 activation in hepatocytes during APAP‑induced liver injury. Therefore, ERK1/2‑mediated Fra‑1 expression is responsible for the effect of n‑3 PUFAs on IL‑11 expression.

DNA methylation of tumour necrosis factor (TNF) alpha gene is associated with specific blood fatty acid levels in a gender‐specific manner

Article

Full-text available

Apr 2021

Background Fatty acids, specifically polyunsaturated fatty acids (PUFAs) play an important role in inflammation and its resolution, however, their interaction with the epigenome is relatively unexplored. Here we investigate the relationship between circulating blood fatty acids and the DNA methylation of the cytokine encoding gene tumour necrosis factor (TNF, OMIM 191160). Methods Using a cross‐sectional study approach, we collected blood samples from adults (N=88 (30 males, 58 females); 18–74 years old) for DNA methylation pyrosequencing analysis at four sites in TNF exon 1 and gas‐chromatography mass‐spectrometry analysis of the fatty acid profile of dried blood spots (DBS). Results Methylation levels of TNF exon 1 are significantly correlated with specific fatty acids in a gender‐specific manner. In the males the PUFAs Docosahexaenoic Acid (DHA) and Arachidonic Acid (AA) were positively associated with TNF methylation, as was the saturated fatty acid (SFA) Stearic Acid; in contrast, mono‐unsaturated fatty acids (MUFAs) had a negative association. In the females, omega‐6 PUFA γ‐Linolenic acid (GLA) was negatively correlated with TNF methylation; Adrenic acid and Eicosadienoic Acid were positively correlated with TNF methylation. Conclusion These results suggest that one way that fatty acids interact with the inflammation is through altered methylation profiles of cytokine genes; thus, providing potential therapeutic targets for nutritional and health interventions.

Peripheral Blood DNA Methylation Changes after Omega-3 Fatty Acid Treatment Indicate Anti-inflammatory Effects and Individual Variability

Preprint

Full-text available

Oct 2020

Background Omega-3 or n-3 polyunsaturated fatty acids (PUFAs) are widely studied for health benefits based on potential anti-inflammatory effects. However, the factors involved in mediating the anti-inflammatory responses to n-3 PUFAs are not fully understood; furthermore, many effects from n-3 PUFA treatment are not well characterized in humans. Of interest is the role of DNA methylation (DNAm) in mediating the effects of n-3 PUFAs on inflammation. Objective We aimed to characterize the effects of n-3 PUFA treatment on DNAm in inflammation-related signaling pathways in PBMCs of women at high risk of breast cancer Methods PBMCs of women at high risk of breast cancer were obtained at 0 and 6 months of n-3 PUFA treatment in a previously reported dose finding trial (n=10 matched pairs in the 5 g/day EPA+DHA dose arm).[53] DNA methylation of PBMCs were assayed using reduced representation bisulfite sequencing to obtain genome-wide methylation profiles on a single nucleotide level. Analyses were performed to investigate the effects of n-3 PUFA treatment on DNAm both genome-wide and within a set of candidate genes. Results A large number of differentially methylated CpGs (DMCs) in gene promoters (24,842 DMCs in 5507 genes) showed significant enrichment for hypermethylation in both the candidate gene and genome-wide analyses. Using these DNAm changes, pathway analysis identified significantly hypermethylated signaling networks after n-3 PUFA treatment, such as the Toll-like Receptor pathway. Based on analyses of data per individual, DNAm changes from n-3 PUFA treatment appear highly variable between study participants. Conclusions Dietary n-3 PUFA supplementation for six months is associated with DNAm changes in PBMCs with potential for anti-inflammatory effects. PBMC DNAm profiles may offer a novel means of assessing individual response to n-3 PUFAs. This observation warrants further investigation in future n-3 PUFA intervention studies.

Epigenetic changes in blood leukocytes following an omega-3 fatty acid supplementation

Article

Full-text available

Apr 2017

Background Omega-3 polyunsaturated fatty acids (n-3 FAs) have several beneficial effects on cardiovascular (CV) disease risk factors. These effects on CV risk profile may be mediated by several factors, including epigenetic modifications. Our objective is to investigate, using genome-wide DNA methylation analyses, methylation changes following an n-3 FA supplementation in overweight and obese subjects and to identify specific biological pathways potentially altered by the supplementation. Results Blood leukocytes genome-wide DNA methylation profiles of 36 overweight and obese subjects before and after a 6-week supplementation with 3 g of n-3 FAs were compared using GenomeStudio software. After supplementation, 308 CpG sites, assigned to 231 genes, were differentially methylated (FDR-corrected Diffscore ≥│13│~ P ≤ 0.05). Using Ingenuity Pathway Analysis system, a total of 55 pathways were significantly overrepresented following supplementation. Among these pathways, 16 were related to inflammatory and immune response, lipid metabolism, type 2 diabetes, and cardiovascular signaling. Changes in methylation levels of CpG sites within AKT3, ATF1, HDAC4, and IGFBP5 were correlated with changes in plasma triglyceride and glucose levels as well as with changes in the ratio of total cholesterol/HDL-cholesterol following the supplementation. Conclusions These data provide key differences in blood leukocytes DNA methylation profiles of subjects following an n-3 FA supplementation, which brings new, potential insights on metabolic pathways underlying the effects of n-3 FAs on CV health. Electronic supplementary material The online version of this article (doi:10.1186/s13148-017-0345-3) contains supplementary material, which is available to authorized users.

Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry Delesderrier et al.: Ferroptosis and Iron and PUFA Ingestion Review Can Iron and Polyunsaturated Fatty Acid Supplementation Induce Ferroptosis? Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry

Article

Apr 2023
CELL PHYSIOL BIOCHEM

Ferroptosis is a regulated non-apoptotic cell death process triggered by excessive iron-induced lipid peroxidation. Excess intracellular iron promotes lipid peroxidation by increasing reactive oxygen species formation through the Fenton reaction. Thus, iron and polyunsaturated fatty acid intake may trigger ferroptosis under certain conditions. The aims of this review were to compile and examine evidence in the literature for the effects of iron and polyunsaturated fatty acid supplementation on ferroptosis. Omega-6 polyunsaturated fatty acids have relatively greater susceptibility to lipid peroxidation and could, therefore, participate in ferroptosis. By contrast, omega-3 polyunsaturated fatty acids promote intracellular antioxidants synthesis and reduce the formation of hydroperoxides that induce ferroptosis. As intestinal iron absorption is regulated by iron nutritional status, individuals with normal functioning of the hepcidin-ferroportin axis are at low risk of developing iron overload in response to ingestion of iron-rich foods. Therefore, iron supplementation is potentially toxic mainly for the intestinal epithelium and the microbiota. In animal models, iron-rich diets increased oxidative damage, lowered the glutathione concentration within hepatocytes, and downregulated desaturases that synthesize long-chain polyunsaturated fatty acids. These adverse effects of iron supplementation were prevented by omega-3 fatty acid co-supplementation. The impact of food and supplement intake on ferroptosis has seldom been investigated. Scientific evidence still does not allow us to know for sure whether iron and PUFA supplementation are capable of inducing ferroptosis. As the mechanisms that control ferroptosis can determine whether cells proliferate or die, future studies should directly investigate the effects of nutrient supplementation and food intake on the ferroptosis process in different types of cells and tissues.

Can Iron and Polyunsaturated Fatty Acid Supplementation Induce Ferroptosis?

Article

Full-text available

Apr 2023
CELL PHYSIOL BIOCHEM

The High ‘Lipolytic Jump’ of Immobilized Amano A Lipase from Aspergillus niger in Developed ‘ESS Catalytic Triangles’ Containing Natural Origin Substrates

Article

Full-text available

Aug 2022

Lipase Amano A from Aspergillus niger (AA-ANL) is among the most commonly applied enzymes in biocatalysis processes, making it a significant scientific subject in the pharmaceutical and medical disciplines. In this study, we investigated the lipolytic activity of AA-ANL immobilized onto polyacrylic support IB-150A in 23 oils of natural origin containing various amounts of polyunsaturated fatty acids (PUFAs) and monounsaturated fatty acids (MUFAs). The created systems were expressed as an ‘ESS catalytic triangle’. A distinct ‘jump’ (up to 2400%) of lipolytic activity of immobilized AA-ANL compared to free lipase and hyperactivation in mostly tested substrates was observed. There was a ‘cutoff limit’ in a quantitative mutual ratio of ω-PUFAs/MUFAs, for which there was an increase or decrease in the activity of the immobilized AA-ANL. In addition, we observed the beneficial effect of immobilization using three polyacrylic supports (IB-150A, IB-D152, and IB-EC1) characterized by different intramolecular interactions. The developed substrate systems demonstrated considerable hyperactivation of immobilized AA-ANL. Moreover, a ‘lipolytic jump’ in the full range of tested temperature and pH was also observed. The considerable activity of AA-ANL-IB-150A after four reuse cycles was demonstrated. On the other hand, we observed an essential decrease in stability of immobilized lipase after 168 h of storage in a climate chamber. The tested kinetic profile of immobilized AA-ANL confirmed the increased affinity to the substrate relative to lipase in the free form.

Maternal PUFAs, Placental Epigenetics, and Their Relevance to Fetal Growth and Brain Development

Article

Full-text available

Jun 2022

Dietary polyunsaturated fatty acids (PUFAs), especially omega-3 (n-3) and n-6 long-chain (LC) PUFAs, are indispensable for the fetus' brain supplied by the placenta. Despite being highly unsaturated, n-3 LCPUFA-docosahexaenoic acid (DHA) plays a protective role as an antioxidant in the brain. Deficiency of DHA during fetal development may cause irreversible damages in neurodevelopment programming. Dietary PUFAs can impact placental structure and functions by regulating early placentation processes, such as angiogenesis. They promote remodeling of uteroplacental architecture to facilitate increased blood flow and surface area for nutrient exchange. The placenta's fatty acid transfer depends on the uteroplacental vascular development, ensuring adequate maternal circulatory fatty acids transport to fulfill the fetus' rapid growth and development requirements. Maternal n-3 PUFA deficiency predominantly leads to placental epigenetic changes than other fetal developing organs. A global shift in DNA methylation possibly transmits epigenetic instability in developing fetuses due to n-3 PUFA deficiency. Thus, an optimal level of maternal omega-3 (n-3) PUFAs may protect the placenta's structural and functional integrity and allow fetal growth by controlling the aberrant placental epigenetic changes. This narrative review summarizes the recent advances and underpins the roles of maternal PUFAs on the structure and functions of the placenta and their relevance to fetal growth and brain development.

Inhalation of Nebulized Omega-3 Fatty Acids Mitigate LPS-Induced Acute Lung Inflammation in Rats: Implications for Treatment of COPD and COVID-19

Article

Mar 2022
PROSTAG LEUKOTR ESS

Many current treatment options for lung inflammation and thrombosis come with unwanted side effects. The natural omega-3 fatty acids (O3FA) are generally anti-inflammatory and antithrombotic. O3FA are always administered orally and occasionally by intravenous (IV) infusion. The main goal of this study is to determine if O3FA administered by inhalation of a nebulized formulation mitigates LPS-induced acute lung inflammation in male Wistar rats. Inflammation was triggered by intraperitoneal injection of LPS once a day for 14 days. One hour post-injection, rats received nebulized treatments consisting of egg lecithin emulsified O3, budesonide and Montelukast, and blends of O3 and melatonin or Montelukast or Cannabidiol; O3 was in the form of free fatty acids for all groups except one group with ethyl esters. Lung histology and cytokines were determined in n=3 rats per group at day 8 and day 15. All groups had alveolar histiocytosis severity scores half or less than that of the disease control (Cd) treated with LPS and saline only inhalation. IL-6, TNF-α, TGF-β, and IL-10 were attenuated in all O3FA groups. IL-1β was attenuated in most but not all O3 groups. O3 administered as ethyl ester was overall most effective in mitigating LPS effects. No evidence of lipid pneumonia or other chronic distress was observed. These preclinical data suggest that O3FA formulations should be further investigated as treatments in lung inflammation and thrombosis related lung disorders, including asthma, chronic obstructive pulmonary disease, lung cancer and acute respiratory distress such as COVID-19.

Omega‐3 polyunsaturated fatty acids supplementation improve clinical symptoms in patients with Covid‐19: A randomized clinical trial

Article

Sep 2021

Aims We hypothesized that omega-3 fatty acids would be an appropriate adjunct therapy for alleviating the inflammatory response and clinical manifestation in hospitalized patients with Covid-19 disease. Methods This was a single-blind randomized controlled trial in Amir-Alam hospital in Tehran. Thirty adult men and women diagnosed with Covid-19 were allocated to either control group (receiving Hydroxychloroquine) or intervention group (receiving Hydroxychloroquine plus 2 grams of Docosahexaenoic acid [DHA]+ Eicosapentaenoic acid [EPA]) for 2 weeks. Primary outcome of the intervention including C-reactive protein (CRP), Erythrocyte sedimentation rate (ESR) as well as clinical symptoms including body pain, fatigue, appetite and olfactory and secondary outcomes including liver enzymes were determined at the baseline and after omega-3 supplementation. Clinical signs were measured using self-reported questionnaires. There were commercial kits for determination of CRP and liver enzymes concentrations in the serum of patients. For determination of ESR automated hematology analyzer was applied. The study of “Comparison of the effectiveness of omega-3 and Hydroxychloroquine on Inflammatory factors, liver enzymes and clinical symptoms in diabetic Covid-19 patients” was registered in Iranian Registry of Clinical Trials (IRCT) with ID number: IRCT20200511047399N1 Results In comparison to control group, patients receiving omega-3 indicated favorable changes in all clinical symptoms except for olfactory (p<0.001 for body pain and fatigue, p= 0.03 for appetite and p=0.21 for olfactory). Reducing effects of omega-3 supplementation compared to control group were also observed in the levels of ESR and CRP after treatment (p<0.001 for CRP and p=0.02 for ESR). However, no between group differences in the liver enzymes serum concentrations were observed after supplementation (p>0.05). Conclusion Current observations are very promising and indicate that supplementation with moderate dosages of omega-3 fatty acids may be beneficial in the management of inflammation-mediated clinical symptoms in Covid-19 patients.

Parenteral Omega-3 Fatty Acid Supplementation Improves Outcome of Sepsis: A Real-World, Retrospective Cohort Study

Preprint

Full-text available

May 2021

Objectives: The role of omega-3 fatty acids in the treatment of sepsis is always on paradox. we tried to retrieve and download the patients’ data in a certain period through the hospital information system, used data sorting so as to screen out the patients with sepsis so as to find out the role of omega-3 fatty acids in sepsis. Methods: Through the hospital information system, retrieve and include the patients who were admitted to the Department of critical medicine of Shenzhen People's Hospital from December 2016 to June 2019, screen out patients diagnosed with sepsis according to a certain criterion. The patients were grouped by whether they were applicated with omega-3 fatty acid or not. Results: A total of 1733 cases included into analysis, among of whom 303 cases were applicated with omega-3 fatty acid. The amounts and baseline conditions between both groups were imbalance. Severity of omega-3 fatty acid group was higher than that of control group. Chi-square test found that the mortality rate of omega-3 fatty acid was higher than that of control group (p < 0.0001). But age, gender, whether there is abdominal infection, whether there is septicemia, shock, the need for mechanical ventilation, and the need for renal replacement therapy may all affect the prognosis of the patients. If these factors were used as covariates, multiple logistic regression analysis showed that there was no significant difference in mortality rate between the treatment group and the control group (P = 0.574). Survival analysis showed that the survival rate of treatment group was higher than that of the control group when at the end of total treatment duration (P = 0.035). Conclusion: For patients with more severe sepsis, doctors are more likely to use omega-3 fatty acids in the early stage. Omega-3 fatty acids may improve the long-term prognosis of sepsis, but the conclusion still needs to be accepted carefully.

Interaction between iron and omega-3 fatty acids metabolisms: where is the cross-link?

Article

Dec 2020

Iron is an essential micronutrient for almost all living organisms. It plays an important role in DNA, RNA, and protein synthesis and takes part in electron transport, cellular respiration, cell proliferation and differentiation, and gene expression regulation. However, there is a fine line between excessive and insufficient body iron content. Iron overload is biochemically dangerous. It causes serious toxicities and generates reactive oxygen species via the Fenton reaction, leading to damage to cellular membranes, proteins, and DNA. Omega-3 fatty acids play an essential role in many physiological processes, including energy metabolism and signal transduction, as well as acting as structural components of cell membranes. Omega-3 fatty acids also help to maintain homeostasis and combat diseases. Recent studies using model organisms as well as clinical studies have revealed a link between omega-3 fatty acids and iron metabolism. Moreover, various iron-related disorders are significantly affected by omega-3 fatty acids. There is a clear relationship between iron and omega-3 fatty acid metabolisms; however, the underlying mechanisms are unknown. Therefore, in-depth research is needed to determine the exact nature of the metabolic interactions of these nutrients. Here, we focus on iron and omega-3 fatty acid metabolisms at their crossroads in the liver and brain.

SnoVault and encodeD: A novel object-based storage system and applications to ENCODE metadata

Preprint

Full-text available

Jul 2016

The Encyclopedia of DNA elements (ENCODE) project is an ongoing collaborative effort[1–6] to create a comprehensive catalog of functional elements initiated shortly after the completion of the Human Genome Project[7][1]. The current database exceeds 6500 experiments across more than 450 cell lines and tissues using a wide array of experimental techniques to study the chromatin structure, regulatory and transcriptional landscape of the H. sapiens and M. musculus genomes. All ENCODE experimental data, metadata, and associated computational analyses are submitted to the ENCODE Data Coordination Center (DCC) for validation, tracking, storage, unified processing, and distribution to community resources and the scientific community. As the volume of data increases, the identification and organization of experimental details becomes increasingly intricate and demands careful curation. The ENCODE DCC[8–10] has created a general purpose software system, known as SnoVault, that supports metadata and file submission, a database used for metadata storage, web pages for displaying the metadata and a robust API for querying the metadata. The software is fully open-source, code and installation instructions can be found at: http://github.com/ENCODE-DCC/snovault/ (for the generic database) and http://github.com/ENCODE-DCC/encoded/ to store genomic data in the manner of ENCODE. The core database engine, SnoVault (which is completely independent of ENCODE, genomic data, or bioinformatic data) has been released as a separate Python package. Database URL: https://www.encodeproject.org/

Parenteral supplementation of omega-3 fatty acid on the prognosis of sepsis: a real world retrospective study

Preprint

Full-text available

Aug 2020

Maternal dietary deficiency of n-3 fatty acids affects metabolic and epigenetic phenotypes of the developing fetus

Article

May 2020
PROSTAG LEUKOTR ESS

Maternal Intake of n-3 Polyunsaturated Fatty Acids During Pregnancy Is Associated With Differential Methylation Profiles in Cord Blood White Cells

Article

Full-text available

Oct 2019

A healthy diet during pregnancy is pivotal for the offspring health at birth and later in life. N-3 polyunsaturated fatty acids (n-3 PUFAs) are not endogenously produced in humans and are exclusively derived from the diet. They are pivotal for the fetus growth and neuronal development and seem beneficial in reducing the risk of cardiometabolic diseases and preventing later allergic disorders in the offspring by modulating the inflammatory immune response. In the present study, we investigated the association between maternal intakes of n-3PUFAs, profiled on maternal erythrocyte membranes at pregnancy term, and offspring DNA methylation on cord blood mononuclear cells in a sample of 118 mother–newborn pairs randomly drawn from the “Feeding fetus’ low-grade inflammation and insulin-resistance” study cohort. N-3 PUFA content on erythrocyte membranes is a validated biomarker to measure objectively medium term intake of n-3 PUFAs. Based on distribution of n-3 PUFA in the whole cohort of mothers, we identified mothers with low (n-3 PUFA concentration <25th percentile), medium (n-3 PUFAs between 25th and 75th percentiles), and high n-3 PUFA content (>75th percentile). The HumanMethylation450 BeadChip (Illumina) was used for the epigenome-wide association study using the Infinium Methylation Assay. The overall DNA methylation level was not different between the three groups while there was significant difference in methylation levels at certain sites. Indeed, 8,503 sites had significantly different methylations between low and high n-3 PUFA groups, 12,716 between low and medium n-3 PUFA groups, and 18,148 between high and medium n-3 PUFA groups. We found differentially methylated genes that belong prevalently to pathways of signal transduction, metabolism, downstream signaling of G protein-coupled receptors, and gene expression. Within these pathways, we identified four differentially methylated genes, namely, MSTN, IFNA13, ATP8B3, and GABBR2, that are involved in the onset of insulin resistance and adiposity, innate immune response, phospholipid translocation across cell membranes, and mechanisms of addiction to high fat diet, alcohol, and sweet taste. In conclusion, findings of this preliminary investigation suggest that maternal intake of n-3 PUFAs during pregnancy has potential to influence the offspring DNA methylation. Validation of results in a larger cohort and investigation of biological significance and impact on the phenotype are warranted.

The regulation of inflammation-related genes after palmitic acid and DHA treatments is not mediated by DNA methylation

Article

Aug 2019

Fatty acids (FAs) are known to participate in body inflammatory responses. In particular, saturated FAs such as palmitic acid (PA) induce inflammatory signals in macrophages, whereas polyunsaturated FAs, including docosahexaenoic acid (DHA), have been related to anti-inflammatory effects. Several studies have suggested a role of fatty acids on DNA methylation, epigenetically regulating gene expression in inflammation processes. Therefore, this study investigated the effect of PA and DHA on the inflammation-related genes on human macrophages. In addition, a second aim was to study the epigenetic mechanism underlying the effect of FAs on the inflammatory response. For these purposes, human acute monocytic leukaemia cells (THP-1) were differentiated into macrophages with 12-O-tetradecanoylphorbol-13-acetate (TPA), followed by an incubation with PA or DHA. At the end of the experiment, mRNA expression, protein secretion, and CpG methylation of the following inflammatory genes were analysed: interleukin 1 beta (IL1B), tumour necrosis factor (TNF), plasminogen activator inhibitor-1 (SERPINE1) and interleukin 18 (IL18). The results showed that the treatment with PA increased IL-18 and TNF-α production. Contrariwise, the supplementation with DHA reduced IL-18, TNF-α and PAI-1 secretion by macrophages. However, the incubation with these fatty acids did not apparently modify the DNA methylation status of the investigated genes in the screened CpG sites. This research reveals that PA induces important pro-inflammatory markers in human macrophages, whereas DHA decreases the inflammatory response. Apparently, DNA methylation is not directly involved in the fatty acid-mediated regulation of the expression of these inflammation-related genes.

Rola kwasów tłuszczowych z rodziny n-3 w patogenezie i dietoterapii reumatoidalnego stawów

Article

Jan 2017

Dorota Gumiela

Reumatoidalne zapalenie stawów (RZS) to przewlekła choroba autoimmunizacyjna, w której dochodzi do zapalenia błony maziowej i destrukcji chrząstki stawowej i kości. W zachorowaniu na RZS istotną rolę odgrywają czynniki genetyczne, które stanowią 60% w ogólnym ryzyku wystąpienia choroby, z czego 30% uwarunkowane jest polimorfizmem genu HLA-DRB1. Do czynników środowiskowych związanych z zachorowaniem na RZS zalicza się palenie papierosów oraz dietę, w tym spożycie ryb i kwasów z rodziny omega-3 (n-3). Palenie tytoniu predysponuje do rozwoju bardziej agresywnej postaci choroby oraz słabszej odpowiedzi na farmakoterapię. Tłuste ryby morskie, m.in. łosoś, śledź czy makrela, ze względu na wysoką zawartość kwasów tłuszczowych z rodziny n-3 wykazują korzyści w pierwotnym, jak i wtórnym zapobieganiu RZS. Niższe ryzyko wystąpienia choroby obserwuje się u osób, które spożywają w/w ryby 1-3 razy w tygodniu. Potencjalny efekt ochronny kwasów tłuszczowych n-3 na autoimmunizację występującą w RZS jest najbardziej korzystny u osób wykazujących podatność genetyczną na jego wystąpienie – polimorfizm HLA klasy II. U osób, u których choroba już wystąpiła, kwasy tłuszczowe n-3 przyczyniają się do obniżenia produkcji cytokin prozapalnych (IL-1, IL-6, TNF-alfa) oraz obniżenia nieakceptowalnego, opornego bólu, jak i zmniejszają zapotrzebowanie na leki przeciwbólowe i niesteroidowe leki przeciwzapalne.

Association of a placental Interleukin-6 genetic variant (rs1800796) with DNA methylation, gene expression and risk of acute chorioamnionitis

Article

Full-text available

Feb 2019
BMC MED GENET

Abstract Background Acute chorioamnionitis (aCA), inflammation of the placenta and fetal membranes, is a frequently reported lesion in preterm deliveries. Genetic variants in innate immune system genes such as Interleukin-6 (IL6) may contribute to the placenta’s inflammatory response, thus predisposing some pregnancies to aCA. These genetic variants may modulate molecular processes such as DNA methylation and gene expression, and in turn might affect susceptibility to aCA. Currently, there is remarkably little research on the role of fetal (placental) genetic variation in aCA. We aimed to explore the associations between genetic variants in candidate immune-system genes and susceptibility towards inflammatory responses in the placenta, which is linked to a strong inflammatory response in the newborn. Methods DNA samples from 269 placentas (72 aCA cases, 197 non-aCA cases) were collected for this study. Samples were genotyped at 55 ancestry informative markers (AIMs) and 16 additional single nucleotide polymorphisms (SNPs) in 12 candidate innate immune system genes using the Sequenom iPLEX Gold Assay. Publicly available datasets were used to obtain DNA methylation (GSE100197, GSE74738, GSE115508, GSE44667, GSE98224) and gene expression data (GSE44711, GSE98224). Results Differences in IL6 placental allele frequencies were associated with aCA (rs1800796, p = 0.04) with the CC genotype specifically implicated (OR = 3.1; p = 0.02). In a subset of the placental samples (n = 67; chorionic villi), we showed that the IL6 SNP (rs1800796) was associated with differential DNA methylation in five IL6-related CpG sites (cg01770232, cg02335517, cg07998387, cg13104385, and cg0526589), where individuals with a CC genotype showed higher DNA methylation levels than individuals carrying the GG genotype. Using two publicly available datasets, we observed that the DNA methylation levels at cg01770232 negatively correlated with IL6 gene expression in the placenta (r = − 0.67, p

Epigenetic Effects of Essential Fatty Acids

Article

Full-text available

Feb 2019

Purpose of Review In this review, the recent knowledge regarding the epigenetic effects of the four most important dietary fatty acids will be discussed. Recent Findings Besides as important sources of fuel for sustaining life, fatty acids are important biomolecules/precursors involved in diverse cellular activities. Insufficient amount of fatty acids present in the body, especially for those essential polyunsaturated fatty acids (PUFAs) which cannot be synthesized (alpha-linolenic acid and linoleic acid)/are inefficiently synthesized (eicosapentaenoic acid and docosahexaenoic acid) by the body, could lead to various human diseases and developmental abnormities. The biological roles of these four essential PUFAs have been extensively studied and reviewed throughout the last decades, e.g., biosynthesis of long-chain PUFAs and eicosanoids, anti-inflammation, cardiovascular protection, inhibition of cancer cell proliferation, anti-metastasis, anti-angiogenesis, and regulation of cancer cell death; interestingly, it has been shown more recently that some of the above attributes could be explained by virtue of PUFAs’ influence on gene activities involving DNA methylation/demethylation, histone modifications, and non-coding RNA expression. Summary Essential PUFAs are important biomolecules that mediate epigenetic control of gene expressions; therefore, understanding more about the epigenetic effects associated with these dietary fatty acids are crucial to finding ways for improving human health.

Dietary Fat Quantity and Type Induce Transcriptome-Wide Effects on Alternative Splicing of Pre-mRNA in Rat Skeletal Muscle

Article

Aug 2017

Background: Fat-enriched diets produce metabolic changes in skeletal muscle, which in turn can mediate changes in gene regulation. Objective: We examined the high-fat-diet–induced changes in skeletal muscle gene expression by characterizing variations in pre-mRNA alternative splicing. Methods: Affymetrix Exon Array analysis was performed on the transcriptome of the gastrocnemius/plantaris complex of male obesity-prone Sprague-Dawley rats fed a 10% or 60% fat (lard) diet for 2 or 8 wk. The validation of exon array results was focused on troponin T (Tnnt3). Tnnt3 splice form analyses were extended in studies of rats fed 10% or 30% fat diets across 1- to 8-wk treatment periods and rats fed 10% or 45% fat diets with fat sources from lard or mono- or polyunsaturated fats for 2 wk. Nuclear magnetic resonance (NMR) was used to measure body composition. Results: Consumption of a 60% fat diet for 2 or 8 wk resulted in alternative splicing of 668 and 726 pre-mRNAs, respectively, compared with rats fed a 10% fat diet. Tnnt3 transcripts were alternatively spliced in rats fed a 60% fat diet for either 2 or 8 wk. The high-fat-diet–induced changes in Tnnt3 alternative splicing were observed in rats fed a 30% fat diet across 1- to 8-wk treatment periods. Moreover, this effect depended on fat type, because Tnnt3 alternative splicing occurred in response to 45% fat diets enriched with lard but not in response to diets enriched with mono- or polyunsaturated fatty acids. Fat mass (a proxy for obesity as measured by NMR) did not differ between groups in any study. Conclusions: Rat skeletal muscle responds to overconsumption of dietary fat by modifying gene expression through pre-mRNA alternative splicing. Variations in Tnnt3 alternative splicing occur independently of obesity and are dependent on dietary fat quantity and suggest a role for saturated fatty acids in the high-fat-diet–induced modifications in Tnnt3 alternative splicing.

Epigenetic DNA Methylation Mediating Octopus vulgaris Early Development: Effect of Essential Fatty Acids Enriched Diet

Article

Full-text available

May 2017

The common octopus, Octopus vulgaris, is a good candidate for aquaculture but a sustainable production is still unviable due to an almost total mortality during the paralarvae stage. DNA methylation regulates gene expression in the eukaryotic genome, and has been shown to exhibit plasticity throughout O. vulgaris life cycle, changing profiles from paralarvae to adult stages. This pattern of methylation could be sensitive to small alterations in nutritional and environmental conditions during the species early development, thus impacting on its health, growth and survival. In this sense, a full understanding of the epigenetic mechanisms operating during O. vulgaris development would contribute to optimizing the culture conditions for this species. Paralarvae of O. vulgaris were cultured over 28 days post-hatching (dph) using two different Artemia sp. based diets: control and a long chain polyunsaturated fatty acids (LC-PUFA) enriched diet. The effect of the diets on the paralarvae DNA global methylation was analyzed by Methyl-Sensitive Amplification Polymorphism (MSAP) and global 5-methylcytosine enzyme-linked immunosorbent assay (ELISA) approaches. The analysis of different methylation states over the time revealed a global demethylation phenomena occurring along O. vulgaris early development being directly driven by the age of the paralarvae. A gradual decline in methylated loci (hemimethylated, internal cytosine methylated, and hypermethylated) parallel to a progressive gain in non-methylated (NMT) loci toward the later sampling points was verified regardless of the diet provided and demonstrate a pre-established and well-defined demethylation program during its early development, involving a 20% of the MSAP loci. In addition, a differential behavior between diets was also observed at 20 dph, with a LC-PUFA supplementation effect over the methylation profiles. The present results show significant differences on the paralarvae methylation profiles during its development and a diet effect on these changes. It is characterized by a process of demethylation of the genome at the paralarvae stage and the influence of diet to favor this methylation loss.

SnoVault and encodeD: A novel object-based storage system and applications to ENCODE metadata

Article

Full-text available

Apr 2017
PLOS ONE

The Encyclopedia of DNA elements (ENCODE) project is an ongoing collaborative effort to create a comprehensive catalog of functional elements initiated shortly after the completion of the Human Genome Project. The current database exceeds 6500 experiments across more than 450 cell lines and tissues using a wide array of experimental techniques to study the chromatin structure, regulatory and transcriptional landscape of the H. sapiens and M. musculus genomes. All ENCODE experimental data, metadata, and associated computational analyses are submitted to the ENCODE Data Coordination Center (DCC) for validation, tracking, storage, unified processing, and distribution to community resources and the scientific community. As the volume of data increases, the identification and organization of experimental details becomes increasingly intricate and demands careful curation. The ENCODE DCC has created a general purpose software system, known as SnoVault, that supports metadata and file submission, a database used for metadata storage, web pages for displaying the metadata and a robust API for querying the metadata. The software is fully open-source, code and installation instructions can be found at: http://github.com/ENCODE-DCC/snovault/ (for the generic database) and http://github.com/ENCODE-DCC/encoded/ to store genomic data in the manner of ENCODE. The core database engine, SnoVault (which is completely independent of ENCODE, genomic data, or bioinformatic data) has been released as a separate Python package.

Impact of polyunsaturated and saturated fat overfeeding on the DNA-methylation pattern in human adipose tissue: A randomized controlled trial

Article

Mar 2017
AM J CLIN NUTR

Background: Dietary fat composition can affect ectopic lipid accumulation and, thereby, insulin resistance. Diets that are high in saturated fatty acids (SFAs) or polyunsaturated fatty acids (PUFAs) have different metabolic responses. Objective: We investigated whether the epigenome of human adipose tissue is affected differently by dietary fat composition and general overfeeding in a randomized trial. Design: We studied the effects of 7 wk of excessive SFA (n = 17) or PUFA (n = 14) intake (+750 kcal/d) on the DNA methylation of ~450,000 sites in human subcutaneous adipose tissue. Both diets resulted in similar body weight increases. We also combined the data from the 2 groups to examine the overall effect of overfeeding on the DNA methylation in adipose tissue. Results: The DNA methylation of 4875 Cytosine-phosphate-guanine (CpG) sites was affected differently between the 2 diets. Furthermore, both the SFA and PUFA diets increased the mean degree of DNA methylation in adipose tissue, particularly in promoter regions. However, although the mean methylation was changed in 1797 genes [e.g., alpha-ketoglutarate dependent dioxygenase (FTO), interleukin 6 (IL6), insulin receptor (INSR), neuronal growth regulator 1 (NEGR1), and proopiomelanocortin (POMC)] by PUFAs, only 125 genes [e.g., adiponectin, C1Q and collagen domain containing (ADIPOQ)] were changed by SFA overfeeding. In addition, the SFA diet significantly altered the expression of 28 transcripts [e.g., acyl-CoA oxidase 1 (ACOX1) and FAT atypical cadherin 1 (FAT1)], whereas the PUFA diet did not significantly affect gene expression. When the data from the 2 diet groups were combined, the mean methylation of 1444 genes, including fatty acid binding protein 1 (FABP1), fatty acid binding protein 2 (FABP2), melanocortin 2 receptor (MC2R), MC3R, PPARG coactivator 1 α (PPARGC1A), and tumor necrosis factor (TNF), was changed in adipose tissue by overfeeding. Moreover, the baseline DNA methylation of 12 CpG sites that was annotated to 9 genes [e.g., mitogen-activated protein kinase 7 (MAPK7), melanin concentrating hormone receptor 1 (MCHR1), and splicing factor SWAP homolog (SFRS8)] was associated with the degree of weight increase in response to extra energy intake. Conclusions: SFA overfeeding and PUFA overfeeding induce distinct epigenetic changes in human adipose tissue. In addition, we present data that suggest that baseline DNA methylation can predict weight increase in response to overfeeding in humans. This trial was registered at clinicaltrials.gov as NCT01427140.

Jacobs Journal of Biomarkers DNA Methylation on Interleukin-6 Correlates with Weight Loss in Obese Women

Article

Full-text available

Jan 2017

Introduction Obesity and its associated comorbidities are major health problems worldwide. Obesity is accompanied by a systemic low-grade inflammation with elevated blood-levels of inflammatory mediators like Interleukin-6. Interleukin-6 was described to be regulated by epigenetic mechanisms such as DNA methylation.

Identification of IL6 as a susceptibility gene for major depressive disorder

Article

Aug 2016

Our previous work implied that interleukin 6 (IL6) may be a biological marker for major depressive disorder (MDD). In this study, we performed a comprehensive genetic study to determine the association between the gene encoding IL6 (IL6) and MDD in Han Chinese. There were 50 drug-naïve MDD patients and 50 healthy controls undergoing an mRNA expression study. A sample of 772 patients with MDD and 759 healthy controls were used for genetic analysis. Next, we performed an eQTL analysis to identify whether risk SNP(s) is associated with IL6 expression in brain. Our results showed that patients with MDD have higher levels of IL6 than healthy controls (P = 0.008). The SNP rs1800797 has a significant association with MDD (P = 0.01) in a dominant model. The eQTL analysis showed a marginally significant association between the rs1800797 and IL6 expression in the frontal cortex (P = 0.087). Our preliminary findings are suggestive of an association between rs1800797 and the risk of MDD. Further investigations are required to evaluate this association in larger samples to increase statistical power, and to examine the correlation between rs1800797 and IL6 methylation patterns.

Greater methylation of the IL-6 promoter region is associated with decreased integrity of the corpus callosum in schizophrenia

Article

May 2024
J PSYCHIATR RES

Background Schizophrenia is associated with chronic subclinical inflammation and decreased integrity of the corpus callosum (CC). Our previous study showed associations between peripheral IL-6 levels and the integrity of the CC. Epigenetic studies show associations between methylation of the genes related to immunological processes and integrity of the CC. Aim To investigate correlations between methylation status of IL-6 promotor and peripheral IL-6 levels and the integrity of the CC in schizophrenia. Material and Methods The participants were 29 chronic schizophrenia patients (SCH) and 29 controls. Decreased integrity of the CC was understood as increased mean diffusivity (MD) and/or decreased fractional anisotropy (FA) in diffusion tensor imaging. Peripheral IL-6 concentrations were measured in serum samples and IL-6 promoter methylation status of 6 CpG sites was analyzed in peripheral leukocytes by pyrosequencing. Results Moderate positive correlations were found between CpG1 methylation and the MD of proximal regions of the CC (CCR1–CCR3) and between CpGmean and MD of CCR1 in SCH. Weaker positive correlations were found for CpGmean with CCR2 and CCR3 and negative correlations were found for CpG1 and FA of CCR3 in SCH. Multivariate regression showed that methylation of CpG1, type of antipsychotic treatment, and their interaction were significant independent predictors of MD of CCR1 in SCH. Methylation of CpG2 was negatively correlated with serum IL-6 in SCH. Conclusions The methylation level of the IL-6 promotor region in peripheral leukocytes is associated with the integrity of the CC in schizophrenia and this association may depend on the type of antipsychotic treatment. Further studies are necessary to explain the mechanisms of the observed associations.

A Multifaceted Approach to Precision Nutrition: The Genome, Epigenome, and Microbiome in the Prevention and Therapy of Cardiovascular Diseases

Chapter

Jan 2024

José Ordovás

Potential Roles of Polyunsaturated Fatty Acid-Enriched Diets in Modulating Social Stress-Like Features: Differential dietary supplements and social stress

Article

Mar 2023

Fish oil or its major constituents, namely omega-3 poly-unsaturated fatty acid (n3-PUFA), are popular supplements to improve neurogenesis, neuroprotection, and overall brain functions. Our objective was to probe the implications of fat enriched diet with variable PUFAs supplements in ameliorating social stress (SS). We fed mice on either of the three diet types, namely the n-3 PUFA-enriched diet (ERD, n3:n6= 7:1), a balanced diet (BLD, n3:n6= 1:1) or a standard lab diet (STD, n3:n6= 1:6). With respect to the gross fat contents, the customized special diets, namely ERD and BLD were extreme diet, not reflecting the typical human dietary composition. Aggressor-exposed SS (Agg-E SS) model triggered behavioral deficiencies that lingered for 6 weeks (6w) post-stress in mice on STD. ERD and BLD elevated bodyweights but potentially helped in building the behavioral resilience to SS. STD adversely affected the gene networks of brain transcriptomics associated with the cell mortality, energy homeostasis and neurodevelopment disorder. Diverging from the ERD's influences on these networks, BLD showed potential long-term benefits in combatting Agg-E SS. The gene networks linked to cell mortality and energy homeostasis, and their subfamilies, such as cerebral disorder and obesity remained at the baseline level of Agg-E SS mice on BLD 6w post-stress. Moreover, neurodevelopment disorder network and its subfamilies like behavioral deficits remained inhibited in the cohort fed on BLD 6w post Agg-E SS.

Research gaps and opportunities in precision nutrition: an NIH workshop report

Article

Sep 2022

Precision nutrition is an emerging concept that aims to develop nutrition recommendations tailored to different people's circumstances and biological characteristics. Responses to dietary change and the resulting health outcomes from consuming different diets may vary significantly between people based on interactions between their genetic backgrounds, physiology, microbiome, underlying health status, behaviors, social influences, and environmental exposures. On January 11–12, 2021, the National Institutes of Health convened a workshop entitled “Precision Nutrition: Research Gaps and Opportunities” to bring together experts to discuss the issues involved in better understanding and addressing precision nutrition. The Workshop proceeded in three parts: Part I covered many aspects of genetics and physiology that mediate the links between nutrient intake and health conditions such as cardiovascular disease, Alzheimer's disease, and cancer. Part II reviewed potential contributors to interindividual variability in dietary exposures and responses such as baseline nutritional status, circadian rhythm/sleep, environmental exposures, sensory properties of food, stress, inflammation, and the social determinants of health. Part III presented the need for systems approaches, with new methods and technologies that can facilitate the study and implementation of precision nutrition, and workforce development needed to create a new generation of researchers. The workshop concluded that much research will be needed before more precise nutrition recommendations can be achieved. This includes better understanding and accounting for variables such as age, sex, ethnicity, medical history, genetics, and social and environmental factors. The advent of new methods and technologies and the availability of considerably more data bring tremendous opportunity. However, the field must proceed with appropriate levels of caution and make sure the factors listed above are all considered, and systems approaches, and methods are incorporated. It will be important to develop and train an expanded workforce with the goal of reducing health disparities and improving precision nutritional advice for all Americans.

Dietary Omega-3 Fatty Acid Intake Impacts Peripheral Blood DNA Methylation -Anti-inflammatory Effects and Individual Variability in a Pilot Study

Article

Aug 2021
J NUTR BIOCHEM

Omega-3 or n-3 polyunsaturated fatty acids (PUFAs) are widely studied for health benefits that may relate to anti-inflammatory activity. However, mechanisms mediating an anti-inflammatory response to n-3 PUFA intake are not fully understood. Of interest is the emerging role of fatty acids to impact DNA methylation (DNAm) and thereby modulate mediating inflammatory processes. In this pilot study, we investigated the impact of n-3 PUFA intake on DNAm in inflammation-related signaling pathways in peripheral blood mononuclear cells (PBMCs) of women at high risk of breast cancer. PBMCs of women at high risk of breast cancer (n=10) were obtained at baseline and after 6 months of n-3 PUFA (5 g/day EPA+DHA dose arm) intake in a previously reported dose finding trial. DNA methylation of PBMCs was assayed by reduced representation bisulfite sequencing (RRBS) to obtain genome-wide methylation profiles at the single nucleotide level. We examined the impact of n-3 PUFA on genome-wide DNAm and focused upon a set of candidate genes associated with inflammation signaling pathways and breast cancer. We identified 24,842 differentially methylated CpGs (DMCs) in gene promoters of 5507 genes showing significant enrichment for hypermethylation in both the candidate gene and genome-wide analyses. Pathway analysis identified significantly hypermethylated signaling networks after n-3 PUFA treatment, such as the Toll-like Receptor inflammatory pathway. The DNAm pattern in individuals and the response to n-3 PUFA intake are heterogeneous. PBMC DNAm profiling suggests a mechanism whereby n-3 PUFAs may impact inflammatory cascades associated with disease processes including carcinogenesis.

Nutrients, metabolism, and epigenetic change

Chapter

Jan 2021

Nutri-epigenomics seeks to delineate the interactions between the diet and the genome through epigenetic mechanisms. The ability of the epigenome to adapt to environmental factors, including diet, is referred to as “plasticity” and this alters across the lifespan of an organism. Thus, there are periods during which the epigenome is more responsive to change (Kanherkar et al., 2014), for example, increased plasticity occurs in prenatal and neonatal phases, when cell differentiation and specialization is taking place. Environmental factors, such as nutrition, therefore, have more influence during these periods of development. Sometimes the epigenetic consequences can be quite dramatic, for example, when genetically identical larvae of the honeybee are fed royal jelly, the DNA methylation patterns are altered, resulting in differentiation into a Queen bee rather than a worker bee (Kucharski et al., 2008). In mammals, malnutrition of methyl donors vitamin B12 and choline during gestation can lead to epigenetic dysregulation within the offspring, giving rise to obesity and influencing disease in later life (Waterland and Jirtle, 2003).

Bioactive lipids and their impacts on epigenetics

Chapter

Jan 2021

Asim K Duttaroy

Consumption of fatty acids is associated with human health and disease. Fatty acids are crucial for regulating the cellular membranes’ architecture, dynamics, and permeability. Besides, they are involved in regulating gene expression. Majority of the convincing studies show that some of these effects of fatty acids are mediated by epigenetic mechanisms that regulate gene expression. Several fatty acids, such as n−3 and n−6 polyunsaturated fatty acids, monounsaturated fatty acids, saturated fatty acids, short-chain fatty acids (SCFAs), and trans-fatty acids can alter epigenetic mechanisms differently. The data demonstrate that fatty acids can influence DNA methylation and acetylation or deacetylation of histones and miRNAs involve with the repression or activation of genes. The supplementation of different types of fatty acids can affect transgenerational epigenetic mechanisms. However, further studies are needed to understand the regulation of specific genes and the impact of other components such as the gut microbiota. SCFAs are mainly produced by gut microbes, so the interaction will be significant to understand the complete outcome.

Association of IL6 gene methylation in peripheral blood cells with the development and prognosis of autoimmune thyroid diseases

Article

Sep 2019

Autoimmune thyroid diseases (AITDs), including Hashimoto's disease (HD) and Graves' disease (GD), are archetypes of organ-specific autoimmune diseases, but the prognosis of patients with AITD varies. Autoimmune diseases, including AITDs, are believed to develop in response to both genetic and environmental factors. Interleukin (IL)-6 plays a major role in B cell differentiation and T cell proliferation, and methylation of the IL6 gene is associated with IL-6 production. To clarify the role of IL6 gene methylation in the pathogenesis and prognosis of AITDs, we measured the methylation levels of -666, -664, -610, -491 and -426 CpG sites in the IL6 gene. We measured the methylation levels of 5 CpG sites in 29 patients with HD, 31 patients with GD and 16 healthy volunteers using pyrosequencing. The methylation level at each of the -664, -491 and -426 CpG sites was negatively correlated with the age at the time of sampling. Multiple regression analysis indicated that patients with HD, including severe or mild HD, showed higher methylation levels at the -426 CpG site than control subjects. Patients with intractable GD showed lower methylation levels at the -664 and -666 CpG sites than patients with GD in remission. In conclusion, IL6 gene methylation levels were related to the susceptibility to HD and the intractability of GD.

Effects of environmental factors and omega-3 fatty acids on rheumatoid arthritis

Article

Full-text available

Jun 2016

With a prevalence that has been estimated to be 0.5%±0.2% and a female predominance, rheumatoid arthritis (RA) represents the most common chronic systemic autoimmune rheumatism. Typically, RA is characterized by polyarticular pain, morning stiffness, fatigue, joint and bone inflammation and destruction (1). A more severe evolution is encountered in RA patients with an age lower than 50 years at diagnosis, anti-cyclic citrullinated peptides (anti-CCP) autoantibody (Ab) positivity, IgM rheumatoid factor (RF) at elevated levels (>50 UI/mL), and bone erosions (2,3). RA appears to present geographical variations with an apparent reduction from north to the south, and from urban to rural areas (4).

Correlations and interactions in the production of interleukin-6 (IL- 6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF

Article

Full-text available

Jan 1990

Interleukin-6 (IL-6) shares several biologic properties with IL-1, including hematopoietin-1 activity and stimulation of T cells. Because many of their biologic activities overlap, we developed and used a specific radioimmunoassay (RIA) for IL-6 to compare production of this cytokine on a molar basis with that of IL-1 alpha, IL-1 beta, and tumor necrosis factor (TNF)alpha. The RIA correlated well with the hybridoma bioassay for IL-6 (r = .87, P less than .001). Freshly isolated human peripheral blood mononuclear cells (PBMC) cultured in the absence of stimuli did not produce IL-6 in most cases. Kinetics of secretion and cell-association of IL-6 were studied. In contrast to IL-1 alpha but similar to TNF, IL-6 was almost entirely secreted into the extracellular fluid. Incubation with different stimuli (lipopolysaccharide [LPS], phytohemagglutinin [PHA], Staphylococcus epidermidis, or IL-1 alpha) resulted in production of IL-6. However, on a molar basis PBMC produced approximately two to three times less IL-6 than IL-1 alpha, IL-1 beta, or TNF, regardless of the stimulus. The amount of IL-6 produced from PBMC was consistent when measured in the same subjects six time during a 12-week period. In a cohort of 38 donors, the coefficient of variation for IL-6 production was .32, compared with .92 for IL-1 beta and .96 for TNF. Comparing cytokine production by PBMC, there was a significant correlation between IL-6 and IL-1 beta (r = .72) and between IL-6 and TNF (r = .66). IL-6 did not stimulate IL-1 beta or TNF production, but suppressed IL-1 beta and TNF production induced by LPS or PHA by 30% (P less than .01). This suppression of IL-1 beta and TNF by IL-6 appears to be on the level of transcription.

Inhibition of tumour necrosis factor-alpha and interleukin 6 production by mononuclear cells following dietary fish-oil supplementation in healthy men and response to antioxidant co-supplementation

Article

Full-text available

Aug 2003
BRIT J NUTR

Increased dietary consumption of the n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (20 : 5n-3; EPA) and docosahexaenoic acid (22 : 6n-6; DHA) is associated with their incorporation into circulating phospholipid and increased production of lipid peroxide metabolites. The relationship between peripheral blood mononuclear cell (PBMC) function, n-3 PUFA intake and antioxidant co-supplementation is poorly defined. We therefore investigated tumour necrosis factor (TNF)-alpha and interleukin (IL) 6 production by PBMC and phospholipid fatty acid composition in plasma and erythrocytes of healthy male subjects (n 16) receiving supplemental intakes of 0.3, 1.0 and 2.0 g EPA+DHA/d, as consecutive 4-week courses. All subjects were randomised in a double-blind manner to receive a concurrent antioxidant supplement (200 microg Se, 3 mg Mn, 30 mg D-alpha-tocopheryl succinate, 90 mg ascorbic acid, 450 microg vitamin A (beta-carotene and retinol)) or placebo. There was a positive dose-dependent relationship between dietary n-3 PUFA intake and EPA and DHA incorporation into plasma phosphatidylcholine and erythrocyte phosphatidylethanolamine, with a tendency towards a plateau at higher levels of intake. Production of TNF-alpha and IL-6 by PBMC decreased with increasing n-3 PUFA intake but tended towards a 'U-shaped' dose response. Both responses appeared to be augmented by antioxidant co-supplementation at intermediate supplementary n-3 PUFA intakes. Thus, increased dietary n-3 PUFA consumption resulted in defined but contrasting patterns of modulation of phospholipid fatty acid composition and PBMC function, which were further influenced by antioxidant intake.

Genetic variants modify the effect of age on APOE methylation in the Genetics of Lipid Lowering Drugs and Diet Network study

Article

Full-text available

Dec 2014
AGING CELL

Although apolipoprotein E (APOE) variants are associated with age-related diseases, the underlying mechanism is unknown and DNA methylation may be a potential one. With methylation data, measured by the Infinium Human Methylation 450 array, from 993 participants (age ranging from 18 to 87 years) in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, and from Encyclopedia of DNA Elements (ENCODE) consortium, combined with published methylation datasets, we described the methylation pattern of 13 CpG sites within APOE locus, their correlations with gene expression across cell types, and their relationships with age, plasma lipids, and sequence variants. Based on methylation levels and the genetic regions, we categorized the 13 APOE CpG sites into three groups: Group 1 showed hypermethylation (> 50%) and were located in the promoter region, Group 2 exhibited hypomethylation (< 50%) and were located in the first two exons and introns, and Group 3 showed hypermethylation (> 50%) and were located in the exon 4. APOE methylation was negatively correlated with gene expression (minimum r = -0.66, P = 0.004). APOE methylation was significantly associated with age (minimum P = 2.06E-08) and plasma total cholesterol (minimum P = 3.53E-03). Finally, APOE methylation patterns differed across APOE ε variants (minimum P = 3.51E-05) and the promoter variant rs405509 (minimum P = 0.01), which further showed a significant interaction with age (P = 0.03). These findings suggest that methylation may be a potential mechanistic explanation for APOE functions related to aging and call for further molecular mechanistic studies. © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Temporal Stability and Determinants of White Blood Cell DNA Methylation in the Breakthrough Generations Study

Article

Full-text available

Nov 2014

Background: Epigenome-wide association studies (EWAS) using measurements of blood DNA methylation are performed to identify associations of methylation changes with environmental and lifestyle exposures and disease risk. However, little is known about the variation of methylation markers in the population and their stability over time, both important factors in the design and interpretation of EWAS. We aimed to identify stable variable methylated probes (VMP), i.e., markers that are variable in the population, yet stable over time. Methods: We estimated the intraclass correlation coefficient (ICC) for each probe on the Illumina 450K methylation array in paired samples collected approximately 6 years apart from 92 participants in the Breakthrough Generations Study. We also evaluated relationships with age, reproductive and hormonal history, weight, alcohol intake, and smoking. Results: Approximately 17% of probes had an ICC > 0.50 and were considered stable VMPs (stable-VMPs). Stable-VMPs were enriched for probes located in "shores" bordering CpG islands, and at approximately 1.3 kb downstream from the transcription start site in the transition between the unmethylated promoter and methylated gene body. Both cross-sectional and longitudinal data analyses provided strong evidence for associations between changes in methylation levels and aging. Smoking-related probes at 2q37.1 and AHRR were stable-VMPs and related to time since quitting. We also observed associations between methylation and weight changes. Conclusion: Our results provide support for the use of white blood cell DNA methylation as a biomarker of exposure in EWAS. Impact: Larger studies, preferably with repeated measures over time, will be required to establish associations between specific probes and exposures.

Methylation at CPT1A locus is associated with lipoprotein subfraction profiles

Article

Full-text available

Apr 2014

Lipoprotein subfractions help discriminate cardiometabolic disease risk. Genetic loci validated as associating with lipoprotein measures do not account for a large proportion of the individual variation in lipoprotein measures. We hypothesized that DNA methylation levels across the genome contribute to inter-individual variation in lipoprotein measures. Using data from participants of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n= 663 for discovery and n=331 for replication stages respectively), we conducted the first systematic screen of the genome to determine associations between methylation status at ~470,000 cytosine-guanine dinucleotide (CpG) sites in CD4+ T-cells and fourteen lipoprotein subfraction measures. We modeled associations between methylation at each CpG site and each lipoprotein measure separately using linear mixed models, adjusted for age, sex, study site, cell purity, and family structure. We identified two CpGs, both in the carnitine palmitoyltransferase-1A (CPT1A) gene which reached significant levels of association with VLDL and LDL subfraction parameters in both discovery and replication phases (P<1.1x10-7 in the discovery phase; P<.004 in the replication phase; P<1.1*10-12 in the full sample). CPT1A is regulated by the peroxisome proliferator-activated receptor-alpha (PPARα), a ligand for drugs used to reduce cardiovascular disease (CVD). Our associations between methylation in CPT1A and lipoprotein measures highlight the epigenetic role of this gene in metabolic dysfunction.

Effects of ω-3 Polyunsaturated Fatty Acids on Plasma Proteome in Rett Syndrome

Article

Full-text available

Jan 2013
MEDIAT INFLAMM

The mechanism of action of omega-3 polyunsaturated fatty acids ( ω -3 PUFAs) is only partially known. Prior reports suggest a partial rescue of clinical symptoms and oxidative stress (OS) alterations following ω -3 PUFAs supplementation in patients with Rett syndrome (RTT), a devastating neurodevelopmental disorder with transient autistic features, affecting almost exclusively females and mainly caused by sporadic mutations in the gene encoding the methyl CpG binding protein 2 (MeCP2) protein. Here, we tested the hypothesis that ω -3 PUFAs may modify the plasma proteome profile in typical RTT patients with MECP2 mutations and classic phenotype. A total of 24 RTT girls at different clinical stages were supplemented with ω -3 PUFAs as fish oil for 12 months and compared to matched healthy controls. The expression of 16 proteins, mainly related to acute phase response (APR), was changed at the baseline in the untreated patients. Following ω -3 PUFAs supplementation, the detected APR was partially rescued, with the expression of 10 out of 16 (62%) proteins being normalized. ω -3 PUFAs have a major impact on the modulation of the APR in RTT, thus providing new insights into the role of inflammation in autistic disorders and paving the way for novel therapeutic strategies.

The 256TC Polymorphism in the Apolipoprotein AII Gene Promoter Is Associated with Body Mass Index and Food Intake in the Genetics of Lipid Lowering Drugs and Diet Network Study

Article

Full-text available

Jun 2007

Background: Apolipoprotein A-II (APOA2) plays an ambiguous role in lipid metabolism, obesity, and atherosclerosis. Methods: We studied the association between a functional APOA2 promoter polymorphism (-265T>C) and plasma lipids (fasting and postprandial), anthropometric variables, and food intake in 514 men and 564 women who participated in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study. We obtained fasting and postprandial (after consuming a high-fat meal) measures. We measured lipoprotein particle concentrations by proton nuclear magnetic resonance spectroscopy and estimated dietary intake by use of a validated questionnaire. Results: We observed recessive effects for this polymorphism that were homogeneous by sex. Individuals homozygous for the -265C allele had statistically higher body mass index (BMI) than did carriers of the T allele. Consistently, after multivariate adjustment, the odds ratio for obesity in CC individuals compared with T allele carriers was 1.70 (95% CI 1.02-2.80, P = 0.039). Interestingly, total energy intake in CC individuals was statistically higher [mean (SE) 9371 (497) vs 8456 (413) kJ/d, P = 0.005] than in T allele carriers. Likewise, total fat and protein intakes (expressed in grams per day) were statistically higher in CC individuals (P = 0.002 and P = 0.005, respectively). After adjustment for energy, percentage of carbohydrate intake was statistically lower in CC individuals. These associations remained statistically significant even after adjustment for BMI. We found no associations with fasting lipids and only some associations with HDL subfraction distribution in the postprandial state. Conclusions: The -265T>C polymorphism is consistently associated with food consumption and obesity, suggesting a new role for APOA2 in regulating dietary intake.

Long-chain n-3 PUFAs reduce adipose tissue and systemic inflammation in severely obese nondiabetic patients: A randomized controlled trial

Article

Full-text available

Oct 2012
AM J CLIN NUTR

Chronic adipose tissue inflammation is a hallmark of obesity, triggering the development of associated pathologies, particularly type 2 diabetes. Long-chain n-3 PUFAs reduce cardiovascular events and exert well-established antiinflammatory effects, but their effects on human adipose tissue inflammation are unknown. We investigated whether n-3 PUFAs reduce adipose tissue inflammation in severely obese nondiabetic patients. We treated 55 severely obese nondiabetic patients, scheduled to undergo elective bariatric surgery, with 3.36 g long-chain n-3 PUFAs/d (EPA, DHA) or an equivalent amount of butterfat as control, for 8 wk, in a randomized open-label controlled clinical trial. The primary efficacy measure was inflammatory gene expression in visceral and subcutaneous adipose tissue samples (subcutaneous adipose tissue and visceral adipose tissue), collected during surgery after the intervention. Secondary efficacy variables were adipose tissue production of antiinflammatory n-3 PUFA-derived eicosanoids, plasma concentrations of inflammatory markers, metabolic control, and the effect of the Pro12Ala PPARG polymorphism on the treatment response. Treatment with n-3 PUFAs, which was well tolerated, decreased the gene expression of most analyzed inflammatory genes in subcutaneous adipose tissue (P < 0.05) and increased production of antiinflammatory eicosanoids in visceral adipose tissue and subcutaneous adipose tissue (P < 0.05). In comparison with control subjects who received butterfat, circulating interleukin-6 and triglyceride concentrations decreased significantly in the n-3 PUFA group (P = 0.04 and P = 0.03, respectively). The Pro12Ala polymorphism affected the serum cholesterol response to n-3 PUFA treatment. Treatment with long-chain n-3 PUFAs favorably modulated adipose tissue and systemic inflammation in severely obese nondiabetic patients and improved lipid metabolism. These effects may be beneficial in the long-term treatment of obesity. This trial was registered at clinicaltrials.gov as NCT00760760.

Epigenetic Control of Viral Life-Cycle by a DNA-Methylation Dependent Transcription Factor

Article

Full-text available

Oct 2011
PLOS ONE

Epstein-Barr virus (EBV) encoded transcription factor Zta (BZLF1, ZEBRA, EB1) is the prototype of a class of transcription factor (including C/EBPalpha) that interact with CpG-containing DNA response elements in a methylation-dependent manner. The EBV genome undergoes a biphasic methylation cycle; it is extensively methylated during viral latency but is reset to an unmethylated state following viral lytic replication. Zta is expressed transiently following infection and again during the switch between latency and lytic replication. The requirement for CpG-methylation at critical Zta response elements (ZREs) has been proposed to regulate EBV replication, specifically it could aid the activation of viral lytic gene expression from silenced promoters on the methylated genome during latency in addition to preventing full lytic reactivation from the non-methylated EBV genome immediately following infection. We developed a computational approach to predict the location of ZREs which we experimentally assessed using in vitro and in vivo DNA association assays. A remarkably different binding motif is apparent for the CpG and non-CpG ZREs. Computational prediction of the location of these binding motifs in EBV revealed that the majority of lytic cycle genes have at least one and many have multiple copies of methylation-dependent CpG ZREs within their promoters. This suggests that the abundance of Zta protein coupled with the methylation status of the EBV genome act together to co-ordinate the expression of lytic cycle genes at the majority of EBV promoters.

Identification of genetic elements that autonomously determine DNA methylation states

Article

Full-text available

Oct 2011
Nat Genet

Cytosine methylation is a repressive, epigenetically propagated DNA modification. Although patterns of DNA methylation seem tightly regulated in mammals, it is unclear how these are specified and to what extent this process entails genetic or epigenetic regulation. To dissect the role of the underlying DNA sequence, we sequentially inserted over 50 different DNA elements into the same genomic locus in mouse stem cells. Promoter sequences of approximately 1,000 bp autonomously recapitulated correct DNA methylation in pluripotent cells. Moreover, they supported proper de novo methylation during differentiation. Truncation analysis revealed that this regulatory potential is contained within small methylation-determining regions (MDRs). MDRs can mediate both hypomethylation and de novo methylation in cis, and their activity depends on developmental state, motifs for DNA-binding factors and a critical CpG density. These results demonstrate that proximal sequence elements are both necessary and sufficient for regulating DNA methylation and reveal basic constraints of this regulation.

Differential Methylation of the HPV 16 Upstream Regulatory Region during Epithelial Differentiation and Neoplastic Transformation

Article

Full-text available

Sep 2011
PLOS ONE

High risk human papillomaviruses are squamous epitheliotropic viruses that may cause cervical and other cancers. HPV replication depends on squamous epithelial differentiation. Transformation of HPV-infected cells goes along with substantial alteration of the viral gene expression profile and preferentially occurs at transformation zones usually at the uterine cervix. Methylation of the viral genome may affect regulatory features that control transcription and replication of the viral genome. Therefore, we analyzed the methylation pattern of the HPV16 upstream regulatory region (URR) during squamous epithelial differentiation and neoplastic transformation and analyzed how shifts in the HPV URR methylome may affect viral gene expression and replication. HPV 16 positive biopsy sections encompassing all stages of an HPV infection (latent, permissive and transforming) were micro-dissected and DNA was isolated from cell fractions representing the basal, intermediate, and superficial cell layers, each, as well as from transformed p16(INK4a)-positive cells. We observed fundamental changes in the methylation profile of transcription factor binding sites in the HPV16 upstream regulatory region linked to the squamous epithelial differentiation stage. Squamous epithelial transformation indicated by p16(INK4a) overexpression was associated with methylation of the distal E2 binding site 1 leading to hyper-activation of the HPV 16 URR. Adjacent normal but HPV 16-infected epithelial areas retained hyper-methylated HPV DNA suggesting that these viral genomes were inactivated. These data suggest that distinct shifts of the HPV 16 methylome are linked to differentiation dependent transcription and replication control and may trigger neoplastic transformation.

CpG methylation of half-CRE sequences creates C/EBP binding sites that activate some tissue-specific genes

Article

Full-text available

Nov 2010
P NATL ACAD SCI USA

DNA methylation of the cytosine in the CpG dinucleotide is typically associated with gene silencing. Genomic analyses have identified low CpG promoters that are both methylated and transcriptionally active, but the mechanism underlying the activation of these methylated promoters remains unclear. Here we show that CpG methylation of the CRE sequence (TGACGTCA) enhances the DNA binding of the C/EBPα transcription factor, a protein critical for activation of differentiation in various cell types. Transfection assays also show that C/EBPα activates the CRE sequence only when it is methylated. The biological significance of this observation was seen in differentiating primary keratinocyte cultures from newborn mice where certain methylated promoters are both bound by C/EBPα and activated upon differentiation. Experimental demethylation by either 5-azacytidine treatment or DNMT1 depletion diminished both C/EBPα binding and activation of the same methylated promoters upon differentiation suggesting that CpG methylation can localize C/EBPα. Transfection studies in cell cultures using methylated tissue-specific proximal promoters identified half-CRE (CGTCA) and half-C/EBP (CGCAA) sequences that need to be methylated for C/EBPα mediated activation. In primary dermal fibroblasts, C/EBPα activates a different set of methylated tissue-specific promoters upon differentiation into adipocytes. These data identify a new function for methyl CpGs: producing DNA binding sites at half-CRE and half-C/EBP sequences for C/EBPα that are needed to activate tissue-specific genes.

MeCP2/H3meK9 are involved in IL-6 gene silencing in pancreatic adenocarcinoma cell lines

Article

Full-text available

Oct 2009
NUCLEIC ACIDS RES

The aim of the present study was to analyse the molecular mechanisms involved in the Interleukin-6 (IL-6) silencing in pancreatic adenocarcinoma cell lines. Our results demonstrate that TNF-α, a major IL-6 inducer, is able to induce IL-6 only in three out of six cell lines examined. 5-aza-2′-deoxycytidine (DAC), but not trichostatin A (TSA), activates the expression of IL-6 in all cell lines, indicating that DNA methylation, but not histone deacetylation, plays an essential role in IL-6 silencing. Indeed, the IL-6 upstream region shows a methylation status that correlates with IL-6 expression and binds MeCP2 and H3meK9 only in the non-expressing cell lines. Our results suggest that critical methylations located from positions –666 to –426 relative to the transcription start site of IL-6 may act as binding sites for MeCP2.

DHA Supplementation Decreases Serum C-Reactive Protein and Other Markers of Inflammation in Hypertriglyceridemic Men

Article

Full-text available

Jan 2009
J NUTR

Dietary (n-3) PUFA reduce inflammation, an independent risk factor for cardiovascular disease. The antiinflammatory effects of docosahexaenoic acid (DHA) in hypertriglyceridemic men have not been previously reported, to our knowledge, and were the focus of this study. Hypertriglyceridemic men (n = 17 per group) aged 39-66 y, participated in a double-blind, randomized, placebo-controlled parallel study. They received no supplements for the first 8 d and then received either 7.5 g/d DHA oil (3 g DHA/d) or olive oil (placebo) for the last 90 d. Blood samples were collected from fasting men on study days -7, 0, 45, 84, and 91. DHA supplementation for 45 and 91 d decreased the number of circulating neutrophils by 11.7 and 10.5%, respectively (P < 0.05). It did not alter the circulating concentrations of other inflammatory markers tested within 45 d, but at 91 d it reduced (P < 0.05) concentrations of C-reactive protein (CRP) by 15%, interleukin-6 by 23%, and granulocyte monocyte-colony stimulating factor by 21% and DHA increased the concentration of antiinflammatory matrix metalloproteinase-2 by 7%. The number of circulating neutrophils was positively associated with the weight percent (wt %) of 20:4(n-6) in RBC lipids, and negatively to the wt % of 20:5(n-3) and 22:6(n-3). Concentrations of CRP and serum amyloid A were positively associated with the sum of SFA and negatively with the wt % of 18:1(n-9) and 17:0 in RBC lipids; CRP was also positively associated with the wt % of 20:2(n-6). The mean size of VLDL particles was positively associated with plasma concentrations of neutrophils and CRP. In conclusion, DHA may lessen the inflammatory response by altering blood lipids and their fatty acid composition.

Correlations and interactions in the production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF

Article

Full-text available

Feb 1990

NHLBI Family Heart Study: objectives and design

Article

Full-text available

Jul 1996
AM J EPIDEMIOL

The NHLBI Family Heart Study is a multicenter, population-based study of genetic and nongenetic determinants of coronary heart disease (CHD), atherosclerosis, and cardiovascular risk factors. In phase I, 2,000 randomly selected participants and 2,000 with family histories of CHD were identified among 14,592 middle-aged participants in epidemiologic studies. Medical histories from these individuals, their parents, and their siblings were used to calculate family risk scores that compared the number of reported and validated CHD events with the number expected based on the size, sex, and age of family members. A total of 657 families with the highest risk scores and early-onset CHD and 588 randomly sampled families had clinic examinations that included electrocardiograms, carotid artery ultrasound scans, spirometry, measurements of body size, blood pressure, lipids, lipoproteins, hemostatic factors, insulin, glucose, and routine chemistries. Additional biochemical and genetic studies are being performed on selected participants. Serum, plasma, lymphocytes, red cells, and DNA are stored for future studies, including genotyping of candidate genes and anonymous markers. Contributions of genes, shared and individual environments, and behaviors to variations in risk factors, preclinical atherosclerosis, and CHD will be estimated. Linkage studies, including the quantitative trait loci approach, are planned.

Low-Grade Systemic Inflammation and the Development of Type 2 Diabetes: The Atherosclerosis Risk in Communities Study

Article

Full-text available

Aug 2003
DIABETES

To examine the association of low-grade systemic inflammation with diabetes, as well as its heterogeneity across subgroups, we designed a case-cohort study representing the approximately 9-year experience of 10,275 Atherosclerosis Risk in Communities Study participants. Analytes were measured on stored plasma of 581 incident cases of diabetes and 572 noncases. Statistically significant hazard ratios of developing diabetes for those in the fourth (versus first) quartile of inflammation markers, adjusted for age, sex, ethnicity, study center, parental history of diabetes, and hypertension, ranged from 1.9 to 2.8 for sialic acid, orosomucoid, interleukin-6, and C-reactive protein. After additional adjustment for BMI, waist-to-hip ratio, and fasting glucose and insulin, only the interleukin-6 association remained statistically significant (HR = 1.6, 1.01-2.7). Exclusion of GAD antibody-positive individuals changed associations minimally. An overall inflammation score based on these four markers plus white cell count and fibrinogen predicted diabetes in whites but not African Americans (interaction P = 0.005) and in nonsmokers but not smokers (interaction P = 0.13). The fully adjusted hazard ratio comparing white nonsmokers with score extremes was 3.7 (P for linear trend = 0.008). In conclusion, a low-grade inflammation predicts incident type 2 diabetes. The association is absent in smokers and African-Americans.

Inhibition of tumour necrosis factor-?? and interleukin-6 production by mononuclear cells following dietary fish-oil supplementation in healthy men and response to antioxidant co-supplementation

Article

Full-text available

Sep 2003

Circulating levels of MCP-1 and IL-8 are elevated in human obese subjects and associated with obesity-related parameters

Article

Full-text available

Oct 2006

Background: Chemotactic cytokines, referred to as chemokines, play an important role in leukocyte trafficking. The circulating levels of chemokines have been shown to increase in inflammatory processes including obesity-related pathologies (e.g. atherosclerosis and diabetes). However, little is currently known about the relationship between chemokines and human obesity. In the present study, we investigated the circulating levels of selected chemokines (monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1alpha (MIP-1alpha), leukotactin-1, interleukin-8 (IL-8)) and the association between the chemokine levels and obesity-related parameters: body mass index (BMI), waist circumference, fasting glucose and insulin levels, lipids profile, and the level of C-reactive protein (CRP). Methods: A total of 100 subjects, 50 obese (BMI>or=25 kg/m2) and 50 who were not obese (BMI<25 kg/m2) participated in the present study. The levels of chemokines and CRP were measured in a fasting state serum by sandwich enzyme-linked immunosorbent assay. Total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglyceride, glucose, and insulin levels were measured by enzymatic analysis and immunoassay. Results: The circulating levels of MCP-1 and IL-8 in the serum were significantly (P<0.05) higher in obese subjects (BMI>30 kg/m2) compared with those of nonobese controls (BMI<25 kg/m2). The levels of CRP were positively correlated with BMI (P<0.001) or waist circumference (P<0.0001). The levels of MCP-1 and IL-8 were positively related to BMI (MCP-1, P<0.02; IL-8, P<0.01) and/or waist circumference (MCP-1, P<0.009; IL-8, P<0.03). The levels of MCP-1 were positively related to the levels of CRP (P<0.007) or interleukin-6 (IL-6) (P<0.0001), and negatively related to the levels of HDL-cholesterol (P<0.01). Homeostasis model assessment (HOMA) score was positively related to the levels of MCP-1 (P<0.02) or IL-8 (P<0.03) in obese subject. Discussion: Our data demonstrated that the circulating levels of MCP-1 and IL-8 are related to obesity-related parameters such as BMI, waist circumference, CRP, IL-6, HOMA and HDL-cholesterol. These findings suggest that the circulating MCP-1 and/or IL-8 may be a potential candidate linking obesity with obesity-related metabolic complications such as atherosclerosis and diabetes.

Adiponectin-induced secretion of interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1, CCL2) and interleukin-8 (IL-8, CXCL8) is impaired in monocytes from patients with type I diabetes

Article

Full-text available

Feb 2006
CARDIOVASC DIABETOL

Systemic adiponectin is reduced in patients with cardiovascular disease (CVD) and low adiponectin may contribute to the pathogenesis of atherosclerosis. However, circulating adiponectin is elevated in type 1 diabetes (T1D) patients, who have also a higher incidence to develop CVD. Because monocytes play an important role in atherosclerosis, we analysed the influence of adiponectin on cytokine and chemokine release in monocytes from T1D patients and controls. Systemic adiponectin was determined in the plasma and the high-molecular weight (HMW) form of adiponectin was analysed by immunoblot. Monocytes were isolated from T1D patients and controls and the adiponectin-stimulated release of interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1, CCL2) and interleukin-8 (IL-8, CXCL8) was analysed. Systemic adiponectin was higher in T1D patients. Immunoblot analysis of the plasma indicate abundance of HMW adiponectin in T1D patients and controls. IL-6, CCL2 and CXCL8 secretion in response to adiponectin were found induced in monocytes from controls whereas only IL-6 was upregulated in T1D cells. The induction of IL-6 by adiponectin was abrogated by an inhibitor of the NFkappaB pathway. These data indicate that adiponectin-mediated induction of IL-6, CCL2 and CXCL8 is disturbed in monocytes from T1D patients and therefore elevated systemic adiponectin in T1D patients may be less protective when compared to controls.

Distribution, Silencing Potential and Evolutionary Impact of Promoter DNA Methylation in the Human Genome

Article

Full-text available

May 2007

To gain insight into the function of DNA methylation at cis-regulatory regions and its impact on gene expression, we measured methylation, RNA polymerase occupancy and histone modifications at 16,000 promoters in primary human somatic and germline cells. We find CpG-poor promoters hypermethylated in somatic cells, which does not preclude their activity. This methylation is present in male gametes and results in evolutionary loss of CpG dinucleotides, as measured by divergence between humans and primates. In contrast, strong CpG island promoters are mostly unmethylated, even when inactive. Weak CpG island promoters are distinct, as they are preferential targets for de novo methylation in somatic cells. Notably, most germline-specific genes are methylated in somatic cells, suggesting additional functional selection. These results show that promoter sequence and gene function are major predictors of promoter methylation states. Moreover, we observe that inactive unmethylated CpG island promoters show elevated levels of dimethylation of Lys4 of histone H3, suggesting that this chromatin mark may protect DNA from methylation.

Interleukin1β Genetic Polymorphisms Interact with Polyunsaturated Fatty Acids to Modulate Risk of the Metabolic Syndrome

Article

Full-text available

Aug 2007

Chronic inflammation has been identified as an important component of the metabolic syndrome (MetS). Therefore, environmental and genetic factors contributing to the variation of inflammatory responses could affect individuals' susceptibility to MetS. We investigated the association between common IL1beta genetic polymorphisms, inflammation, and the MetS, and the modulation of diet-related variables (i.e., erythrocyte membrane fatty acid composition) in a white U.S. population. IL1beta single nucleotide polymorphisms (SNP) (-1473G > C, -511G > A, -31T > C, 3966C > T, 6054G > A), clinical and biochemical measurements were characterized in a total of 1120 subjects (540 males and 580 females) participating in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study. The 6054 G > A SNP was significantly associated with plasma C-reactive protein (P = 0.054), adiponectin (P = 0.021), and the prevalence of MetS (P = 0.004). Moreover, there was a significant interaction between the 6054G > A SNP and erythrocyte membrane (n-3) PUFA (P = 0.019). Among subjects with low (n-3) PUFA content (below the median), the 6054 G allele was associated with increased risk of the MetS (OR = 3.29, 95%CI = 1.49-7.26 for GG and OR = 1.95, 95%CI = 0.85-4.46 for GA, P < 0.001) compared with the AA genotype, but there were no significant genotype associations among subjects with high (n-3) PUFA content (above the median). Further analyses supported a significant haplotype global effect on the MetS (P = 0.017) among subjects with low (n-3) PUFA content. These results suggested that IL1beta genetic variants were associated with measures of chronic inflammation and the MetS risk, and that genetic influences were more evident among subjects with low (n-3) PUFA intake.

Erythrocyte Fatty Acid Composition and the Metabolic Syndrome: A National Heart, Lung, and Blood Institute GOLDN Study

Article

Full-text available

Jan 2008

Different fatty acids may vary in their effect on the metabolic syndrome (MetS). We tested whether fatty acid classes measured in erythrocytes are associated with the MetS or its components. Included were men [n = 497; mean (SD) age, 49 (16) years] and women [n = 539; age, 48 (16) years] from 187 families in a National Heart, Lung, and Blood Institute (NHLBI) family study of the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) conducted in Utah and Minnesota. We used gas chromatography to measure erythrocyte fatty acids and obtained data on potential confounding variables from interviewer-administered questionnaires. The prevalence of the MetS as defined by the updated Adult Treatment Panel III criteria was 36.8% in Utah and 39.6% in Minnesota (P >0.05). In a multivariate model that included 4 fatty acid classes, covariates, and pedigree as a random effect, the odds ratios (95% confidence interval) for the MetS in the 1st, 2nd, 3rd, and 4th quartile of polyunsaturated fatty acids were 1.00, 0.72 (0.47-1.10), 0.67 (0.43-1.05), and 0.39 (0.24-0.64), respectively (P for trend = 0.0002). For the corresponding quartiles of saturated fatty acids, the odds ratios were 1.00, 1.19 (0.77-1.84), 1.48 (0.94-2.34), and 1.63 (1.01-2.63), respectively (P for trend = 0.03). Unlike n6 fatty acids, which showed an inverse association (P <0.05) with MetS, n3, trans, and monounsaturated fatty acids were not associated with the MetS (P >0.05). We observed significant correlations (P <0.05) between fatty acid classes, insulin, and components of the MetS. Polyunsaturated fats are inversely associated with the MetS, whereas saturated fatty acids are positively associated with the MetS, probably through their effect on lipids, adiposity, insulin, and blood pressure.

Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation

Article

Full-text available

Aug 2008
Nat Genet

Allele-specific DNA methylation (ASM) is a hallmark of imprinted genes, but ASM in the larger nonimprinted fraction of the genome is less well characterized. Using methylation-sensitive SNP analysis (MSNP), we surveyed the human genome at 50K and 250K resolution, identifying ASM as recurrent genotype call conversions from heterozygosity to homozygosity when genomic DNAs were predigested with the methylation-sensitive restriction enzyme HpaII. Using independent assays, we confirmed ASM at 16 SNP-tagged loci distributed across various chromosomes. At 12 of these loci (75%), the ASM tracked strongly with the sequence of adjacent SNPs. Further analysis showed allele-specific mRNA expression at two loci from this methylation-based screen--the vanin and CYP2A6-CYP2A7 gene clusters--both implicated in traits of medical importance. This recurrent phenomenon of sequence-dependent ASM has practical implications for mapping and interpreting associations of noncoding SNPs and haplotypes with human phenotypes.

Dietary fatty acids modulate associations between genetic variants and circulating fatty acids in plasma and erythrocyte membranes: Meta-analysis of nine studies in the CHARGE consortium

Article

Jan 2015
MOL NUTR FOOD RES

Tissue concentrations of omega-3 fatty acids may reduce cardiovascular disease risk, and genetic variants are associated with circulating fatty acids concentrations. Whether dietary fatty acids interact with genetic variants to modify circulating omega-3 fatty acids is unclear. We evaluated interactions between genetic variants and fatty acid intakes for circulating alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA). We conducted meta-analyses (N to 11668) evaluating interactions between dietary fatty acids and genetic variants (rs174538 and rs174548 in FADS1 (fatty acid desaturase 1), rs7435 in AGPAT3 (1-acyl-sn-glycerol-3-phosphate), rs4985167 in PDXDC1 (pyridoxal-dependent decarboxylase domain-containing 1), rs780094 in GCKR (glucokinase regulatory protein) and rs3734398 in ELOVL2 (fatty acid elongase 2)). Stratification by measurement compartment (plasma vs. erthyrocyte) revealed compartment-specific interactions between FADS1 rs174538 and rs174548 and dietary ALA and linoleic acid for DHA and DPA. Our findings reinforce earlier reports that genetically-based differences in circulating fatty acids may be partially due to differences in the conversion of fatty acid precursors. Further, fatty acids measurement compartment may modify gene-diet relationships, and considering compartment may improve the detection of gene-fatty acids interactions for circulating fatty acid outcomes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Chapter 3 Effect of Hormone Replacement Therapy on Inflammatory Biomarkers

Article

Dec 2009
ADV CLIN CHEM

Cardiovascular disease is the leading cause of death among women. Inflammation plays a central role in the pathogenesis of many forms of vascular disease, including atherosclerosis. Women present with cardiovascular disease a decade after men and this has been attributed to the protective effect of female ovarian sex hormones. Hormone replacement therapy (HRT), including a variety of estrogen preparations with or without a progestin, has negative effects on most of these soluble inflammatory markers, including E-selectin, cell adhesion molecules, monocyte chemoattractant protein-1, and tumor necrosis factor-α, inconsistent effects on interleukin-6, and stimulatory effects on vasoprotective cytokine, such as the transforming growth factor-α. C-reactive protein, a circulating proinflammatory cytokine produced in both liver and atherosclerotic arteries, increases in response to oral conjugated estrogens but not to transdermal estrogen. Animal and observational studies have shown beneficial effects of hormone therapy in the perimenopausal period or before the development of significant atherosclerosis, whereas randomized trials in older women have not shown any benefit in either primary prevention or secondary prevention of cardiovascular events. Many important questions about the effects of ovarian hormones on vascular inflammation and the pathogenesis of vascular disease cannot be answered in human subjects. This review outlines the effects of HRT on inflammatory biomarkers, summarizes results from observational and randomized trials, and highlights unanswered questions of hormone therapy and cardiovascular risk.

W08-P-035 Circulating levels of MCP-1 and IL8 are elevated in human obese subjects and associated with obesity-related parameters

Article

Apr 2005
Atherosclerosis Suppl

SNPs located at CpG sites modulate genome-epigenome interaction

Article

Jun 2013
EPIGENETICS

DNA methylation is an important molecular-level phenotype that links genotypes and complex disease traits. Previous studies have found local correlation between genetic variants and DNA methylation levels (cis-meQTLs). However, general mechanisms underlying cis-meQTLs are unclear. We conducted a cis-meQTL analysis of the Genetics of Lipid Lowering Drugs and Diet Network data (n = 593). We found that over 80% of genetic variants at CpG sites (meSNPs) are meQTL loci (P-value < 10 (-9) ), and meSNPs account for over two thirds of the strongest meQTL signals (P-value < 10 (-200) ). Beyond direct effects on the methylation of the meSNP site, the CpG-disrupting allele of meSNPs were associated with lowered methylation of CpG sites located within 45 bp. The effect of meSNPs extends to as far as 10 kb and can contribute to the observed meQTL signals in the surrounding region, likely through correlated methylation patterns and linkage disequilibrium. Therefore, meSNPs are behind a large portion of observed meQTL signals and play a crucial role in the biological process linking genetic variation to epigenetic changes.

Inflammatory markers and onset of cardiovascular events

Article

Feb 2004

Background— Inflammation plays an important role in cardiovascular disease. The aim of this study is to investigate the predictive value of several inflammatory markers on the incidence of cardiovascular events in well-functioning older persons. Methods and Results— The subjects were 2225 participants 70 to 79 years old, without baseline cardiovascular disease, who were enrolled in the Health, Aging, and Body Composition study. Incident coronary heart disease (CHD), stroke, and congestive heart failure (CHF) events were detected during an average follow-up of 3.6 years. Blood levels of interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) were assessed. After adjustment for potential confounders, IL-6 was significantly associated with all outcomes (CHD events, per IL-6 SD increase: RR, 1.27; 95% CI, 1.10 to 1.48; stroke events, per IL-6 SD increase: RR, 1.45; 95% CI, 1.12 to 1.86; CHF events, per IL-6 SD increase: RR, 1.72; 95% CI, 1.40 to 2.12). TNF-α showed significant associations with CHD (per TNF-α SD increase: RR, 1.22; 95% CI, 1.04 to 1.43) and CHF (per TNF-α SD increase: RR, 1.59; 95% CI, 1.30 to 1.95) events. CRP was significantly associated with CHF events (per CRP SD increase: RR, 1.48; 95% CI, 1.23 to 1.78). A composite summary indicator of inflammation showed a strong association with incident cardiovascular events, with an especially high risk if all 3 inflammatory markers were in the highest tertile. Conclusions— Findings suggest that inflammatory markers are independent predictors of cardiovascular events in older persons. Received April 7, 2003; de novo received July 14, 2003; revision received August 12, 2003; accepted August 14, 2003.

Expression, polymorphism and methylation pattern of interleukin-6 in periodontal tissues

Article

Dec 2012

Periodontitis is considered an inflammatory disorder of bacterial etiology that results in periodontal tissue destruction, as a result of complex interactions between periodontal pathogens, host and immune response. Genetic and epigenetic mechanisms may modulate the individual response since it is able to influence the gene expression. The aim of this study was to evaluate the impact of -174 G/C polymorphism and the methylation status of the promoter region of IL-6 gene on the expression of IL-6 in gingival samples from individuals with chronic periodontitis. Gingival biopsies were collected from 21 patients with chronic periodontitis and 21 controls. Histologic sections stained by hematoxylin-eosin were used for histopathological evaluation. The IL-6 gene expression was assessed by quantitative real-time PCR. The polymorphism IL-6 -174C/G was studied by polymerase chain reaction (PCR) amplification and restriction endonuclease digestion (HspII). Methylation-specific polymerase chain reaction was used to verify the DNA methylation pattern. The number of inflammatory cells in tissue fragments from individuals with chronic periodontitis was higher than in the control group and the inflammatory infiltrate was predominantly mononuclear. The expression of IL-6 was higher in the group with periodontitis. In polymorphism assay, no statistical difference in the distribution of genotypes and alleles in both groups were observed. The most of samples were partially methylated. No difference was observed in methylation pattern from two different regions of the IL-6 gene among groups. The high expression of IL-6 is an important factor related to chronic periodontitis, but was not associated with methylation status or the -174 (G/C) genetic polymorphism, suggesting that other mechanisms are involved in this gene transcription regulation.

Inflammatory Markers and Onset of Cardiovascular Events: Results From the Health ABC Study

Article

Nov 2003
CIRCULATION

Inflammation plays an important role in cardiovascular disease. The aim of this study is to investigate the predictive value of several inflammatory markers on the incidence of cardiovascular events in well-functioning older persons. The subjects were 2225 participants 70 to 79 years old, without baseline cardiovascular disease, who were enrolled in the Health, Aging, and Body Composition study. Incident coronary heart disease (CHD), stroke, and congestive heart failure (CHF) events were detected during an average follow-up of 3.6 years. Blood levels of interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-alpha) were assessed. After adjustment for potential confounders, IL-6 was significantly associated with all outcomes (CHD events, per IL-6 SD increase: RR, 1.27; 95% CI, 1.10 to 1.48; stroke events, per IL-6 SD increase: RR, 1.45; 95% CI, 1.12 to 1.86; CHF events, per IL-6 SD increase: RR, 1.72; 95% CI, 1.40 to 2.12). TNF-alpha showed significant associations with CHD (per TNF-alpha SD increase: RR, 1.22; 95% CI, 1.04 to 1.43) and CHF (per TNF-alpha SD increase: RR, 1.59; 95% CI, 1.30 to 1.95) events. CRP was significantly associated with CHF events (per CRP SD increase: RR, 1.48; 95% CI, 1.23 to 1.78). A composite summary indicator of inflammation showed a strong association with incident cardiovascular events, with an especially high risk if all 3 inflammatory markers were in the highest tertile. Findings suggest that inflammatory markers are independent predictors of cardiovascular events in older persons.

DNA methylation at promoter regions of interleukin 1B, interleukin 6, and interleukin 8 in non-small cell lung cancer

Article

Aug 2012
CANCER IMMUNOL IMMUN

Epidemiologic and experimental evidences support the concept that inflammation promotes the development and progression of cancers. Interleukins (ILs) regulate the expression of several molecules and signaling pathways involved in inflammation. High expression of some ILs in the tumor microenvironment has been associated with a more virulent tumor phenotype. To examine the role of IL-1β, IL-6, and IL-8 in non-small cell lung cancer, we measured mRNA levels and promoter DNA methylation in a panel of cultured human lung cells (n = 23) and in matched pair lung tumor versus adjacent non-tumorous tissues (n = 24). We found that lung cancer cells or tissues had significantly different DNA methylation and mRNA levels than normal human bronchial epithelial cells or adjacent non-tumorous tissues, respectively. High DNA methylation of ILs promoters in lung cancer cells or tissues was associated with low mRNA levels. We found an inverse correlation between DNA methylation of IL1B, IL6, and IL8 gene promoters and their corresponding mRNA levels, such inverse correlation was more significant for IL1B (i.e., all cancer cell lines used in this study had a hypermethylated IL1B promoter which was associated with silencing of the gene). Our results underline for the first time the role of epigenetic modifications in the regulation of the expression of key cytokines involved in the inflammatory response during lung cancer development.

The role of oxidative stress in Rett syndrome: An overview

Article

Jul 2012
ANN NY ACAD SCI

The main cause of Rett syndrome (RTT), a pervasive development disorder almost exclusively affecting females, is a mutation in the methyl-CpG binding protein 2 (MeCP2) gene. To date, no cure for RTT exists, although disease reversibility has been demonstrated in animal models. Emerging evidence from our and other laboratories indicates a potential role of oxidative stress (OS) in RTT. This review examines the current state of the knowledge on the role of OS in explaining the natural history, genotype-phenotype correlation, and clinical heterogeneity of the human disease. Biochemical evidence of OS appears to be related to neurological symptom severity, mutation type, and clinical presentation. These findings pave the way for potential new genetic downstream therapeutic strategies aimed at improving patient quality of life. Further efforts in the near future are needed for investigating the yet unexplored "black box" between the MeCP2 gene mutation and subsequent OS derangement.

A genome-wide association study of inflammatory biomarker changes in response to fenofibrate treatment in the Genetics of Lipid Lowering Drug and Diet Network

Article

Mar 2012

Despite the evidence in support of the anti-inflammatory and triglyceride-lowering effects of fenofibrate, little is known about genetic determinants of the observed heterogeneity in treatment response. This study provides the first genome-wide examination of fenofibrate effects on systemic inflammation. Biomarkers of inflammation were measured in participants of the Genetics of Lipid Lowering Drugs and Diet Network (n=1092) before and after a 3-week daily treatment with 160 mg of fenofibrate. Two inflammatory patterns [high-sensitivity C-reactive protein-interleukin-6 and monocyte chemoattractant protein-1-tumor necrosis factor (MCP1-TNF-α)] were derived using principal component analysis. Associations between single nucleotide polymorphisms on the Affymetrix 6.0 chip and phenotypes were assessed using mixed linear models, adjusted for age, sex, study center, and ancestry as fixed effects and pedigree as a random effect. Before fenofibrate treatment, the strongest evidence for association was observed for polymorphisms near or within the IL2RA gene with the high-sensitivity C-reactive protein-interleukin-6 (IL6) pattern (rs7911500, P=5×10 and rs12722605, P=5×10). Associations of the MCP1-TNF-α pattern with loci in several biologically plausible genes [CYP4F8 (rs3764563), APBB1IP (rs1775246), COL13A1 (rs2683572), and COMMD10 (rs1396485)] approached genome-wide significance (P=3×10, 5×10, 6×10, and 7×10, respectively) before fenofibrate treatment. After fenofibrate treatment, the rs12722605 locus in IL2RA was also associated with the MCP1-TNF-α pattern (P=3×10). The analyses of individual biomarker response to fenofibrate did not yield genome-wide significant results, but the rs6517147 locus near the immunologically relevant IFNAR2 gene was suggestively associated with IL6 (P=7×10). We have identified several novel biologically relevant loci associated with systemic inflammation before and after fenofibrate treatment.

Interleukin 6 Underlies Angiotensin II-Induced Hypertension and Chronic Renal Damage

Article

Nov 2011
Hypertension

Chronic kidney disease (CKD) is a prevalent life-threatening disease frequently associated with hypertension, progression to renal fibrosis, and eventual renal failure. Although the pathogenesis of CKD remains largely unknown, an increased inflammatory response is known to be associated with the disease and has long been speculated to contribute to disease development. However, the causative factors, the exact role of the increased inflammatory cascade in CKD, and the underlying mechanisms for its progression remain unidentified. Here we report that interleukin 6 (IL-6) expression levels were significantly increased in the kidneys collected from CKD patients and further elevated in CKD patients characterized with hypertension. Functionally, we determined that angiotensin II is a causative factor responsible for IL-6 induction in the mouse kidney and that genetic deletion of IL-6 significantly reduced hypertension and key features of CKD, including renal injury and progression to renal fibrosis in angiotensin II-infused mice. Mechanistically, we provide both human and mouse evidence that IL-6 is a key cytokine functioning downstream of angiotensin II signaling to directly induce fibrotic gene expression and preproendothelin 1 mRNA expression in the kidney. Overall, both the mouse and human studies reported here provide evidence that angiotensin II induces IL-6 production in the kidney, and that, in addition to its role in hypertension, increased IL-6 may play an important pathogenic role in CKD by inducing fibrotic gene expression and ET-1 gene expression. These findings immediately suggest that the IL-6 signaling is a novel therapeutic target to manage this devastating disorder affecting millions worldwide.

Interaction between smoking and the interleukin-6 gene affects systemic levels of inflammatory biomarkers

Article

Nov 2009
NICOTINE TOB RES

Smoking is associated with a systemic inflammatory response. However, the role of genetic predisposition is not well known. We assessed whether circulatory acute phase reactants were associated with smoking and whether or not the association was modified by the major cytokine gene of the acute phase reaction, interleukin-6 (IL-6). In total, 1,003 postmyocardial infarction patients were recruited in six European cities and six repeated clinical examinations performed. C-reactive protein (CRP), interleukin 6 (IL-6), and fibrinogen levels were assayed at 5,659 subject visits. Genotyping of single nucleotide polymorphisms was performed in the IL-6 gene. Cumulative smoking (pack-years) and time since smoking cessation were strongly associated with blood levels of all three inflammatory markers. Among subjects without any respiratory disorder, these associations remained statistically significant for CRP and IL-6. A polymorphism in the IL-6 gene (rs2069840) showed an interaction with smoking on CRP (p < .001) and IL-6 (p = .049) peripheral levels. These results indicate a potential role of the IL-6 gene in the inflammatory response associated with smoking and suggest rs2069840 polymorphism deserves attention.

Effect of hormone replacement therapy on inflammatory biomarkers

Article

Feb 2009
ADV CLIN CHEM

Cardiovascular disease is the leading cause of death among women. Inflammation plays a central role in the pathogenesis of many forms of vascular disease, including atherosclerosis. Women present with cardiovascular disease a decade after men and this has been attributed to the protective effect of female ovarian sex hormones. Hormone replacement therapy (HRT), including a variety of estrogen preparations with or without a progestin, has negative effects on most of these soluble inflammatory markers, including E-selectin, cell adhesion molecules, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha, inconsistent effects on interleukin-6, and stimulatory effects on vasoprotective cytokine, such as the transforming growth factor-alpha. C-reactive protein, a circulating proinflammatory cytokine produced in both liver and atherosclerotic arteries, increases in response to oral conjugated estrogens but not to transdermal estrogen. Animal and observational studies have shown beneficial effects of hormone therapy in the perimenopausal period or before the development of significant atherosclerosis, whereas randomized trials in older women have not shown any benefit in either primary prevention or secondary prevention of cardiovascular events. Many important questions about the effects of ovarian hormones on vascular inflammation and the pathogenesis of vascular disease cannot be answered in human subjects. This review outlines the effects of HRT on inflammatory biomarkers, summarizes results from observational and randomized trials, and highlights unanswered questions of hormone therapy and cardiovascular risk.

Assessment of gene–nutrient interactions on inflammatory status of the elderly with the use of a zinc diet score — ZINCAGE study

Article

Jun 2009

Although zinc plays an important role in health status of the elderly, their dietary habits in relation to zinc intake are not well documented. The main objective of the current study was the assessment of dietary zinc intake in European old populations and the investigation of its impact on plasma zinc and inflammatory cytokines concentrations, in relation to genetic markers. Within the ZINCAGE study, 819 healthy old Europeans (>or=60 years old) were recruited. Plasma zinc, interleukin-6 (IL-6) and interleukin-8 (IL-8) were measured. Genotype data were obtained for the -174G/C polymorphism in the IL-6 gene. Dietary data were collected with a food frequency questionnaire and were used to calculate a zinc diet score. Zinc score was validated using additional dietary data (24-h recalls), in a subsample of 105 subjects. Zinc score was different among most of the European centres (P<.001), while an age-dependent decline was documented (P=4.4x10(-12)). Plasma zinc concentrations were significantly correlated with the zinc score (standardized beta=0.144, P=8.8x10(-5)). The minor allele frequency for the -174G/C polymorphism was f(C) 0.31. There was a significant interaction of zinc diet score and GG (-174G/C) genotype on higher plasma IL-6 levels (beta+/-S.E.=0.014+/-0.0, P=.008). The main finding of our study was the detection of gene-nutrient and biochemical-nutrient interactions in a multiethnic cohort based on a common dietary assessment tool.

Inverse association of erythrocyte n-3 fatty acid levels with inflammatory biomarkers in patients with stable coronary artery disease: The Heart and Soul Study

Article

Dec 2008

Dietary intake of polyunsaturated n-3 fatty acids has been associated with a reduced incidence of adverse cardiovascular events. The protective mechanisms involved are not fully understood, but may include anti-inflammatory factors. We sought to investigate the relationship between n-3 fatty acid levels in erythrocyte membranes and markers of systemic inflammation in 992 individuals with stable coronary artery disease. Cross-sectional associations of C-reactive protein (CRP) and Interleukin-6 (Il-6) with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EHA) were evaluated in multivariable linear regression models adjusted for demographics, cardiovascular risk factors, medication use, exercise capacity, body-mass index, and waist-to-hip ratio. After multivariable adjustment, n-3 fatty acid levels (DHA+EPA) were inversely associated with CRP and IL-6. The inverse association of n-3 fatty acids with CRP and IL-6 was not modified by demographics, body-mass index, smoking, LDL-cholesterol, or statin use (p values for interaction>0.1). In patients with stable coronary artery disease, an independent and inverse association exists between n-3 fatty acid levels and inflammatory biomarkers. These findings suggest that inhibition of systemic inflammation may be a mechanism by which n-3 fatty acids prevent recurrent cardiovascular events.

Association between IL6 gene variants −174G>C and −572G>C and serum IL-6 levels: Interactions with social position in the Whitehall II cohort

Article

Sep 2008

To examine the impact of -174G>C and -572G>C variants in the promoter region of the IL6 gene, and their interactions with social position, on interleukin-6 (IL-6) levels in the Whitehall II cohort. SNPs were genotyped by TaqMan. IL-6 was measured by ELISA. Employment grade was assessed to indicate social position. ANOVAs were used to examine genotype-phenotype associations. 4165 white men and women provided data on IL-6 levels at two study time points, Phase 3 (1991-1993) and Phase 7 (2002-2004). Distributions were as expected for Hardy-Weinberg equilibrium. At Phase 3, overall IL-6 levels did not differ by either genotype, but -174C was associated with higher IL-6 levels within the lowest employment grades (p(interaction)=0.046). At Phase 7, IL-6 levels overall were 6% higher in -174C (p=0.002) and 9% lower in -572C (p=0.003) carriers. The lowering effect of -572C was not apparent in the lowest employment grades (p(interaction)=0.05). IL-6 levels are determined in part by interaction between common functional IL6 gene variants and yet to be identified components of social position. These results highlight the importance of considering interactions between genes and social environments in future study designs.

Smoking, inflammatory patterns and postprandial hypertriglyceridemia

Article

Sep 2008

Smoking is associated with increased postprandial hypertriglyceridemia (PPT). Inflammation and insulin resistance are potential "drivers" for this phenomenon. We tested whether inflammatory patterns and/or insulin resistance explain the effect of smoking on PPT. Men and women in the NHLBI Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) study (n=1036, age 49+/-16y) were included. Each participant was asked to suspend use of lipid-lowering drugs for 3 weeks and was given a high-fat milkshake (83% fat and 700kcal/m(2)). Triglyceride concentrations at 0, 3.5 and 6h after the fat load were measured. Inflammatory markers were measured at baseline. Principal component analysis was used to derive inflammatory patterns from individual inflammatory markers (hsCRP, IL2 soluble receptor-alpha, IL6, TNF-alpha and MCP1). Insulin resistance (IR) was estimated using the HOMA equation. Repeated measures-ANOVA was used for analyses. Two inflammatory patterns, namely CRP-IL6 pattern and MCP1-TNF-alpha pattern, were derived. We found significant main (smoking and time) and interaction (smokingxtime) effects (P<0.01) for triglycerides. The multivariate-adjusted triglyceride (mg/dL) concentrations (mean+/-S.E.M.) for never, past and current smokers were 127.38+/-1.04, 119.82+/-1.05 and 134.92+/-1.08 at 0h; 229.42+/-1.04, 238.39+/-1.05 and 293.94+/-1.08 at 3.5h; and 194.63+/-1.04, 208.38+/-1.05 and 248.27+/-1.08 at 6h after the fat load, respectively. Smoking remained significant after adjusting for HOMA-IR and/or inflammatory patterns which showed independent associations with PPT (P<0.05). These data confirm impaired metabolism of fat among smokers and suggest that mechanisms other than inflammation or insulin resistance may explain the observed hypertriglyceridemia among smokers.

Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis

Article

Sep 2008
ARTHRIT RHEUM-ARTHR

Genetic variation in the gene for interleukin-6 (IL-6) contributes to the pathogenesis of inflammatory arthritis, but the role, if any, of epigenetic variability has not been reported. The aims of this study were to compare the DNA methylation status of the IL6 promoter in rheumatoid arthritis (RA) patients and control subjects and to study the effects on gene expression. Genomic DNA was isolated from peripheral blood mononuclear cells (PBMCs) obtained from RA patients and healthy controls. Macrophages from healthy controls were isolated and stimulated with lipopolysaccharide (LPS). Methylation status was determined using bisulfite genomic sequencing and IL6 messenger RNA (mRNA) levels by quantitative polymerase chain reaction. Gel shift assays were performed with methylated or unmethylated probes and HeLa cell nuclear extract. The proximal CpG motifs (-666 to +27) were predominantly unmethylated and the upstream motifs (-1099 to -1001) were highly methylated in PBMCs from patients and controls. Methylation of individual CpG motifs was similar, except at -1099C, which was less methylated in the patients than in the controls (58% versus 98%; P = 1 x 10(-6)). To test whether this observation might relate to gene regulation, LPS-stimulated macrophages were grouped according to their IL6 mRNA stimulation index (SI). The level of methylation at -1099C was significantly lower in the group with high (SI >75) compared with the group with low (SI <10) induced mRNA levels (71% versus 93%; P = 0.007). Gel shift assays revealed decreased protein binding to the -1099C unmethylated probe. These data suggest that methylation of a single CpG in the IL6 promoter region may affect IL6 gene regulation and may play a role in the pathogenesis of RA.

Effect of influenza vaccine on markers of inflammation and lipid profile

Article

Jun 2005
J Lab Clin Med

Despite wide use of the influenza vaccine, relatively little is known about its effect on the measurement of inflammatory markers. Because inflammatory markers such as C-reactive protein (CRP) are increasingly being used in conjunction with lipids for the clinical assessment of cardiovascular disease and in epidemiologic studies, we evaluated the effect of influenza vaccination on markers of inflammation and plasma lipid concentrations. We drew blood from 22 healthy individuals 1 to 6 hours before they were given an influenza vaccination and 1, 3, and 7 days after the vaccination. Plasma CRP, interleukin (IL)-6, monocyte chemotactic protein 1, tumor necrosis factor alpha, IL-2 soluble receptor alpha, and serum amyloid A were measured, and differences in mean concentrations of absolute and normalized values on days 1, 3, and 7 were compared with mean baseline values. There was a significant increase in mean IL-6 (P < .01 absolute values, P < .001 normalized values) on day 1 after receiving the influenza vaccine. The mean increases in normalized high sensitivity CRP values were significant on day 1 (P < .01) and day 3 (P = .05), whereas the mean increase in normalized serum amyloid A was significant only on day 1 (P < .05). No significant changes were seen in mean concentrations of IL-2 soluble receptor alpha, monocyte chemotactic protein-1, or tumor necrosis factor-alpha. Of the lipids, significant decreases in mean concentrations of normalized triglyceride values were seen on days 1 (P < .05), 3 (P < .001), and 7 (P < .05) after vaccination. Our findings show that the influenza vaccination causes transient changes in select markers of inflammation and lipids. Consequently, clinical and epidemiologic interpretation of the biomarkers affected should take into account the possible effects of influenza vaccination.

Cao J, Schwichtenberg KA, Hanson NQ, Tsai MY. Incorporation and clearance of omega-3 fatty acids in erythrocyte membranes and plasma phospholipids. Clin Chem 52 (Suppl 12), S2265-S2272

Article

Jan 2007

The sum of eicosapentaenoic acid (EPA, 20:5 omega3) and docosahexaenoic acid (DHA, 22:6 omega3) in erythrocyte membranes, termed the omega-3 index, can indicate suboptimal intake of omega-3 fatty acids, a risk factor for cardiovascular disease (CVD). To study the effects of fatty acid supplementation, we investigated the rate of incorporation and clearance of these fatty acids in erythrocyte membranes and plasma after intake of supplements. Twenty study participants received supplementation with either fish oil (1296 mg EPA + 864 mg DHA/day) or flaxseed oil (3510 mg alpha-linolenic acid + 900 mg linoleic acid/day) for 8 weeks. We obtained erythrocyte membrane and plasma samples at weeks 0, 4, 8, 10, 12, 14, 16, and 24 and extracted and analyzed fatty acids by gas chromatography. After 8 weeks of fish oil supplementation, erythrocyte membrane EPA and DHA increased 300% (P < 0.001) and 42% (P < 0.001), respectively. The mean erythrocyte omega-3 index reached a near optimal value of 7.8%, and remained relatively high until week 12. EPA and DHA showed greater increases and more rapid washout period decreases in plasma phospholipids than in erythrocyte membranes. Flaxseed oil supplementation increased erythrocyte membrane EPA to 133% (P < 0.05) and docosapentaenoic acid (DPA, 22:5 omega3) to 120% (P < 0.01) of baseline, but DHA was unchanged. In plasma phospholipids, EPA, DPA, and DHA showed a slight but statistically insignificant increase. Erythrocyte membrane EPA+DHA increases during relatively short intervals in response to supplementation at rates related to amount of supplementation. These results may be useful to establish appropriate dosage for omega-3 fatty acid supplementation.

Influence of the IL-6 -572C>G polymorphism on inflammatory markers according to cigarette smoking in Korean healthy men

Article

Sep 2007

We investigated whether smoking would interact with the interleukin-6 (IL-6) polymorphisms (-174G>C and -572C>G, -597G>A and -1363G>T) in determining circulating levels of inflammatory markers and its consequence to oxidative stress. The G/G genotype (n=26) of the -572C>G in nonsmokers (n=376) was associated with higher IL-6 (P=0.028), fibrinogen (P=0.007) and ox-LDL (P=0.006) than those with C/C (n=209) or C/G (n=141). Results were similar for nonsmokers and smokers (n=268), but in smokers, the -572G/G genotype was associated with a greater difference in levels of IL-6 (P=0.031), fibrinogen (P=0.001), ox-LDL (P=0.037) and PGF(2alpha) (P=0.050). IL-6 had positive relations with CRP, fibrinogen, ox-LDL and PGF(2alpha). There was no evidence of an effect of -572C>G genotype on CRP levels in nonsmokers, however, this polymorphism was associated with a highly significant effect on CRP in smokers (P<0.001) (genotype-smoking interaction P=0.04, adjusted for age, BMI and IL-6). The C allele frequency at the -174 promoter region of IL-6 was very rare (<0.01) and -597G>A and -1363G>T were monomorphic in this study. Our results suggest that IL-6 -572C>G has a greater response over time to the inflammatory effects of smoking and this may result in smokers having higher oxidative stress in subjects with G/G compared to C/C or C/G.

Stress-induced cytokine responses and central adiposity in young women

Article

Mar 2008
INT J OBESITY

Evidence suggests that people who are more responsive to psychological stress are at an increased risk of developing obesity. However, the biological mechanisms underlying this phenomenon are poorly understood. The cytokines leptin, interleukin-1 receptor antagonist (IL-1Ra) and interleukin-6 (IL-6) play a key role in fat metabolism and abnormal circulating levels of these proteins have been reported in obese people and in individuals subject to stress. This study investigated whether cytokine responses to acute mental stress are associated with adiposity in healthy young women. A laboratory study of 67 women, aged 18-25 years, recruited from University College London. Height, weight and waist circumference were measured and body fat mass was estimated by bioelectrical impedance body composition analysis. Laboratory mental stress testing was carried out and blood pressure and heart rate were recorded at baseline, during two moderately challenging tasks (Stroop and speech) and during recovery 40-45 min post-stress. Blood samples taken at baseline, immediately post-stress and 45 min post-stress, were used for assessment of circulating cytokines. Saliva samples taken throughout the session were assessed for cortisol. Women who had larger cytokine responses to stress were more abdominally obese than women with smaller cytokine stress responses. Specifically, there was a positive correlation between waist circumference and stress-induced increases in plasma levels of leptin (r=0.35, P<0.05) and IL-1Ra responses (r=0.29, P<0.05). There was also a significant positive correlation between prolonged diastolic blood pressure responses to stress and measures of total and abdominal obesity (r=0.28-0.33, P<0.05). Increased cytokine production could be a mechanism linking stress and abdominal obesity.

Incorporation and clearance of omega- 3 fatty acids in erythrocyte membranes and plasma phospholipids

Jan 2006
2265-2272

J Cao
K A Schwichtenberg
N Q Hanson
M Y Tsai

Cao, J., Schwichtenberg, K. A., Hanson, N. Q., Tsai, M. Y., Incorporation and clearance of omega- 3 fatty acids in erythrocyte membranes and plasma phospholipids. Clinical chemistry 2006, 52, 2265- 2272.

Temporal stability and determinants of white blood cell DNA methylation in the breakthrough generations study. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

Jan 2015
221-229

J M Flanagan
M N Brook
N Orr
K Tomczyk

Flanagan, J. M., Brook, M. N., Orr, N., Tomczyk, K., et al., Temporal stability and determinants of white blood cell DNA methylation in the breakthrough generations study. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2015, 24, 221-229.

Incorporation and clearance of omega-3 fatty acids in erythrocyte membranes and plasma phospholipids

Jan 2006
2265

The effects of omega-3 polyunsaturated fatty acids and genetic variants on methylation levels of the interleukin-6 gene promoter

Abstract

No full-text available

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