[Show abstract][Hide abstract] ABSTRACT: Assessment of compliance with dietary interventions is necessary to understand the observed magnitude of the health effects of the diet per se. To avoid reporting bias, different dietary biomarkers (DBs) could be used instead of self-reported data. However, few studies investigated a combination of DBs to assess compliance and its influence on cardiometabolic risk factors. The objectives of this study were to use a combination of DBs to assess compliance and to investigate how a healthy Nordic diet (ND) influences cardiometabolic risk factors in participants with high apparent compliance compared with the whole study population. From a recently conducted isocaloric randomized trial, SYSDIET (Systems Biology in Controlled Dietary Interventions and Cohort Studies), in 166 individuals with metabolic syndrome, several DBs were assessed to reflect different key components of the ND: canola oil (serum phospholipid α-linolenic acid), fatty fish [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)], vegetables (plasma β-carotene), and whole grains (plasma alkylresorcinols). High-fat dairy intake (expectedly low in the ND) was reflected by serum pentadecanoic acid. All participants with biomarker data (n = 154) were included in the analyses. Biomarkers were combined by using a biomarker rank score (DB score) and principal component analysis (PCA). The DB score was then used to assess compliance. During the intervention, median concentrations of alkylresorcinols, α-linolenic acid, EPA, and DHA were >25% higher in the ND individuals compared with the controls (P < 0.05), whereas median concentrations of pentadecanoic acid were 14% higher in controls (P < 0.05). Median DB score was 57% higher in the ND compared with controls (P < 0.001) during the intervention, and participants were ranked similarly by DB score and PCA score. Overall, estimates of group difference in cardiometabolic effects generally appeared to be greater among compliant participants than in the whole study population (e.g., estimates of treatment effects on blood pressure and lipoproteins were ∼1.5- to 2-fold greater in the most compliant participants), suggesting that poor compliance attenuated the dietary effects. With adequate consideration of their limitations, DB combinations (e.g., DB score) could be useful for assessing compliance in intervention studies investigating cardiometabolic effects of healthy dietary patterns. The study was registered at clinicaltrials.gov as NCT00992641.
[Show abstract][Hide abstract] ABSTRACT: At northern latitudes, vitamin D is not synthesized endogenously during winter, causing low plasma 25-hydroxyvitamin D (25(OH)D) concentrations. Therefore, we evaluated the effects of a healthy Nordic diet based on Nordic nutrition recommendations (NNR) on plasma 25(OH)D and explored its dietary predictors.
In a Nordic multi-centre trial, subjects (n = 213) with metabolic syndrome were randomized to a control or a healthy Nordic diet favouring fish (≥300 g/week, including ≥200 g/week fatty fish), whole-grain products, berries, fruits, vegetables, rapeseed oil and low-fat dairy products. Plasma 25(OH)D and parathyroid hormone were analysed before and after 18- to 24-week intervention.
At baseline, 45 % had vitamin D inadequacy (<50 nmol/l), whereas 8 % had deficiency (<25 nmol/l). Dietary vitamin D intake was increased by the healthy Nordic diet (P < 0.001). The healthy Nordic and the control diet reduced the prevalence of vitamin D inadequacy by 42 % (P < 0.001) and 19 % (P = 0.002), respectively, without between-group difference (P = 0.142). Compared with control, plasma 25(OH)D (P = 0.208) and parathyroid hormone (P = 0.207) were not altered by the healthy Nordic diet. Predictors for 25(OH)D were intake of vitamin D, eicosapentaenoic acids (EPA), docosahexaenoic acids (DHA), vitamin D supplement, plasma EPA and plasma DHA. Nevertheless, only vitamin D intake and season predicted the 25(OH)D changes.
Consuming a healthy Nordic diet based on NNR increased vitamin D intake but not plasma 25(OH)D concentration. The reason why fish consumption did not improve vitamin D status might be that many fish are farmed and might contain little vitamin D or that frying fish may result in vitamin D extraction. Additional ways to improve vitamin D status in Nordic countries may be needed.
European Journal of Nutrition 02/2014; · 3.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background/Objectives:Few studies have used biomarkers of whole-grain intake to study its relation to glucose metabolism. We aimed to investigate the association between plasma alkylresorcinols (AR), a biomarker of whole-grain rye and wheat intake, and glucose metabolism in individuals with metabolic syndrome (MetS).Subjects/Methods:Participants were 30-65 years of age, with body mass index 27-40 kg/m(2) and had MetS without diabetes. Individuals were recruited through six centers in the Nordic countries and randomized to a healthy Nordic diet (ND, n=96), rich in whole-grain rye and wheat, or a control diet (n=70), for 18-24 weeks. In addition, associations between total plasma AR concentration and C17:0/C21:0 homolog ratio as an indication of the relative whole-grain rye intake, and glucose metabolism measures from oral glucose tolerance tests were investigated in pooled (ND+control) regression analyses at 18/24 weeks.Results:ND did not improve glucose metabolism compared with control diet, but the AR C17:0/C21:0 ratio was inversely associated with fasting insulin concentrations (P=0.002) and positively associated with the insulin sensitivity indices Matsuda ISI (P=0.026) and disposition index (P=0.022) in pooled analyses at 18/24 weeks, even after adjustment for confounders. The AR C17:0/C21:0 ratio was not significantly associated with insulin secretion indices. Total plasma AR concentration was not related to fasting plasma glucose or fasting insulin at 18/24 weeks.Conclusions:The AR C17:0/C21:0 ratio, an indicator of relative whole-grain rye intake, is associated with increased insulin sensitivity in a population with MetS.European Journal of Clinical Nutrition advance online publication, 19 February 2014; doi:10.1038/ejcn.2014.12.
European journal of clinical nutrition 02/2014; · 3.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction
Polyamines play a fundamental role during embryogenesis by regulating cell growth and proliferation and by interacting with RNA, DNA and protein. The polyamine pools are regulated by metabolism and uptake from exogenous sources. The use of certain inhibitors of polyamine synthesis causes similar defects to those seen in alcohol exposure e.g. retarded embryo growth and endothelial cell sprouting.
CD-1 mice received two intraperitoneal injections of 3 g/kg ethanol at 4 h intervals 8.75 days post coitum (dpc). The fetal head, trunk, yolk sac and placenta were collected at 9.5 and 12.5 dpc and polyamine concentrations were determined.
No measurable quantity of polyamines could be detected in the embryo head at 9.5 dpc, 12 h after ethanol exposure. Putrescine was not detectable in the trunk of the embryo at that time, whereas polyamines in yolk sac and placenta were at control level. Polyamine deficiency was associated with slow cell growth, reduction in endothelial cell sprouting, an altered pattern of blood vessel network formation and consequently retarded migration of neural crest cells and growth restriction.
Our results indicate that the polyamine pools in embryonic and extraembryonic tissues are developmentally regulated. Alcohol administration, at the critical stage, perturbs polyamine levels with various patterns, depending on the tissue and its developmental stage. The total absence of polyamines in the embryo head at 9.5 dpc may explain why this stage is so vulnerable to the development of neural tube defect, and growth restriction, the findings previously observed in fetal alcohol syndrome.
Biochemical and Biophysical Research Communications 01/2014; · 2.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It is becoming increasingly recognised that early-life nutritional, metabolic and environmental factors can have a long term impact on the early onset of obesity, type 2 diabetes and cardiovascular diseases. Numerous experimental and epidemiological observations support the concept that an individual's response to its adult life-style and nutritional environment depends not only on their genetic susceptibility but also their previous early-life experiences. The current research challenge is to determine the primary pathways contributing to "non- or epi-genetic" causes of excess adult weight gain and adiposity. Evidence from the fields of genetic epidemiology, life-course modelling and diet-induced fetal programming all support a role for the FTO gene in this complex biological interaction. It may provide a missing link in the developmental regulation of energy metabolism. Our review therefore considers the role of the FTO gene in the early-life determination of body weight, body composition and energy balance. We will summarise current knowledge on FTO biology combining human genetic epidemiology, molecular models and findings from animal studies. Notably, we will focus on the role of FTO in energy balance in humans, the importance of FTO polymorphisms in childhood growth and the impact of fetal nutrition. Ultimately we propose a new hypothesis for future research designed to understand the role of FTO in setting gene expression in metabolically active tissues. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Context:Statins have been shown to improve hyperandrogenism in women with polycystic ovary syndrome (PCOS). However, their use has also been associated with impairment of glucose metabolism and an increased risk of type 2 diabetes mellitus. Because women with PCOS are prone to disturbances in glucose metabolism, statin therapy could also have negative effects.Objective:Our objective was to explore the effects of atorvastatin therapy on hormonal and metabolic parameters in women with PCOS.Design and Setting:We conducted a randomized, double-blind, placebo-controlled 6-month follow-up study conducted at Oulu University Hospital, Finland.Patients:Women with PCOS (Rotterdam criteria) were treated with atorvastatin (20 mg/d, n = 15) or placebo (n = 13) for 6 months.Interventions:Fasting serum samples were collected at baseline and at 3 and 6 months. Oral and iv glucose tolerance tests were performed at 0 and 6 months.Main Outcome Measures:Androgen secretion and glucose metabolism were measured.Results:Fasting levels and area under the curve of insulin increased significantly and insulin sensitivity (insulinogenic and Matsuda indexes) decreased during 6 months of atorvastatin therapy. Serum levels of dehydroepiandrosterone sulfate decreased in the atorvastatin group, whereas no change was observed in serum testosterone levels. Levels of C-reactive protein, total and low-density lipoprotein-cholesterol, and triglycerides decreased significantly during statin therapy.Conclusions:Atorvastatin therapy improves chronic inflammation and lipid profile, but it impairs insulin sensitivity in women with PCOS. Because women with PCOS have an increased risk of developing type 2 diabetes mellitus, the results suggest that statin therapy should be initiated on the basis of generally accepted criteria and individual risk assessment of cardiovascular disease, and not only because of PCOS.
The Journal of clinical endocrinology and metabolism 10/2013; · 6.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Biomarkers of dietary intake can be important tools in nutrition research. Our aim was to assess whether plasma alkylresorcinols (AR) and β-carotene concentrations could be used as dietary biomarkers for whole-grain, fruits and vegetables in a healthy Nordic diet (ND). Participants (n = 166), 30-65 y with a body mass index of 27-40 kg/m(2) and two more features of metabolic syndrome (International Diabetes Federation definition, slightly modified), were recruited through six centers in the Nordic countries and randomized to ND or control diet for 18 or 24 wk, depending on study center. Plasma AR and β-carotene were analyzed and nutrient intake calculated from 4-d food records. Median fiber intake increased in the ND group from 2.5 g/MJ at baseline to 4.1 g/MJ (P < 0.001) at end point (week 18 or 24), and median (IQR) total fasting plasma AR concentration increased from 73 (88) to 106 (108) nmol/L, or 45%, from baseline to end point (P < 0.001). AR concentration was significantly higher in the ND group (P < 0.001) than in the control group at end point. β-Carotene intake tended to increase in the ND group (P = 0.07), but plasma β-carotene concentration did not change significantly throughout the study and did not differ between the groups at follow-up. In conclusion, an ND resulted in higher dietary fiber intake and increased total plasma AR concentration compared with the control diet, showing that AR might be a valid biomarker for an ND in which whole-grain wheat and rye are important components. No significant difference in plasma β-carotene concentrations was observed between the ND and control groups, suggesting that β-carotene may not be a sensitive enough biomarker of the ND.
Journal of Nutrition 07/2013; · 4.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bile acids play multiple roles in the physiology of vertebrates; they facilitate lipid absorption, serve as signaling molecules to control carbohydrate and lipid metabolism, and provide a disposal route for cholesterol. Unexpectedly, the α-methylacyl-CoA racemase (Amacr) deficient mice, which are unable to complete the peroxisomal cleavage of C27-precursors to the mature C24-bile acids, are physiologically asymptomatic when maintained on a standard laboratory diet. The aim of this study was to uncover the underlying adaptive mechanism with special reference to cholesterol and bile acid metabolisms that allow these mice to have a normal life span. Intestinal cholesterol absorption in Amacr-/- mice is decreased resulting in a 2-fold increase in daily cholesterol excretion. Also fecal excretion of bile acids (mainly C27-sterols) is enhanced 3-fold. However, the body cholesterol pool remains unchanged, although Amacr-deficiency accelerates hepatic sterol synthesis 5-fold. Changes in lipoprotein profiles are mainly due to decreased phospholipid transfer protein activity. Thus Amacr-deficient mice provide a unique example of metabolic regulation, which allows them to have a normal lifespan in spite of the disruption of a major metabolic pathway. This metabolic adjustment can be mainly explained by setting cholesterol and bile acid metabolism to a new balanced level in the Amacr-deficient mouse.
Biochimica et Biophysica Acta 05/2013; · 4.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSE:: To study the association of single-nucleotide polymorphisms of interleukin 8, vascular endothelial growth factor, erythropoietin, complement factor H, complement component C3, and LOC387715 genes with the response to bevacizumab treatment in exudative age-related macular degeneration. METHODS:: Clinical records, smoking history, optical coherence tomography, and angiographies of 96 bevacizumab-treated exudative age-related macular degeneration patients were analyzed retrospectively. Blood DNA was collected. Based on the disappearance of intra- or subretinal fluid in optical coherence tomography, patients were graded as responders, partial responders, or nonresponders after 3 initial treatment visits and a median time of 3.5 months. RESULTS:: Interleukin 8 promoter polymorphism -251A/T was significantly associated with persisting fluid in optical coherence tomography. The A allele was more frequent in nonresponders than in responders (P = 0.033). In multivariate modeling, the AA genotype of -251A/T (P = 0.043) and occult (P = 0.042) or predominantly classic (P = 0.040) lesions predicted poorer outcome. Visual acuity change was better in responders than in nonresponders (P = 0.006). Baseline lesion size (P = 0.006) and retinal cysts after the treatment (P < 0.001) correlated with less visual acuity gain. CONCLUSION:: The A allele and the homozygous AA genotype of interleukin 8 -251A/T were associated with anatomical nonresponse to bevacizumab treatment.
[Show abstract][Hide abstract] ABSTRACT: We conducted a randomized, open, placebo-controlled crossover trial to investigate the effects of pregnane X receptor (PXR) agonist rifampin on oral glucose tolerance test (OGTT) in 12 healthy volunteers. The subjects were administered 600 mg rifampin or placebo once daily for seven days and OGTT was performed on the eighth day. The mean incremental glucose and insulin areas under the plasma concentration-time curves (AUCincr) increased by 192% (P = 0.008) and 45% (P = 0.031), respectively. The fasting glucose, insulin and C-peptide and the homeostasis model assessment for insulin resistance were not affected. The glucose AUCincr during OGTT was significantly increased in rats after 4-day treatment with pregnenolone 16α-carbonitrile (PCN), an agonist of the rat PXR. The hepatic level of glucose transporter 2 (Glut2) mRNA was down-regulated by PCN. In conclusion, both human and rat PXR agonists elicited postprandial hyperglycemia suggesting detrimental role of PXR activation on glucose tolerance.Clinical Pharmacology & Therapeutics (2013); accepted article preview online 5 March 2013; doi:10.1038/clpt.2013.48.
[Show abstract][Hide abstract] ABSTRACT: Recent studies suggest that meal frequencies influence the risk of obesity in children and adolescents. It has also been shown that multiple genetic loci predispose to obesity already in youth. However, it is unknown whether meal frequencies could modulate the association between single nucleotide polymorphisms (SNPs) and the risk of obesity. We examined the effect of two meal patterns on weekdays -5 meals including breakfast (regular) and ≤4 meals with or without breakfast (meal skipping) - on the genetic susceptibility to increased body mass index (BMI) in Finnish adolescents. Eight variants representing 8 early-life obesity-susceptibility loci, including FTO and MC4R, were genotyped in 2215 boys and 2449 girls aged 16 years from the population-based Northern Finland Birth Cohort 1986. A genetic risk score (GRS) was calculated for each individual by summing the number of BMI-increasing alleles across the 8 loci. Weight and height were measured and dietary data were collected using self-administered questionnaires. Among meal skippers, the difference in BMI between high-GRS and low-GRS (<8 and ≥8 BMI-increasing alleles) groups was 0.90 (95% CI 0.63,1.17) kg/m(2), whereas in regular eaters, this difference was 0.32 (95% CI 0.06,0.57) kg/m(2) (p interaction = 0.003). The effect of each MC4R rs17782313 risk allele on BMI in meal skippers (0.47 [95% CI 0.22,0.73] kg/m(2)) was nearly three-fold compared with regular eaters (0.18 [95% CI -0.06,0.41] kg/m(2)) (p interaction = 0.016). Further, the per-allele effect of the FTO rs1421085 was 0.24 (95% CI 0.05,0.42) kg/m(2) in regular eaters and 0.46 (95% CI 0.27,0.66) kg/m(2) in meal skippers but the interaction between FTO genotype and meal frequencies on BMI was significant only in boys (p interaction = 0.015). In summary, the regular five-meal pattern attenuated the increasing effect of common SNPs on BMI in adolescents. Considering the epidemic of obesity in youth, the promotion of regular eating may have substantial public health implications.
PLoS ONE 01/2013; 8(9):e73802. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this study, Prokopenko and colleagues provide novel evidence for causal relationship between adiposity and heart failure and increased liver enzymes using a Mendelian randomization study design.
Please see later in the article for the Editors' Summary
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Long-term physical inactivity seems to cause many health problems. We studied whether persistent physical activity compared to inactivity has a global effect on serum metabolome towards reduced cardio-metabolic disease risk. METHODS AND RESULTS: Sixteen same-sex twin pairs (mean age 60 yrs) were selected from a cohort of twin pairs on the basis of their over 30-year discordance for physical activity. Persistently (≥5 years) active and inactive groups in three population-based cohorts (mean ages 31 to 52 years) were also studied (1037 age- and sex-matched pairs). Serum metabolome was quantified by nuclear magnetic resonance spectroscopy. We used permutation analysis to estimate significance of the multivariate effect combined across all metabolic measures; univariate effects were estimated by paired testing in twins as well as in matched pairs, in the cohorts, and by meta-analysis over all sub-studies. Persistent physical activity was associated with the multivariate metabolic profile in the twins (P=0.003), and a similar pattern was observed in all three population cohorts with differing mean ages. Isoleucine, α1-acid glycoprotein and glucose were lower in the physically active than in the inactive individuals (P<0.001 in meta-analysis), serum fatty acid composition was shifted towards a less saturated profile, and lipoprotein subclasses towards lower VLDL (P<0.001) and higher large and very large HDL (P<0.001) particle concentrations. The findings persisted after adjustment for body-mass index. CONCLUSIONS: The numerous differences found between persistently physically active and inactive individuals in the circulating metabolome coherently indicate better metabolic health in the physically active than in inactive individuals.
[Show abstract][Hide abstract] ABSTRACT: Background/Aim: Inflammatory markers have been observed in proliferative diabetic retinopathy (PDR). We assessed vitreous concentrations of adhesion molecules and cytokines in PDR and non-diabetic controls and plasma concentrations to differentiate local inflammation from the breakdown of the blood-retina barrier. Methods: 38 patients with PDR and 16 controls with macular hole or epiretinal membrane underwent vitrectomy. Vitreous and plasma soluble adhesion molecules [sE-selectin, intercellular adhesion molecule (sICAM)-1 and -3, platelet-endothelial cell adhesion molecule (sPECAM)-1, sP-selectin, vascular cell adhesion molecule (sVCAM)-1] and cytokines [interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 (p70), tumour necrosis factor-α and -β, γ-interferon] were detected by the multiplex assay. Results: Levels of IL-6 and IL-8 were 26-fold (p = 0.001) and 6-fold higher (p = 0.001) in vitreous than in plasma in PDR. Vitreous IL-10 (p = 0.004), sPECAM-1, sE-selectin, sICAM-1 and sVCAM-1 were higher in PDR than controls (p = 0.001 for all). Adhesion molecule concentrations in vitreous in PDR were less than 10% of those in plasma. IL-10 was lower in vitreous than plasma (3.0 vs. 12.8 pg/ml, p = 0.007), and the vitreous IL-10/IL-8 ratio was significantly lower in PDR than in controls (0.10 vs. 0.55 pg/ml, p = 0.003). Conclusion: The elevated IL-6 and IL-8 levels in vitreous, but not in plasma, are evidence favouring local over systemic inflammation in PDR. Furthermore, there was imbalance between inflammatory and anti-inflammatory cytokines in the vitreous.
Ophthalmic Research 12/2012; 49(2):108-114. · 1.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: Apolipoproteins B (apoB) and A1 (apoA1) may be better markers of atherosclerosis than serum lipids. We used computational methods to estimate apoB and apoA1 from serum total cholesterol, HDL-cholesterol and triglycerides and tested their clinical value in comparison to measured apoB and apoA1 values. METHODS: ApoB and apoA1 were measured with standard methods and estimated based on neural network regression models in 2166 young adult with data on carotid artery intima-media thickness (cIMT). RESULTS: Correlations between estimated and measured apoB and apoA1 were r = 0.98 and r = 0.95, respectively. ApoB/apoA1-ratio (both measured and estimated) associated with cIMT in multivariable models, and predicted cIMT at all levels of LDL-cholesterol concentration. Strong correlations between the estimated apolipoproteins and those measured from fasting samples were replicated in over 15,000 Caucasian subjects (r = 0.93-0.96 for apoB and r = 0.91-0.92 for apoA1). Correlations with cIMT were replicated in over 2000 individuals. Estimated apoB/apoA1-ratio calculated from non-fasting lipids in over 20,000 individuals in the INTERHEART study was better than any of the cholesterol measures for estimation of the myocardial risk. CONCLUSIONS: Serum cholesterol, HDL-cholesterol and triglycerides can be used to compute clinically useful estimates of apoB and apoA1. Using this methodology, estimates of apolipoproteins could be routinely added to laboratory reports to complement lipoprotein lipids in risk assessment.
[Show abstract][Hide abstract] ABSTRACT: Acute alcohol exposure induces malformation and malfunction of placenta-yolk sac tissues in rodents, reducing the labyrinth zone in the placenta and altering the permeability and fluidity of the cell membrane. During normal mouse placentation the cells line up in an optimal way to form a hemotrichorial placenta where layers II and III are connected through gap junctions. These act as molecular sieves that limit the passage of large molecules. PlGF is a developmentally regulated protein that controls the passage of molecules in the vasculosyncytial membranes and media of large blood vessels in the placental villi. In addition to the chorioallontoic placenta, rodents also have another type of placenta that consists of Reichert's membrane within the trophoblast cell layer on the maternal side and the parietal endodermal cells on the embryonic site. This forms a separate materno-fetal transport system. We study here whether alcohol affects these two placental barriers, leading to placental malfunction that in turn diminishes the nutrient supply to the embryo.
CD-1 mice received two intraperitoneal injections of 3 g/kg ethanol at 4 h intervals at 8.75 days post coitum (dpc). The placentas were collected on 9.5, 11.5 and 14.5 dpc and used for histopathological protein studies. Hemotrichorial cell layer structure interactions through connective tissue and gap junction were analyzed by electron microscopy. The permeability of the feto-maternal barrier was visualized with Evans Blue.
VEGF, a permeability inducer, was found to be up-regulated in the mouse placenta after acute alcohol exposure, and permeability was also affected by altered structures in the barriers that separate the feto-maternal blood circulation which destroyed the gap junctions in the hemotrichorial cell layer, reduced the thickness of Reichert's membrane and interfered with with Reichert's trophoblast/Reichert's parietal interaction. These defects together could have caused the permeability malfunction of the placenta-yolk sac tissues as visualized and quantified here by Evans Blue leakage.
An altered PlGF/VEGF ratio together with barrier malformation may contribute to placental malfunction by altering the permeability of the feto-maternal barriers. Further studies are needed in order to show whether premature permeability is involved in the intrauterine growth restriction observed in human FAS embryos.
[Show abstract][Hide abstract] ABSTRACT: Association testing of multiple correlated phenotypes offers better power than univariate analysis of single traits. We analyzed 6,600 individuals from two population-based cohorts with both genome-wide SNP data and serum metabolomic profiles. From the observed correlation structure of 130 metabolites measured by nuclear magnetic resonance, we identified 11 metabolic networks and performed a multivariate genome-wide association analysis. We identified 34 genomic loci at genome-wide significance, of which 7 are novel. In comparison to univariate tests, multivariate association analysis identified nearly twice as many significant associations in total. Multi-tissue gene expression studies identified variants in our top loci, SERPINA1 and AQP9, as eQTLs and showed that SERPINA1 and AQP9 expression in human blood was associated with metabolites from their corresponding metabolic networks. Finally, liver expression of AQP9 was associated with atherosclerotic lesion area in mice, and in human arterial tissue both SERPINA1 and AQP9 were shown to be upregulated (6.3-fold and 4.6-fold, respectively) in atherosclerotic plaques. Our study illustrates the power of multi-phenotype GWAS and highlights candidate genes for atherosclerosis.
[Show abstract][Hide abstract] ABSTRACT: Oxidized low-density lipoproteins (oxLDL) and antibodies against them (anti-oxLDLs) are thought to play a central role in atherosclerosis. One proposed antiatherosclerotic mechanism for HDL is to prevent oxidation of LDL. This study examined whether plasma HDL-cholesterol (HDL-C) is related to plasma anti-oxLDL levels.
We collected families based on probands with low HDL-C and premature coronary heart disease (CHD). Antibody levels were determined in samples from 405 subjects. Immunoglobulin G, M and A levels against two in vitro models of oxLDL, malondialdehyde-acetaldehyde-modified LDL (MAA-LDL) and copper oxidized LDL (CuOx-LDL), were measured by ELISA. We carried out heritability estimation of antibody traits and bivariate analyses between HDL-C, LDL-C and antibody traits.
All the antibody levels were significantly inherited (p < 0.001), heritability estimates ranging from 0.28 to 0.65. HDL-C exhibited no environmental or genetic cross-correlations with antibody levels. Significant environmental correlations were detected between LDL-C and both IgG levels (ρ(E) = 0.40, p = 0.046 and ρ(E) = 0.39, p < 0.001). There were no differences in antibody levels between subjects with normal and low HDL-C, or between CHD-affected and non-affected subjects.
In this study, low HDL-C level displayed no significant associations with the anti-oxLDL levels measured. The heritability of the anti-oxLDL levels was a novel and interesting finding.