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Current opinion in lipidology 12/2012; 23(6):591-2. · 6.13 Impact Factor
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ABSTRACT: Cholesteryl ester transfer protein (CETP) is important clinically and is the current target for new drug development. Its structure and mechanism of action has not been well understood. We have combined current new structural and functional methods to compare with relevant prior data. These analyses have led us to propose several steps in CETP's function at the molecular level, in the context of its interactions with lipoproteins, e.g., sensing, penetration, docking, selectivity, ternary complex formation, lipid transfer, and HDL dissociation. These new molecular insights improve our understanding of CETP's mechanisms of action.
The Journal of Lipid Research 06/2012; 53(8):1451-8. · 5.56 Impact Factor
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ABSTRACT: A negative correlation between HDL cholesterol levels and risk of coronary artery disease has long been recognized. Emerging knowledge of the molecular speciation and functional properties of HDL provides an opportunity to study the atheroprotective effects of specific metabolic processes. The discovery of the quantum particle among the molecular species of HDL (prebeta-1 HDL) and its role in cholesterol efflux from the artery wall, offer a means of assessing the efficiency of efflux. This review presents observations on the structure and metabolism of this particle and its emerging role as a predictor of risk for atherosclerotic vascular disease.
Prebeta-1 HDL is now recognized as the primary acceptor of cholesterol effluxed by the dominant ATP-binding cassette A1 (ABCA1) transporter in arterial macrophages, a critical step in reverse cholesterol transport. Several studies have revealed an association between high levels of this particle and risk of globally defined coronary artery disease and carotid intima-media thickness. Recently, these findings have been confirmed and extended to include myocardial infarction. High levels of prebeta-1 HDL may serve as an index of functional impairment of cholesterol efflux or esterification, either of which would be expected to impede reverse cholesterol transport.
Recent studies underscore the critical role of prebeta-1 HDL in reverse cholesterol transport and its use as a marker of risk for structural coronary disease, myocardial infarction, and cerebral vascular disease.
Current opinion in lipidology 04/2012; 23(4):367-71. · 6.13 Impact Factor
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Catherine T Jordan,
Li Cao,
Elisha D O Roberson,
Shenghui Duan,
Cynthia A Helms,
Rajan P Nair,
Kristina Callis Duffin,
Philip E Stuart,
David Goldgar,
Genki Hayashi, [......],
Michelle A Lowes,
Lynette Peddle,
Vinod Chandran,
Wilson Liao,
Proton Rahman,
Gerald G Krueger,
Dafna Gladman,
James T Elder,
Alan Menter,
Anne M Bowcock
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ABSTRACT: Psoriasis is a common inflammatory disorder of the skin and other organs. We have determined that mutations in CARD14, encoding a nuclear factor of kappa light chain enhancer in B cells (NF-kB) activator within skin epidermis, account for PSORS2. Here, we describe fifteen additional rare missense variants in CARD14, their distribution in seven psoriasis cohorts (>6,000 cases and >4,000 controls), and their effects on NF-kB activation and the transcriptome of keratinocytes. There were more CARD14 rare variants in cases than in controls (burden test p value = 0.0015). Some variants were only seen in a single case, and these included putative pathogenic mutations (c.424G>A [p.Glu142Lys] and c.425A>G [p.Glu142Gly]) and the generalized-pustular-psoriasis mutation, c.413A>C (p.Glu138Ala); these three mutations lie within the coiled-coil domain of CARD14. The c.349G>A (p.Gly117Ser) familial-psoriasis mutation was present at a frequency of 0.0005 in cases of European ancestry. CARD14 variants led to a range of NF-kB activities; in particular, putative pathogenic variants led to levels >2.5× higher than did wild-type CARD14. Two variants (c.511C>A [p.His171Asn] and c.536G>A [p.Arg179His]) required stimulation with tumor necrosis factor alpha (TNF-α) to achieve significant increases in NF-kB levels. Transcriptome profiling of wild-type and variant CARD14 transfectants in keratinocytes differentiated probably pathogenic mutations from neutral variants such as polymorphisms. Over 20 CARD14 polymorphisms were also genotyped, and meta-analysis revealed an association between psoriasis and rs11652075 (c.2458C>T [p.Arg820Trp]; p value = 2.1 × 10(-6)). In the two largest psoriasis cohorts, evidence for association increased when rs11652075 was conditioned on HLA-Cw*0602 (PSORS1). These studies contribute to our understanding of the genetic basis of psoriasis and illustrate the challenges faced in identifying pathogenic variants in common disease.
The American Journal of Human Genetics 04/2012; 90(5):796-808. · 10.60 Impact Factor
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May M Luke,
Klaus Berger,
Charles M Rowland,
Joseph J Catanese,
Carmen H Tong,
David A Ross,
Veronica Garcia,
Gregor Kuhlenbaeumer,
E Bernd Ringelstein,
Clive R Pullinger,
Mary J Malloy,
Prakash Deedwania,
Stephen G Ellis, John P Kane,
James J Devlin,
Wolfgang Lalouschek,
Christine Mannhalter
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ABSTRACT: Gene variants associated with disease could reveal novel mechanisms. We searched for single nucleotide polymorphisms (SNPs) associated with noncardioembolic stroke (nonCES).
We tested 24,926 SNPs in or near genes for association with nonCES in the Vienna Study (551 cases, 815 controls) and then evaluated the associated SNPs in the UCSF-CC Study (570 cases, 1,604 controls) first in pooled DNA samples and then in individual DNA samples. We then asked whether the risk alleles of the SNPs associated with increased risk in both studies were also associated with increased risk of nonCES in the German Study (728 cases, 1,041 controls).
Six of the 46 SNPs that were associated with nonCES in both the Vienna and the UCSF-CC Studies were also associated with nonCES in the German Study: rs362277 in HTT (OR 1.39, 90% CI 1.12-1.71), rs2924914 near CSMD1 (OR 1.22, 90% CI 1.04-1.43), rs1264352 near DDR1 (OR 1.20, 90% CI 1.02-1.41), rs544115 in NEU3 (OR 1.63, 90% CI 1.02-2.62), rs12481805 in UMODL1 (OR 1.31, 90% CI 1.01-1.81), and rs2857595 near NCR3 (OR 1.15, 90% CI 1.00-1.32). Accounting for multiple testing of 46 SNPs, these 6 SNPs had a false discovery rate of 0.69.
Some of the 6 SNPs may be associated with nonCES but most may be false positives. These 6 SNPs merit investigation in additional nonCES study populations.
Cerebrovascular Diseases 12/2011; 33(1):80-5. · 2.72 Impact Factor
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Lin T Guey,
Clive R Pullinger,
Brian Y Ishida,
Patricia M O'Connor,
Christian Zellner,
Omar L Francone,
Jason M Laramie,
Josefina M Naya-Vigne,
Ketevan A Siradze,
Prakash Deedwania,
Rita F Redberg,
Philip H Frost,
Albert B Seymour, John P Kane,
Mary J Malloy
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ABSTRACT: Preβ-1 high-density lipoprotein (HDL) plays a key role in reverse cholesterol transport by promoting cholesterol efflux. Our aims were (1) to test previous associations between preβ-1 HDL and coronary heart disease (CHD) and (2) to investigate whether preβ-1 HDL levels also are associated with risk of myocardial infarction (MI). Plasma preβ-1 HDL was measured by an ultrafiltration-isotope dilution technique in 1,255 subjects recruited from the University of California-San Francisco Lipid and Cardiovascular Clinics and collaborating cardiologists. Preβ-1 HDL was significantly and positively associated with CHD and MI even after adjustment for established risk factors. Inclusion of preβ-1 HDL in a multivariable model for CHD led to a modest improvement in reclassification of subjects (net reclassification index 0.15, p = 0.01; integrated discrimination improvement 0.003, p = 0.2). In contrast, incorporation of preβ-1 HDL into a risk model of MI alone significantly improved reclassification of subjects (net reclassification index 0.21, p = 0.008; integrated discrimination improvement 0.01, p = 0.02), suggesting that preβ-1 HDL has more discriminatory power for MI than for CHD in our study population. In conclusion, these results confirm previous associations between preβ-1 HDL and CHD in a large well-characterized clinical cohort. Also, this is the first study in which preβ-1 HDL was identified as a novel and independent predictor of MI above and beyond traditional CHD risk factors.
The American journal of cardiology 08/2011; 108(3):360-6. · 3.58 Impact Factor
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Steven G DuBois,
Robert Goldsby,
Mark Segal,
Jonathan Woo,
Kirsten Copren, John P Kane,
Clive R Pullinger,
Katherine K Matthay,
John Witte,
Stephen L Lessnick,
Leslie L Robison,
Smita Bhatia,
Louise C Strong
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ABSTRACT: Ewing sarcoma is a malignant bone tumor characterized by a high frequency of somatic EWSR1 translocations. Ewing sarcoma is less common in people of African or African-American ancestry, suggesting a genetic etiology.
Germline DNA from white patients with Ewing sarcoma (n = 135), white controls with Wilms tumor (n = 200), and African-American controls (n = 285) was genotyped at 21 SNPs in the EWSR1 gene. Intron 7 of EWSR1, the most common site of translocation, was also sequenced in all subjects. Genetic variation between groups was evaluated statistically using exact logistic regression and Fisher exact tests.
One SNP in EWSR1 (rs2857461) showed a low level of statistical association with the diagnosis of Ewing sarcoma compared to Wilms tumor. The odds ratio for having Ewing sarcoma in people with at least one copy of the minor allele of rs2857461 was 3.57 (95% confidence interval 0.79-21.7; P = 0.07). No other SNPs or variations in intron 7 of EWSR1 were associated with Ewing sarcoma. The median relative difference in minor allele frequencies between white subjects with Ewing sarcoma and African-American controls at the evaluated EWSR1 SNPs was 45%.
Variations in EWSR1 at known SNPs or across intron 7 are not associated with the diagnosis of Ewing sarcoma. EWSR1 does not appear to be an Ewing sarcoma susceptibility gene. The genetic basis for this disease remains unknown.
Pediatric Blood & Cancer 07/2011; 59(1):52-6. · 1.89 Impact Factor
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Gualberto Ruaño,
Andreas Windemuth,
Alan H B Wu, John P Kane,
Mary J Malloy,
Clive R Pullinger,
Mohan Kocherla,
Kali Bogaard,
Bruce R Gordon,
Theodore R Holford,
Ankur Gupta,
Richard L Seip,
Paul D Thompson
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ABSTRACT: We investigated genetic variants predictive of muscular side effects in patients treated with statins. We utilized a physiogenomic approach to prototype a multi-gene panel correlated with statin-induced myalgia.
Statin-induced myalgia occurs in ∼10% of lipid clinic outpatients. Its clinical manifestation may depend in part upon gene variation from patient to patient.
We genotyped 793 patients (377 with myalgia and 416 without) undergoing statin therapy at four U.S. outpatient clinic sites to evaluate 31 candidate genes from the literature for their association with statin-induced common myalgia.
Three previously hypothesized candidate genes were validated: COQ2 (rs4693570) encoding para-hydroxybenzoate-polyprenyltransferase, which participates in the biosynthesis of coenzyme Q10 (p<0.000041); ATP2B1 (rs17381194) which encodes a calcium transporting ATPase involved in calcium homeostasis (p<0.00079); and DMPK (rs672348) which encodes a protein kinase implicated in myotonic dystrophy (p<0.0016).
The candidate genes COQ2, ATP2B1, and DMPK, representing pathways involved in myocellular energy transfer, calcium homeostasis, and myotonic dystonia, respectively, were validated as markers for the common myalgia observed in patients receiving statin therapy. The three genes integrated into a physiogenomic predictive system could be relevant to myalgia diagnosis and prognosis in clinical practice.
Atherosclerosis 07/2011; 218(2):451-6. · 3.79 Impact Factor
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Omar L Francone,
Brian Y Ishida,
Margarita de la Llera-Moya,
Lori Royer,
Christiane Happe,
Jian Zhu,
Robert J Chalkey,
Peter Schaefer,
Cheryl Cox,
Al Burlingame, John P Kane,
George H Rothblat
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ABSTRACT: Given the increased prevalence of cardiovascular disease in the world, the search for genetic variations that impact risk factors associated with the development of this disease continues. Multiple genetic association studies demonstrate that procollagen C-proteinase enhancer 2 (PCPE2) modulates HDL levels. Recent studies revealed an unexpected role for this protein in the proteolytic processing of pro-apolipoprotein (apo) A-I by enhancing the cleavage of the hexapeptide extension present at the N-terminus of apoA-I. To investigate the role of the PCPE2 protein in an in vivo model, PCPE2-deficient (PCPE2 KO) mice were examined, and a detailed characterization of plasma lipid profiles, apoA-I, HDL speciation, and function was done. Results of isoelectric focusing (IEF) electrophoresis together with the identification of the amino terminal peptides DEPQSQWDK and WHVWQQDEPQSQWDVK, representing mature apoA-I and pro-apoA-I, respectively, in serum from PCPE2 KO mice confirmed that PCPE2 has a role in apoA-I maturation. Lipid profiles showed a marked increase in plasma apoA-I and HDL-cholesterol (HDL-C) levels in PCPE2 KO mice compared with wild-type littermates, regardless of gender or diet. Changes in HDL particle size and electrophoretic mobility observed in PCPE2 KO mice suggest that the presence of pro-apoA-I impairs the maturation of HDL. ABCA1-dependent cholesterol efflux is defective in PCPE2 KO mice, suggesting that the functionality of HDL is altered.
The Journal of Lipid Research 07/2011; 52(11):1974-83. · 5.56 Impact Factor
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Eusebio Chiefari,
Sinan Tanyolaç,
Francesco Paonessa,
Clive R Pullinger,
Carmelo Capula,
Stefania Iiritano,
Tommaso Mazza,
Michele Forlin,
Alfredo Fusco,
Vincent Durlach,
Anne Durlach,
Mary J Malloy, John P Kane,
Steven W Heiner,
Mirella Filocamo,
Daniela P Foti,
Ira D Goldfine,
Antonio Brunetti
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ABSTRACT: High-mobility group A1 (HMGA1) protein is a key regulator of insulin receptor (INSR) gene expression. We previously identified a functional HMGA1 gene variant in 2 insulin-resistant patients with decreased INSR expression and type 2 diabetes mellitus (DM).
To examine the association of HMGA1 gene variants with type 2 DM.
Case-control study that analyzed the HMGA1 gene in patients with type 2 DM and controls from 3 populations of white European ancestry. Italian patients with type 2 DM (n = 3278) and 2 groups of controls (n = 3328) were attending the University of Catanzaro outpatient clinics and other health care sites in Calabria, Italy, during 2003-2009; US patients with type 2 DM (n = 970) were recruited in Northern California clinics between 1994 and 2005 and controls (n = 958) were senior athletes without DM collected in 2004 and 2009; and French patients with type 2 DM (n = 354) and healthy controls (n = 50) were enrolled at the University of Reims in 1992. Genomic DNA was either directly sequenced or analyzed for specific HMGA1 mutations. Messenger RNA and protein expression for HMGA1 and INSR were measured in both peripheral lymphomonocytes and cultured Epstein-Barr virus-transformed lymphoblasts from patients with type 2 DM and controls.
The frequency of HMGA1 gene variants among cases and controls. Odds ratios (ORs) for type 2 DM were estimated by logistic regression analysis.
The most frequent functional HMGA1 variant, IVS5-13insC, was present in 7% to 8% of patients with type 2 DM in all 3 populations. The prevalence of IVS5-13insC variant was higher among patients with type 2 DM than among controls in the Italian population (7.23% vs 0.43% in one control group; OR, 15.77 [95% confidence interval {CI}, 8.57-29.03]; P < .001 and 7.23% vs 3.32% in the other control group; OR, 2.03 [95% CI, 1.51-3.43]; P < .001). In the US population, the prevalence of IVS5-13insC variant was 7.7% among patients with type 2 DM vs 4.7% among controls (OR, 1.64 [95% CI, 1.05-2.57]; P = .03). In the French population, the prevalence of IVS5-13insC variant was 7.6% among patients with type 2 DM and 0% among controls (P = .046). In the Italian population, 3 other functional variants were observed. When all 4 variants were analyzed, HMGA1 defects were present in 9.8% of Italian patients with type 2 DM and 0.6% of controls. In addition to the IVS5 C-insertion, the c.310G>T (p.E104X) variant was found in 14 patients and no controls (Bonferroni-adjusted P = .01); the c.*82G>A variant (rs2780219) was found in 46 patients and 5 controls (Bonferroni-adjusted P < .001); the c.*369del variant was found in 24 patients and no controls (Bonferroni-adjusted P < .001). In circulating monocytes and Epstein-Barr virus-transformed lymphoblasts from patients with type 2 DM and the IVS5-13insC variant, the messenger RNA levels and protein content of both HMGA1 and the INSR were decreased by 40% to 50%, and these defects were corrected by transfection with HMGA1 complementary DNA.
Compared with healthy controls, the presence of functional HMGA1 gene variants in individuals of white European ancestry was associated with type 2 DM.
JAMA The Journal of the American Medical Association 03/2011; 305(9):903-12. · 30.03 Impact Factor
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Jeffrey L Waugh,
Jeremy Celver,
Meenakshi Sharma,
Robert L Dufresne,
Dimitra Terzi,
S Craig Risch,
William G Fairbrother,
Rachael L Neve, John P Kane,
Mary J Malloy,
Clive R Pullinger,
Harvest F Gu,
Christos Tsatsanis,
Steven P Hamilton,
Stephen J Gold,
Venetia Zachariou,
Abraham Kovoor
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ABSTRACT: Regulator of G protein signaling 9-2 (RGS9-2) is a protein that is highly enriched in the striatum, a brain region that mediates motivation, movement and reward responses. We identified a naturally occurring 5 nucleotide deletion polymorphism in the human RGS9 gene and found that the mean body mass index (BMI) of individuals with the deletion was significantly higher than those without. A splicing reporter minigene assay demonstrated that the deletion had the potential to significantly decrease the levels of correctly spliced RGS9 gene product. We measured the weights of rats after virally transduced overexpression of RGS9-2 or the structurally related RGS proteins, RGS7, or RGS11, in the nucleus accumbens (NAc) and observed a reduction in body weight after overexpression of RGS9-2 but not RGS7 or 11. Conversely, we found that the RGS9 knockout mice were heavier than their wild-type littermates and had significantly higher percentages of abdominal fat. The constituent adipocytes were found to have a mean cross-sectional area that was more than double that of corresponding cells from wild-type mice. However, food intake and locomotion were not significantly different between the two strains. These studies with humans, rats and mice implicate RGS9-2 as a factor in regulating body weight.
PLoS ONE 01/2011; 6(11):e27984. · 4.09 Impact Factor
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Lei Zhang,
James Song,
Giorgio Cavigiolio,
Brian Y Ishida,
Shengli Zhang, John P Kane,
Karl H Weisgraber,
Michael N Oda,
Kerry-Anne Rye,
Henry J Pownall,
Gang Ren
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ABSTRACT: Plasma lipoprotein levels are predictors of risk for coronary artery disease. Lipoprotein structure-function relationships provide important clues that help identify the role of lipoproteins in cardiovascular disease. The compositional and conformational heterogeneity of lipoproteins are major barriers to the identification of their structures, as discovered using traditional approaches. Although electron microscopy (EM) is an alternative approach, conventional negative staining (NS) produces rouleau artifacts. In a previous study of apolipoprotein (apo)E4-containing reconstituted HDL (rHDL) particles, we optimized the NS method in a way that eliminated rouleaux. Here we report that phosphotungstic acid at high buffer salt concentrations plays a key role in rouleau formation. We also validate our protocol for analyzing the major plasma lipoprotein classes HDL, LDL, IDL, and VLDL, as well as homogeneously prepared apoA-I-containing rHDL. High-contrast EM images revealed morphology and detailed structures of lipoproteins, especially apoA-I-containing rHDL, that are amenable to three-dimensional reconstruction by single-particle analysis and electron tomography.
The Journal of Lipid Research 10/2010; 52(1):175-84. · 5.56 Impact Factor
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ABSTRACT: LPA encodes apolipoprotein(a), and a CCTC haplotype in the LPA locus is associated with CHD. The 4399Met variant (rs3798220) of LPA has a risk estimate for CHD similar to that of the CCTC haplotype. We asked whether co-incidence with the 4399Met variant explained the association of the haplotype with CHD.
We stratified by the 4399Met variant and another LPA SNP (rs10455872) associated with CHD and tested the association between CHD and 4 SNPs that define two haplotypes associated with CHD: CCTC and CTTG.
For CCTC, in the presence of the rs3798220 risk allele the OR was 1.68 (95% CI: 1.05-2.68, P=0.03) versus 0.30 (95% CI: 0.06-1.59, P=0.16) with the non-risk allele. For CTTG, in the presence of the rs10455872 risk allele the OR was 1.57 (95% CI: 1.15-2.13, P=0.004) versus 1.04 (95% CI: 0.79-1.35, P=0.77) with the non-risk allele.
The rs3798220 and rs10455872 SNPs explain the association of the CCTC and CTTG haplotypes with CHD.
Atherosclerosis 09/2010; 212(1):193-6. · 3.79 Impact Factor
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ABSTRACT: Administered at maximal dosages, the most common statins--atorvastatin, simvastatin and rosuvastatin--lower low-density lipoprotein cholesterol (LDLC) by an average of 37-57% in patients with primary hypercholesterolemia. We hypothesized novel genetic underpinnings for variation in LDLC levels in the context of statin therapy.
Genotyping of 384 SNPs in 202 volunteers from a lipid outpatient clinic was accomplished and LDLC levels obtained from chart records. The SNPs were distributed across 222 genes representing physiological pathways such as general metabolism, cholesterol biochemistry, cardiovascular function, inflammation, neurobiology and cell proliferation. We discovered significant associations with LDLC levels for the rs34274 SNP (p < 0.0002) and for rs2241220 (p < 0.008) in the acetyl-coenzyme A carboxylase beta (ACACB) gene. When corrected for multiple testing, the false-discovery rate associated with rs34274 was 0.076 (significance threshold: 0.10) and for rs2241220 the false-discovery rate was 0.93 (not significant). The acetyl coenzyme A carboxylase beta enzyme synthesizes malonyl coenzyme A, an essential substrate for hepatic fatty acid synthesis and an inhibitor of fatty acid oxidation.
The SNPs were in weak linkage disequilibrium (D = 0.302). Minor alleles at these sites demonstrate opposing influences on LDLC; the C>T substitution at rs34724 is a risk marker and the C>T substitution at rs2241220 a protective marker for LDLC levels. These SNPs hypothetically influence enzymatic activity through different mechanisms, rs34274 through the PII promoter and rs2241220 via alteration of the protein's responsiveness to allosteric influence.
Physiogenomic evidence suggests a novel link between LDLC levels and the regulation of fatty acid metabolism. The findings complement previously discovered novel SNP relationships to myalgia (pain) and myositis (serum creatine kinase activity). By genotyping for myositis, myalgia and LDLC levels, a physiogenomic model may be developed to help clinicians maximize effectiveness and minimize side effects in prescribing statins.
Pharmacogenomics 07/2010; 11(7):959-71. · 3.97 Impact Factor
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ABSTRACT: Metabolic syndrome is a combination of risk factors for cardiovascular disease and diabetes, It has been reported to be increased in human immunodeficiency virus (HIV)-infected individuals.
In a cohort of HIV-infected adults we examined parameters that contribute to defining the metabolic syndrome and to estimating the 10-year risk of coronary heart disease (CHD). The study group consisted of 296 participants (217 men and 79 women) of mixed ethnicity with a mean age of 45.3 years.
There was an appreciable prevalence of metabolic syndrome (30.0%), with the frequency increasing to 42.5% in those over 50 years of age. Those with the metabolic syndrome had a lower viral load. More women had abdominal obesity (59.5%) than men (20.7%, P < 0.001). The frequency of elevated plasma glucose was higher in females (37.2%) compared to males (16.9%, P = 0.004). High frequencies of decreased high-density lipoprotein cholesterol (HDL-C) and elevated blood pressure were seen in both sexes. Hypertriglyceridemia was less prevalent in African Americans. In those under 50 years of age, the 10-year CHD risk score for men was double that for women (6.2% vs 2.7%, P < 0.001). In older participants, the risk was similar between the sexes, with a third having scores over 10%.
The prevalence of metabolic syndrome was higher than in most other HIV cohorts. Those with the syndrome had significantly lower viral loads. Mean 10-year Framingham Cardiovascular Risk (FCR) scores were nearly doubled for those with metabolic syndrome. Both researchers and clinicians should consider age as well as sex when assessing patients with HIV infection for risks associated with metabolic syndrome.
Metabolic syndrome and related disorders 03/2010; 8(3):279-86.
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ABSTRACT: Preβ-1 high-density lipoprotein (HDL) is an acceptor of peripheral free cholesterol and thus a participant in reverse cholesterol transport. Because patients with diabetes may have defects in reverse cholesterol transport, we hypothesized that (1) preβ-1 HDL might be decreased in diabetes and (2) because niacin improves reverse cholesterol transport and may stimulate preβ-1 HDL maturation, niacin would further decrease steady-state levels of preβ-1 HDL in diabetes. Absolute levels of preβ-1 HDL mass were measured using an isotopic dilution-ultrafiltration assay that measures apolipoprotein (apo) A-I after physically isolating preβ-1. Plasma apo A-I concentration and routine lipids were also evaluated in 11 diabetic patients. Diabetic subjects have a nearly 50% reduction of circulating levels of preβ-1 HDL to 36 ± 22 (1 SD) μg/mL compared with our previously published values of 73 ± 44 μg/mL in 136 healthy subjects. After niacin therapy, there was a further 17% reduction of preβ-1 HDL levels to 30 ± 26 μg/mL (P < .026) compared with baseline. The percentage of preβ-1 HDL in diabetic patients, as a percentage of total apo A-I, was about half of the normal value of 6.1% ± 3.6%; after niacin in diabetic patients, the percentage further decreased from 3.3% ± 2.1% to 2.3% ± 1.9% (P < .003). Absolute levels of apo A-I were similar in diabetic patients (1.14 ± 0.29) and healthy subjects (1.24 ± 0.24), and were unchanged by niacin in diabetic patients. We conclude with the novel observations that diabetes is associated with significantly reduced levels of preβ-1 HDL and that, after niacin treatment, a further lowering of preβ-1 HDL levels occur. Several altered mechanisms of RCT in diabetes are consistent with low levels of preβ-1 HDL both before and after niacin treatment.
Metabolism: clinical and experimental 03/2010; 60(2):292-7. · 2.59 Impact Factor
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ABSTRACT: The LPA I4399M (rs3798220) single nucleotide polymorphism (SNP) is associated with increased plasma levels of Lp(a) and advanced coronary artery disease (CAD). We hypothesized that carriers of the Met allele of the I4399M SNP would also have elevated levels of oxidized phospholipids (OxPL) on apoB (OxPL/apoB) particles.
Plasma levels of Lp(a) and OxPL/apoB were measured in non-carriers (TT genotype, n=116) and carriers (CT/CC genotype, n=58) of the I4399M SNP. Carriers had significantly higher Lp(a) levels [median (interquartile range, IQR)] [43 (9-57)mg/dl vs. 5.5 (2-20)mg/dl, p<0.0001] and smaller apolipoprotein(a) isoforms than non-carriers (number of kringle IV repeats: 18(17-20) vs. 22(18-25), p=0.002). Median (IQR) OxPL/apoB levels were significantly higher in carriers than non-carriers [8019 (6254-31,785) relative light units (RLU) vs. 2168 (1303-5869), p<0.0001]. Patients with small apolipoprotein(a) isoforms had the highest OxPL/apoB levels. The number of kringle IV repeats was inversely related to Lp(a) (r=-0.43, p<0.001) and OxPL/apoB (r=-0.36, p<0.0001) levels.
The CT and CC genotypes of the I4399M SNP in the LPA gene are associated with elevated OxPL/apoB levels, which primarily represent OxPL on Lp(a). The concomitant increase of OxPL/apoB levels in the setting of small apolipoprotein(a) isoforms may potentiate the atherogenic effect on CAD of elevated Lp(a) levels in carriers of the I4399M SNP.
Atherosclerosis 10/2009; 209(2):498-503. · 3.79 Impact Factor
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ABSTRACT: High-density lipoprotein (HDL) appears to be the dominant lipoprotein particle in human follicular fluid (FF). The reported anti-atherogenic properties of HDL have been attributed in part to reverse cholesterol transport. The discoveries of the scavenger receptor class B type I (SR-BI) and the ATP-binding cassette A1 lipid (ABCA1) transporter have generated studies aimed at unraveling the pathways of HDL biogenesis, remodeling and catabolism. The production of SR-BI and ABCA1 knockout mice as well as other lipoprotein metabolism-associated mutants has resulted in reduced or absent fertility, leading us to postulate the existence of a human hepatic-ovarian HDL-associated axis of fertility. Here, we review an evolving literature on the role of HDL metabolism on mammalian fertility and oocyte development.
An extensive online search was conducted of published articles relevant to the section topics discussed. All relevant English language articles contained in Pubmed/Medline, with no specific time frame for publication, were considered for this narrative review. Cardiovascular literature was highly cited due to the wealth of relevant knowledge on HDL metabolism, and the dearth thereof in the reproductive field.
Various vertebrate models demonstrate a role for HDL in embryo development and fertility. In our clinical studies, FF levels of HDL cholesterol and apolipoprotein AI levels were negatively associated with embryo fragmentation, but not with embryo cell cleavage rate. However, the HDL component, paraoxonase 1 arylesterase activity, was positively associated with embryo cell cleavage rate.
HDL contributes to intra-follicular cholesterol homeostasis which appears to be important for successful oocyte and embryo development.
Human Reproduction Update 09/2009; 16(1):20-38. · 9.23 Impact Factor
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ABSTRACT: Hypertriglyceridemia is associated with insulin resistance, type 2 diabetes, and the metabolic syndrome. Membrane glycoprotein PC-1 (also termed ENPP1) is a direct insulin receptor inhibitor, and certain polymorphisms of the ENPP1/PC-1 gene have been associated with insulin resistance, type 2 diabetes, obesity, and diabetic complications.
We examined the effect of 3 ENPP1/PC-1 variants (K121Q, rs1044498, and IVS20delT-11, rs1799774, and A-->G+1044TGA, rs7754561) on plasma triglyceride levels in 1112 subjects of non-Hispanic American white European ancestry.
Two of the ENPP1/PC-1 variants--A-->G+1044TGA (odds ratio [OR] 1.48, 95% confidence interval [CI], 1.54-1.82, P = 0.002) and IVS20delT-11 (OR 1.41, 95% CI, 1.08-1.84, P = 0.012)--were significantly associated with hypertriglyceridemia. Haplotype analyses also revealed an association with hypertriglyceridemia. In the variant analyses and in the haplotype analysis, the associations with hypertriglyceridemia were observed in male but not female subjects. Interestingly, the more widely studied K121Q ENPP1/PC-1 variant was not associated with hypertriglyceridemia in any group or subgroup analysis.
In the present study, we find that genetic variants of the ENPP1/PC-1 gene are associated with hypertriglyceridemia in male subjects, and may contribute to the development of the insulin resistance/metabolic syndrome in this population.
Metabolic syndrome and related disorders 08/2009; 7(6):543-8.
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Guadalupe Ortiz-Muñoz,
Xavier Houard,
Jose-Luis Martín-Ventura,
Brian Y Ishida,
Stéphane Loyau,
Patrick Rossignol,
Juan-Antonio Moreno, John P Kane,
Robert J Chalkley,
Alma L Burlingame,
Jean-Baptiste Michel,
Olivier Meilhac
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ABSTRACT: Various studies using proteomic approaches have shown that HDL can carry many proteins other than its constitutive apolipoprotein A-I (apoA-I). Using mass spectrometry and Western blotting, we showed the presence of alpha(1)-antitrypsin (AAT) (SERPINA1, serpin peptidase inhibitor, clade A, an elastase inhibitor) in HDL, isolated either by ultracentrifugation or by selected-affinity immunosorption using an anti-apoA-I column. Furthermore, we report that HDL possesses potent antielastase activity. We further showed that only HDL but not LDL is able to bind AAT. HDL-associated AAT was able to inhibit extracellular matrix degradation, cell detachment, and apoptosis induced by elastase in human vascular smooth muscle cells (VSMCs) and in mammary artery cultured ex vivo. Degradation of fibronectin by elastase used as a marker of pericellular proteolysis was prevented by addition of HDL. Elastase present in aortic abdominal aneurysm (AAA) thrombus samples was also able to induce apoptosis of VSMCs in culture. This phenomenon was prevented by addition of HDL but not of LDL. Finally, we report that the proportion of AAT in HDL isolated from patients with an AAA is decreased relative to that from matched control subjects, suggesting a reduced capacity of HDL to inhibit elastase in these patients. In conclusion, our data provide evidence of a new potential antiatherogenic property of HDL attributable to AAT and its antielastase activity.
The FASEB Journal 06/2009; 23(9):3129-39. · 5.71 Impact Factor
