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Meta-analysis of genome-wide association studies of HDL cholesterol response to statins.
Postmus I, Warren HR, Trompet S, Arsenault BJ, Avery CL, Bis JC, Chasman DI, de Keyser CE, Deshmukh HA, Evans DS, Feng Q, Li X, Smit RA, Smith AV, Sun F, Taylor KD, Arnold AM, Barnes MR, Barratt BJ, Betteridge J, Boekholdt SM, Boerwinkle E, Buckley BM, Chen YI, de Craen AJ, Cummings SR, Denny JC, Dubé MP, Durrington PN, Eiriksdottir G, Ford I, Guo X, Harris TB, Heckbert SR, Hofman A, Hovingh GK, Kastelein JJ, Launer LJ, Liu CT, Liu Y, Lumley T, McKeigue PM, Munroe PB, Neil A, Nickerson DA, Nyberg F, O'Brien E, O'Donnell CJ, Post W, Poulter N, Vasan RS, Rice K, Rich SS, Rivadeneira F, Sattar N, Sever P, Shaw-Hawkins S, Shields DC, Slagboom PE, Smith NL, Smith JD, Sotoodehnia N, Stanton A, Stott DJ, Stricker BH, Stürmer T, Uitterlinden AG, Wei WQ, Westendorp RG, Whitsel EA, Wiggins KL, Wilke RA, Ballantyne CM, Colhoun HM, Cupples LA, Franco OH, Gudnason V, Hitman G, Palmer CN, Psaty BM, Ridker PM, Stafford JM, Stein CM, Tardif JC, Caulfield MJ, Jukema JW, Rotter JI, Krauss RM
(2016) J Med Genet 53: 835-845
MeSH Terms: Cholesterol Ester Transfer Proteins, Cholesterol, HDL, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Male, Pharmacogenomic Variants, Polymorphism, Single Nucleotide, Treatment Outcome
Show Abstract · Added March 14, 2018
BACKGROUND - In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.
METHODS AND RESULTS - We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1×10 from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5×10) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment.
CONCLUSIONS - Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
0 Communities
1 Members
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11 MeSH Terms
CETP Expression Protects Female Mice from Obesity-Induced Decline in Exercise Capacity.
Cappel DA, Lantier L, Palmisano BT, Wasserman DH, Stafford JM
(2015) PLoS One 10: e0136915
MeSH Terms: Animals, Cholesterol Ester Transfer Proteins, Diet, High-Fat, Female, Gene Expression Regulation, Glutamic Acid, Humans, Malates, Mice, Mitochondria, Muscle, Obesity, Oxidation-Reduction, Physical Conditioning, Animal
Show Abstract · Added September 28, 2015
Pharmacological approaches to reduce obesity have not resulted in dramatic reductions in the risk of coronary heart disease (CHD). Exercise, in contrast, reduces CHD risk even in the setting of obesity. Cholesteryl Ester Transfer Protein (CETP) is a lipid transfer protein that shuttles lipids between serum lipoproteins and tissues. There are sexual-dimorphisms in the effects of CETP in humans. Mice naturally lack CETP, but we previously reported that transgenic expression of CETP increases muscle glycolysis in fasting and protects against insulin resistance with high-fat diet (HFD) feeding in female but not male mice. Since glycolysis provides an important energy source for working muscle, we aimed to define if CETP expression protects against the decline in exercise capacity associated with obesity. We measured exercise capacity in female mice that were fed a chow diet and then switched to a HFD. There was no difference in exercise capacity between lean, chow-fed CETP female mice and their non-transgenic littermates. Female CETP transgenic mice were relatively protected against the decline in exercise capacity caused by obesity compared to WT. Despite gaining similar fat mass after 6 weeks of HFD-feeding, female CETP mice showed a nearly two-fold increase in run distance compared to WT. After an additional 6 weeks of HFD-feeding, mice were subjected to a final exercise bout and muscle mitochondria were isolated. We found that improved exercise capacity in CETP mice corresponded with increased muscle mitochondrial oxidative capacity, and increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). These results suggest that CETP can protect against the obesity-induced impairment in exercise capacity and may be a target to improve exercise capacity in the context of obesity.
1 Communities
4 Members
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13 MeSH Terms
Genome-wide family-based linkage analysis of exome chip variants and cardiometabolic risk.
Hellwege JN, Palmer ND, Raffield LM, Ng MC, Hawkins GA, Long J, Lorenzo C, Norris JM, Ida Chen YD, Speliotes EK, Rotter JI, Langefeld CD, Wagenknecht LE, Bowden DW
(2014) Genet Epidemiol 38: 345-52
MeSH Terms: Adolescent, Adult, African Americans, Aged, Aged, 80 and over, Apolipoproteins, Atherosclerosis, Cholesterol Ester Transfer Proteins, Exome, Female, Genetic Linkage, Genetic Predisposition to Disease, Genome-Wide Association Study, Hispanic Americans, Humans, Insulin Resistance, Lipoproteins, HDL, Lod Score, Male, Middle Aged, Oligonucleotide Array Sequence Analysis, Phenotype, Polymorphism, Single Nucleotide, Young Adult
Show Abstract · Added September 15, 2015
Linkage analysis of complex traits has had limited success in identifying trait-influencing loci. Recently, coding variants have been implicated as the basis for some biomedical associations. We tested whether coding variants are the basis for linkage peaks of complex traits in 42 African-American (n = 596) and 90 Hispanic (n = 1,414) families in the Insulin Resistance Atherosclerosis Family Study (IRASFS) using Illumina HumanExome Beadchips. A total of 92,157 variants in African Americans (34%) and 81,559 (31%) in Hispanics were polymorphic and tested using two-point linkage and association analyses with 37 cardiometabolic phenotypes. In African Americans 77 LOD scores greater than 3 were observed. The highest LOD score was 4.91 with the APOE SNP rs7412 (MAF = 0.13) with plasma apolipoprotein B (ApoB). This SNP was associated with ApoB (P-value = 4 × 10(-19)) and accounted for 16.2% of the variance in African Americans. In Hispanic families, 104 LOD scores were greater than 3. The strongest evidence of linkage (LOD = 4.29) was with rs5882 (MAF = 0.46) in CETP with HDL. CETP variants were strongly associated with HDL (0.00049 < P-value <4.6 × 10(-12)), accounting for up to 4.5% of the variance. These loci have previously been shown to have effects on the biomedical traits evaluated here. Thus, evidence of strong linkage in this genome wide survey of primarily coding variants was uncommon. Loci with strong evidence of linkage was characterized by large contributions to the variance, and, in these cases, are common variants. Less compelling evidence of linkage and association was observed with additional loci that may require larger family sets to confirm.
© 2014 WILEY PERIODICALS, INC.
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1 Members
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24 MeSH Terms
Killing two birds with one stone, maybe: CETP inhibition increases both high-density lipoprotein levels and insulin secretion.
Fazio S, Linton MF
(2013) Circ Res 113: 94-6
MeSH Terms: Animals, Cholesterol Ester Transfer Proteins, Cholesterol, HDL, Humans, Insulin, Insulin Secretion, Male
Added May 27, 2014
0 Communities
1 Members
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7 MeSH Terms
Evaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study.
Buyske S, Wu Y, Carty CL, Cheng I, Assimes TL, Dumitrescu L, Hindorff LA, Mitchell S, Ambite JL, Boerwinkle E, Buzkova P, Carlson CS, Cochran B, Duggan D, Eaton CB, Fesinmeyer MD, Franceschini N, Haessler J, Jenny N, Kang HM, Kooperberg C, Lin Y, Le Marchand L, Matise TC, Robinson JG, Rodriguez C, Schumacher FR, Voight BF, Young A, Manolio TA, Mohlke KL, Haiman CA, Peters U, Crawford DC, North KE
(2012) PLoS One 7: e35651
MeSH Terms: African Americans, Cardiovascular Diseases, Cholesterol Ester Transfer Proteins, Cholesterol, HDL, Cholesterol, LDL, Chromosomes, Human, Cohort Studies, Gene Frequency, Genome-Wide Association Study, Genotype, Humans, Metabolic Diseases, Polymorphism, Single Nucleotide, Quantitative Trait Loci
Show Abstract · Added December 10, 2013
The Metabochip is a custom genotyping array designed for replication and fine mapping of metabolic, cardiovascular, and anthropometric trait loci and includes low frequency variation content identified from the 1000 Genomes Project. It has 196,725 SNPs concentrated in 257 genomic regions. We evaluated the Metabochip in 5,863 African Americans; 89% of all SNPs passed rigorous quality control with a call rate of 99.9%. Two examples illustrate the value of fine mapping with the Metabochip in African-ancestry populations. At CELSR2/PSRC1/SORT1, we found the strongest associated SNP for LDL-C to be rs12740374 (p = 3.5 × 10(-11)), a SNP indistinguishable from multiple SNPs in European ancestry samples due to high correlation. Its distinct signal supports functional studies elsewhere suggesting a causal role in LDL-C. At CETP we found rs17231520, with risk allele frequency 0.07 in African Americans, to be associated with HDL-C (p = 7.2 × 10(-36)). This variant is very rare in Europeans and not tagged in common GWAS arrays, but was identified as associated with HDL-C in African Americans in a single-gene study. Our results, one narrowing the risk interval and the other revealing an associated variant not found in Europeans, demonstrate the advantages of high-density genotyping of common and rare variation for fine mapping of trait loci in African American samples.
0 Communities
1 Members
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14 MeSH Terms
Obesity and altered glucose metabolism impact HDL composition in CETP transgenic mice: a role for ovarian hormones.
Martinez MN, Emfinger CH, Overton M, Hill S, Ramaswamy TS, Cappel DA, Wu K, Fazio S, McDonald WH, Hachey DL, Tabb DL, Stafford JM
(2012) J Lipid Res 53: 379-89
MeSH Terms: Animals, Apolipoprotein C-II, Apolipoproteins A, Blotting, Western, Cholesterol, Cholesterol Ester Transfer Proteins, Chromatography, High Pressure Liquid, Computational Biology, Diet, High-Fat, Female, Hyperinsulinism, Insulin, Lipoproteins, HDL, Lipoproteins, VLDL, Mice, Mice, Transgenic, Obesity, Ovariectomy, Triglycerides, Weight Gain
Show Abstract · Added December 10, 2013
Mechanisms underlying changes in HDL composition caused by obesity are poorly defined, partly because mice lack expression of cholesteryl ester transfer protein (CETP), which shuttles triglyceride and cholesteryl ester between lipoproteins. Because menopause is associated with weight gain, altered glucose metabolism, and changes in HDL, we tested the effect of feeding a high-fat diet (HFD) and ovariectomy (OVX) on glucose metabolism and HDL composition in CETP transgenic mice. After OVX, female CETP-expressing mice had accelerated weight gain with HFD-feeding and impaired glucose tolerance by hyperglycemic clamp techniques, compared with OVX mice fed a low-fat diet (LFD). Sham-operated mice (SHAM) did not show HFD-induced weight gain and had less glucose intolerance than OVX mice. Using shotgun HDL proteomics, HFD-feeding in OVX mice had a large effect on HDL composition, including increased levels of apoA2, apoA4, apoC2, and apoC3, proteins involved in TG metabolism. These changes were associated with decreased hepatic expression of SR-B1, ABCA1, and LDL receptor, proteins involved in modulating the lipid content of HDL. In SHAM mice, there were minimal changes in HDL composition with HFD feeding. These studies suggest that the absence of ovarian hormones negatively influences the response to high-fat feeding in terms of glucose tolerance and HDL composition. CETP-expressing mice may represent a useful model to define how metabolic changes affect HDL composition and function.
1 Communities
5 Members
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20 MeSH Terms
High-density lipoprotein therapeutics and cardiovascular prevention.
Fazio S, Linton MF
(2010) J Clin Lipidol 4: 411-9
MeSH Terms: Apolipoprotein A-I, Cardiovascular Diseases, Cholesterol Ester Transfer Proteins, Cholesterol, HDL, Clinical Trials as Topic, Humans, Lipoproteins, HDL, Probucol
Show Abstract · Added December 10, 2013
The field of cardiovascular prevention has long anticipated the evolution of high-density lipoprotein (HDL) therapy from unproven metabolic tweaking to pillar of risk reduction on par with low-density lipoprotein control. However, the convincing epidemiologic data linking HDL cholesterol (HDL-C) and cardiovascular disease risk in an inverse correlation has not yet translated into clinical trial evidence supporting linearity between HDL-C increases and risk reduction, or identifying obvious goals of therapy. Although HDL-C-increasing lifestyle maneuvers and established HDL drugs such as niacin and fibrates are likely to protect the vasculature, the negative results obtained in trials of a cholesteryl ester transfer protein inhibitor remind us that HDL-C increases are not always beneficial. It is becoming clear that a functional HDL is a more desirable target than simply increasing HDL-C levels. The larger objective of improving HDL functionality (with or without HDL-C level changes) is bound to become the guiding principle for pharmaceutical research in this area. Several new compounds currently being tested bridge the classical aim of increasing HDL-C levels with the novel target of improving HDL function.
Copyright © 2010 National Lipid Association. Published by Elsevier Inc. All rights reserved.
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2 Members
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8 MeSH Terms
The effect of a novel intergenic polymorphism (rs11774572) on HDL-cholesterol concentrations depends on TaqIB polymorphism in the cholesterol ester transfer protein gene.
Junyent M, Lee YC, Smith CE, Arnett DK, Tsai MY, Kabagambe EK, Straka RJ, Province M, An P, Lai CQ, Parnell LD, Shen J, Borecki I, Ordovas JM
(2010) Nutr Metab Cardiovasc Dis 20: 34-40
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Cholesterol Ester Transfer Proteins, Cholesterol, HDL, Chromosomes, Human, Pair 8, DNA, Intergenic, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Hypertriglyceridemia, Insulin Resistance, Linkage Disequilibrium, Lipoproteins, Male, Metabolic Syndrome, Middle Aged, Particle Size, Polymorphism, Single Nucleotide, United States, Young Adult
Show Abstract · Added April 24, 2015
BACKGROUND AND AIMS - Several genes have been shown to individually affect plasma lipoprotein metabolism in humans. Studies on gene-gene interactions could offer more insight into how genes affect lipid metabolism and may be useful in predicting lipid concentrations. We tested for gene-gene interactions between TaqIB SNP in the cholesterol ester transfer protein (CETP) and three novel single nucleotide polymorphisms (SNPs), namely rs11774572, rs7819412 and rs6995374 for their effect on metabolic syndrome (MetS) components and related traits.
METHODS AND RESULTS - The aforementioned SNPs were genotyped in 1002 subjects who participated in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study. Lipids were measured by standard procedures and lipoprotein subfractions, by proton nuclear magnetic resonance spectroscopy. Polymorphism rs11774572 was significantly associated with MetS (P=0.020), mainly driven by the association of the C allele with lower HDL-C (P=0.043) and higher triglycerides (P=0.049) and insulin (P=0.040) concentrations than TT subjects. A significant interaction between SNPs rs11774572 and CETP-TaqIB SNPs was found for HDL-C concentrations (P=0.006) and for HDL (P=0.008) and LDL particle sizes (P=0.009), small LDL (P=0.004), and VLDL concentrations (P=0.021), in which TT homozygotes displayed higher HDL-C concentrations and for HDL and LDL particle sizes, and lower small LDL and VLDL concentrations than C carriers, if they were CETP B2 allele carriers (P values ranging from <0.001 to 0.001).
CONCLUSIONS - The rs11774572 polymorphism may play a role in the dyslipidemia that characterizes MetS. The interaction between rs11774572 and CETP-TaqIB SNPs on HDL-C concentrations provides some insights into the underlying mechanisms.
Copyright 2009 Elsevier B.V. All rights reserved.
0 Communities
1 Members
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23 MeSH Terms
Sorting out the complexities of reverse cholesterol transport: CETP polymorphisms, HDL, and coronary disease.
Fazio S, Linton MF
(2006) J Clin Endocrinol Metab 91: 3273-5
MeSH Terms: Cardiovascular Diseases, Carrier Proteins, Cholesterol Ester Transfer Proteins, Cholesterol, HDL, Glycoproteins, Humans, Polymorphism, Single Nucleotide
Added May 27, 2014
0 Communities
1 Members
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7 MeSH Terms
Unique pathway for cholesterol uptake in fat cells.
Fazio S, Linton MF
(2004) Arterioscler Thromb Vasc Biol 24: 1538-9
MeSH Terms: Adipocytes, Animals, Apolipoproteins E, Biological Transport, Carrier Proteins, Cholesterol, Cholesterol Ester Transfer Proteins, Cholesterol Esters, Cholesterol, HDL, Glycoproteins, Humans, Low Density Lipoprotein Receptor-Related Protein-1, Models, Biological, Organ Specificity, Receptors, Immunologic, Receptors, Scavenger
Added May 27, 2014
0 Communities
1 Members
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16 MeSH Terms