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Genetic variants influencing circulating lipid levels and risk of coronary artery disease.

ABSTRACT: Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides.We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6×10(-8) to 3.1×10(-10)). These include a potentially functional SNP in the SLC39A8 gene for HDL-C, an SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-C, and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (probability values, 1.1×10(-3) to 1.2×10(-9)).We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.

SUBMITTER: Waterworth DM

PROVIDER: S-EPMC3891568 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Genetic variants influencing circulating lipid levels and risk of coronary artery disease.

Waterworth Dawn M DM Ricketts Sally L SL Song Kijoung K Chen Li L Zhao Jing Hua JH Ripatti Samuli S Aulchenko Yurii S YS Zhang Weihua W Yuan Xin X Lim Noha N Luan Jian'an J Ashford Sofie S Wheeler Eleanor E Young Elizabeth H EH Hadley David D Thompson John R JR Braund Peter S PS Johnson Toby T Struchalin Maksim M Surakka Ida I Luben Robert R Khaw Kay-Tee KT Rodwell Sheila A SA Loos Ruth J F RJ Boekholdt S Matthijs SM Inouye Michael M Deloukas Panagiotis P Elliott Paul P Schlessinger David D Sanna Serena S Scuteri Angelo A Jackson Anne A Mohlke Karen L KL Tuomilehto Jaako J Roberts Robert R Stewart Alexandre A Kesäniemi Y Antero YA Mahley Robert W RW Grundy Scott M SM McArdle Wendy W Cardon Lon L Waeber Gérard G Vollenweider Peter P Chambers John C JC Boehnke Michael M Abecasis Gonçalo R GR Salomaa Veikko V Järvelin Marjo-Riitta MR Ruokonen Aimo A Barroso Inês I Epstein Stephen E SE Hakonarson Hakon H HH Rader Daniel J DJ Reilly Muredach P MP Witteman Jacqueline C M JC Hall Alistair S AS Samani Nilesh J NJ Strachan David P DP Barter Philip P van Duijn Cornelia M CM Kooner Jaspal S JS Peltonen Leena L Wareham Nicholas J NJ McPherson Ruth R Mooser Vincent V Sandhu Manjinder S MS

Arteriosclerosis, thrombosis, and vascular biology 20100923 11

<h4>Objective</h4>Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides.<h4>Methods and results</h4>We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lip ...[more]

PMID: 20864672

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Project description:Romosozumab is a newly available treatment for osteoporosis acting by sclerostin inhibition. Its cardiovascular safety has been questioned after finding excess cardiovascular disease (CVD)-related events in a pivotal phase 3 trial. Previous studies of relationships between circulating sclerostin levels and CVD and associated risk factors have yielded conflicting findings, likely reflecting small numbers and selected patient groups. We aimed to characterize relationships between sclerostin and CVD and related risk factors in more detail by examining these in two large cohorts, Ludwigshafen Risk and Cardiovascular Health study (LURIC; 34% female, mean age 63.0 years) and Avon Longitudinal Study of Parents and Children study (ALSPAC) mothers (mean age 48.1 years). Together these provided 5069 participants with complete data. Relationships between sclerostin and CVD risk factors were meta-analyzed, adjusted for age, sex (LURIC), body mass index, smoking, social deprivation, and ethnicity (ALSPAC). Higher sclerostin levels were associated with higher risk of diabetes mellitus (DM) (odds ratio [OR] = 1.25; 95% confidence interval [CI] 1.12, 1.37), risk of elevated fasting glucose (OR 1.15; CI 1.04, 1.26), and triglyceride levels (β 0.03; CI 0.00, 0.06). Conversely, higher sclerostin was associated with lower estimated glomerular filtration rate (eGFR) (β -0.20; CI -0.38, -0.02), HDL cholesterol (β -0.05; CI -0.10, -0.01), and apolipoprotein A-I (β -0.05; CI -0.08, -0.02) (difference in mean SD per SD increase in sclerostin, with 95% CI). In LURIC, higher sclerostin was associated with an increased risk of death from cardiac disease during follow-up (hazard ratio [HR] = 1.13; 1.03, 1.23) and with severity of coronary artery disease on angiogram as reflected by Friesinger score (0.05; 0.01, 0.09). Associations with cardiac mortality and coronary artery severity were partially attenuated after adjustment for risk factors potentially related to sclerostin, namely LDL and HDL cholesterol, log triglycerides, DM, hypertension, eGFR, and apolipoprotein A-I. Contrary to trial evidence suggesting sclerostin inhibition leads to an increased risk of CVD, sclerostin levels appear to be positively associated with coronary artery disease severity and mortality, partly explained by a relationship between higher sclerostin levels and major CVD risk factors. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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Genetic variants influencing circulating lipid levels and risk of coronary artery disease.

Publications

Genetic variants influencing circulating lipid levels and risk of coronary artery disease.

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