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. 2010 Nov;30(11):2264-76.
doi: 10.1161/ATVBAHA.109.201020. Epub 2010 Sep 23.

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

Dawn M Waterworth  1 , Sally L Ricketts, Kijoung Song, Li Chen, Jing Hua Zhao, Samuli Ripatti, Yurii S Aulchenko, Weihua Zhang, Xin Yuan, Noha Lim, Jian'an Luan, Sofie Ashford, Eleanor Wheeler, Elizabeth H Young, David Hadley, John R Thompson, Peter S Braund, Toby Johnson, Maksim Struchalin, Ida Surakka, Robert Luben, Kay-Tee Khaw, Sheila A Rodwell, Ruth J F Loos, S Matthijs Boekholdt, Michael Inouye, Panagiotis Deloukas, Paul Elliott, David Schlessinger, Serena Sanna, Angelo Scuteri, Anne Jackson, Karen L Mohlke, Jaako Tuomilehto, Robert Roberts, Alexandre Stewart, Y Antero Kesäniemi, Robert W Mahley, Scott M Grundy; Wellcome Trust Case Control Consortium; Wendy McArdle, Lon Cardon, Gérard Waeber, Peter Vollenweider, John C Chambers, Michael Boehnke, Gonçalo R Abecasis, Veikko Salomaa, Marjo-Riitta Järvelin, Aimo Ruokonen, Inês Barroso, Stephen E Epstein, Hakon H Hakonarson, Daniel J Rader, Muredach P Reilly, Jacqueline C M Witteman, Alistair S Hall, Nilesh J Samani, David P Strachan, Philip Barter, Cornelia M van Duijn, Jaspal S Kooner, Leena Peltonen, Nicholas J Wareham, Ruth McPherson, Vincent Mooser, Manjinder S Sandhu
Affiliations

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

Dawn M Waterworth et al. Arterioscler Thromb Vasc Biol. 2010 Nov.

Abstract

Objective: 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.

Methods and results: 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)).

Conclusions: 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.

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Figures

Figure 1
Figure 1
Associations between SNPs at loci predominantly associated with circulating levels of (a) LDL-c and (b) TG/HDL-c with risk of CAD in eight studies comprising up to 7,018 cases and 20,765 controls (see Methods for details). There was no material heterogeneity among studies for these associations (Table 4).
Figure 2
Figure 2
Associations between SNPs and circulating lipids at known or recently identified loci that show statistical association with risk of CAD in Figure 1 and Table 4. Associations and effect sizes are based on Stage 1 meta-analyses and natural log transformed data (see Table 1 and Supplementary Table 6 for details).
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Comment in

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