Genetic variants influencing circulating lipid levels and risk of coronary artery disease.
Waterworth DM., Ricketts SL., Song K., Chen L., Zhao JH., Ripatti S., Aulchenko YS., Zhang W., Yuan X., Lim N., Luan J., Ashford S., Wheeler E., Young EH., Hadley D., Thompson JR., Braund PS., Johnson T., Struchalin M., Surakka I., Luben R., Khaw K-T., Rodwell SA., Loos RJF., Boekholdt SM., Inouye M., Deloukas P., Elliott P., Schlessinger D., Sanna S., Scuteri A., Jackson A., Mohlke KL., Tuomilehto J., Roberts R., Stewart A., Kesäniemi YA., Mahley RW., Grundy SM., Wellcome Trust Case Control Consortium None., McArdle W., Cardon L., Waeber G., Vollenweider P., Chambers JC., Boehnke M., Abecasis GR., Salomaa V., Järvelin M-R., Ruokonen A., Barroso I., Epstein SE., Hakonarson HH., Rader DJ., Reilly MP., Witteman JCM., Hall AS., Samani NJ., Strachan DP., Barter P., van Duijn CM., Kooner JS., Peltonen L., Wareham NJ., McPherson R., Mooser V., Sandhu MS.
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.