Kathiresan Sekar, Willer Cristen J, Peloso Gina M, Demissie Serkalem, Musunuru Kiran, Schadt Eric E, Kaplan Lee, Bennett Derrick, Li Yun, Tanaka Toshiko, Voight Benjamin F, Bonnycastle Lori L, Jackson Anne U, Crawford Gabriel, Surti Aarti, Guiducci Candace, Burtt Noel P, Parish Sarah, Clarke Robert, Zelenika Diana, Kubalanza Kari A, Morken Mario A, Scott Laura J, Stringham Heather M, Galan Pilar, Swift Amy J, Kuusisto Johanna, Bergman Richard N, Sundvall Jouko, Laakso Markku, Ferrucci Luigi, Scheet Paul, Sanna Serena, Uda Manuela, Yang Qiong, Lunetta Kathryn L, Dupuis Josée, de Bakker Paul I W, O'Donnell Christopher J, Chambers John C, Kooner Jaspal S, Hercberg Serge, Meneton Pierre, Lakatta Edward G, Scuteri Angelo, Schlessinger David, Tuomilehto Jaakko, Collins Francis S, Groop Leif, Altshuler David, Collins Rory, Lathrop G Mark, Melander Olle, Salomaa Veikko, Peltonen Leena, Orho-Melander Marju, Ordovas Jose M, Boehnke Michael, Abecasis Gonçalo R, Mohlke Karen L, Cupples L Adrienne
Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Nat Genet. 2009 Jan;41(1):56-65. doi: 10.1038/ng.291. Epub 2008 Dec 7.
Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.
血液低密度脂蛋白（LDL）胆固醇、高密度脂蛋白（HDL）胆固醇和甘油三酯水平是心血管疾病的危险因素。为剖析这些性状的多基因基础，我们对19840名个体进行了全基因组关联筛查，并在多达20623名个体中进行了重复验证。我们鉴定出30个与脂蛋白浓度相关的不同位点（每个位点P < 5 × 10⁻⁸），其中11个位点首次达到全基因组显著性水平。这11个新定义的位点包括与ABCG8、MAFB、HNF1A和TIMD4附近的LDL胆固醇相关的常见变异；与ANGPTL4、FADS1 - FADS2 - FADS3、HNF4A、LCAT、PLTP和TTC39B附近的HDL胆固醇相关的常见变异；以及与AMAC1L2、FADS1 - FADS2 - FADS3和PLTP附近的甘油三酯相关的常见变异。超过高LDL胆固醇、低HDL胆固醇和高甘油三酯临床切点的个体比例根据等位基因剂量评分而有所不同（每种趋势的P < 10⁻¹⁵）。这些结果表明，多个常见变异的累积效应导致了多基因性血脂异常。
