|De Bakker, Paul|
|Lathrop, G Mark|
Submitted to: Nature Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/28/2008
Publication Date: 1/1/2009
Citation: Kathiresan, S., Willer, C., Peloso, G., Demissie, S., Musunuru, K., Schadt, E., Kaplan, L., Bennett, D., Li, Y., Tanaka, T., Voight, B., Bonnycastle, L., Jackson, A., Crawford, G., Surti, A., Guiducci, C., Burtt, N., Parish, S., Clarke, R., Zelenika, D., Kubalanza, K., Morken, M., Scott, L., Stringham, H., Galan, P., Swift, A., Kuusisto, J., Bergman, R., Sundvall, J., Laakso, M., Ferrucci, L., Scheet, P., Sanna, S., Uda, M., Yang, Q., Lunetta, K., Dupius, J., De Bakker, P., O'Donnell, C., Scuteri, A., Schlessinger, D., Tuomilehto, J., Collins, F., Groop, L., Altshuler, D., Collins, R., Lathrop, G., Melander, O., Saloma, V., Peltonen, L., Orho-Melander, M., Ordovas, J., Boehnke, M., Abecasis, G., Mohlke, K., Cupples, A. 2009. Common variants at 30 loci contribute to polygenic dyslipidemia. Nature Genetics. 41:56-65. Interpretive Summary: Cardiovascular diseases are the major cause of death and disability in industrialized countries and a major barrier to healthy aging. Cardiovascular diseases are the result of the interaction between a number of genetic and environmental risk factors. Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL)cholesterol and triglyceride levels are risk factors for cardiovascular disease. Despite the considerable amount of work carried out for more than twenty years we only know a small percent of the genes influencing blood lipids and therefore, cardiovascular disease risk. To identify still unknown genes, we conducted a study of of the entire genome, known as genome-wide association screens, in 19,840 individuals and replicated promising findings in up to 20,623 individuals. We identified 30 distinct genomic regions associated with lipoprotein concentrations, including 11 entirely new ones, that were associated with LDL cholesterol, HDL cholesterol and with triglycerides. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to the number of gene variants at these genes. These results suggest that the cumulative effect of multiple gene variants contributes to altered blood lipids. This information will be crucial to develop genetic tests to predict and successfully prevent CVD, the major disease limiting healthy aging in the population.
Technical Abstract: 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.