Sun, 27 Jul 2008 07:27:05 BST CiteULike: omalbam's Groop http://www.citeulike.org/user/omalbam/author/Groop CiteULike.org en-gb Copyright © 2004-2008 citeulike.org http://www.citeulike.org/user/omalbam/article/2565073 <i>N Engl J Med, Vol. 358, No. 12. (20 March 2008), pp. 1240-1249.</i><br /><br />Background Common single-nucleotide polymorphisms (SNPs) that are associated with blood low-density lipoprotein (LDL) or high-density lipoprotein (HDL) cholesterol modestly affect lipid levels. We tested the hypothesis that a combination of such SNPs contributes to the risk of cardiovascular disease. Methods We studied SNPs at nine loci in 5414 subjects from the cardiovascular cohort of the Malmo Diet and Cancer Study. We first validated the association between SNPs and either LDL or HDL cholesterol and subsequently created a genotype score on the basis of the number of unfavorable alleles. We used Cox proportional-hazards models to determine the time to the first cardiovascular event in relation to the genotype score. Results All nine SNPs showed replication of an association with levels of either LDL or HDL cholesterol. With increasing genotype scores, the level of LDL cholesterol increased from 152 mg to 171 mg per deciliter (3.9 to 4.4 mmol per liter), whereas HDL cholesterol decreased from 60 mg to 51 mg per deciliter (1.6 to 1.3 mmol per liter). During follow-up (median, 10.6 years), 238 subjects had a first cardiovascular event. The genotype score was associated with incident cardiovascular disease in models adjusted for covariates including baseline lipid levels (P<0.001). The use of the genotype score did not improve the clinical risk prediction, as assessed by the C statistic. However, there was a significant improvement in risk classification with the use of models that included the genotype score, as compared with those that did not include the genotype score. Conclusions A genotype score of nine validated SNPs that are associated with modulation in levels of LDL or HDL cholesterol was an independent risk factor for incident cardiovascular disease. The score did not improve risk discrimination but did modestly improve clinical risk reclassification for individual subjects beyond standard clinical factors. 10.1056/NEJMoa0706728 Polymorphisms Associated with Cholesterol and Risk of Cardiovascular Events Sekar Kathiresan Olle Melander Dragi Anevski Candace Guiducci Noel Burtt Charlotta Roos Joel Hirschhorn Goran Berglund Bo Hedblad Leif Groop David Altshuler Christopher Newton-Cheh Marju Orho-Melander doi:10.1056/NEJMoa0706728 N Engl J Med, Vol. 358, No. 12. (20 March 2008), pp. 1240-1249. 2008-03-20T07:22:21-00:00 2008 N Engl J Med 358 12 1240 1249 genetic hplp molecular risk http://www.citeulike.org/user/omalbam/article/1281649 <i>Science (26 April 2007)</i><br /><br />New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single nucleotide polymorphisms (SNPs) in 1,464 patients with T2D and 1,467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D) we identify and confirm three loci associated with T2D -- in a non-coding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1 -- and replicate associations near HHEX and in SLC30A8 found by a recent whole genome association study. We identify and confirm association of a SNP in an intron of glucokinase regulatory protein with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues into the pathogenesis of common diseases. Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels. Richa Saxena Benjamin F Voight Valeriya Lyssenko Noel P Burtt Paul I W de Bakker Hong Chen Jeffrey J Roix Sekar Kathiresan Joel N Hirschhorn Mark J Daly Thomas E Hughes Leif Groop David Altshuler Peter Almgren Jose C Florez Joanne Meyer Kristin Ardlie Kristina Bengtsson Bo Isomaa Guillaume Lettre Ulf Lindblad Helen N Lyon Olle Melander Christopher Newton-Cheh Peter Nilsson Marju Orho-Melander Lennart Råstam Elizabeth K Speliotes Marja-Riitta Taskinen Tiinamaija Tuomi Candace Guiducci Anna Berglund Joyce Carlson Lauren Gianniny Rachel Hackett Liselott Hall Johan Holmkvist Esa Laurila Marketa Sjögren Maria Sterner Aarti Surti Margareta Svensson Malin Svensson Ryan Tewhey Brendan Blumenstiel Melissa Parkin Matthew Defelice Rachel Barry Wendy Brodeur Jody Camarata Nancy Chia Mary Fava John Gibbons Bob Handsaker Claire Healy Kieu Nguyen Casey Gates Carrie Sougnez Diane Gage Marcia Nizzari Stacey B Gabriel Gung-Wei Chirn Qicheng Ma Hemang Parikh Delwood Richardson Darrell Ricke Shaun Purcell doi:10.1126/science.1142358 Science (26 April 2007) 2007-05-07T08:53:58-00:00 2007 Science 1095-9203 diabetes diagnosis gwa molecular