ng.75 - LETTERS 2008 Nature Publishing Group...

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Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans Sekar Kathiresan 1–3 , Olle Melander 4 , Candace Guiducci 2 , Aarti Surti 2 , Noe ¨l P Burtt 2 , Mark J Rieder 5 , Gregory M Cooper 5 , Charlotta Roos 6 , Benjamin F Voight 2,7,8 , Aki S Havulinna 9 , Bjo ¨rn Wahlstrand 10 , Thomas Hedner 10 , Dolores Corella 11 , E Shyong Tai 12 , Jose M Ordovas 13 , Go ¨ran Berglund 14 , Erkki Vartiainen 9 , Pekka Jousilahti 9 , Bo Hedblad 15 , Marja-Riitta Taskinen 16 , Christopher Newton-Cheh 1–3 , Veikko Salomaa 9 , Leena Peltonen 2,9,17,18 , Leif Groop 6,19 , David M Altshuler 2,3,7,8,20 & Marju Orho-Melander 6 Blood concentrations of lipoproteins and lipids are heritable 1 risk factors for cardiovascular disease 2,3 . Using genome-wide association data from three studies ( n ¼ 8,816 that included 2,758 individuals from the Diabetes Genetics Initiative specific to the current paper as well as 1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables reported in a companion paper in this issue 4 ) and targeted replication association analyses in up to 18,554 independent participants, we show that common SNPs at 18 loci are reproducibly associated with concentrations of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and/or triglycerides. Six of these loci are new ( P o 5 ± 10 ² 8 for each new locus). Of the six newly identified chromosomal regions, two were associated with LDL cholesterol (1p13 near CELSR2 , PSRC1 and SORT1 and 19p13 near CILP2 and PBX4 ), one with HDL cholesterol (1q42 in GALNT2 ) and five with triglycerides (7q11 near TBL2 and MLXIPL , 8q24 near TRIB1 , 1q42 in GALNT2 , 19p13 near CILP2 and PBX4 and 1p31 near ANGPTL3 ). At 1p13, the LDL-associated SNP was also strongly correlated with CELSR2 , PSRC1 , and SORT1 transcript levels in human liver, and a proxy for this SNP was recently shown to affect risk for coronary artery disease 5 . Understanding the molecular, cellular and clinical consequences of the newly identified loci may inform therapy and clinical care. We recently conducted the Diabetes Genetics Initiative (DGI) gen- ome-wide association study for type 2 diabetes and 18 other traits, including blood lipoprotein and lipid concentrations 6 . Here, we focus on replication analyses related to three traits—concentrations of LDL cholesterol, HDL cholesterol and triglycerides. In DGI, we analyzed the association of 389,878 markers with blood lipo- proteins and lipids in 2,758 individuals. From these results, we selected an initial 196 SNPs for replication on the basis of the strength of statistical evidence. We then combined the DGI results with those from two other genome-wide association studies—the Finland– United States Investigation of NIDDM Genetics (FUSION) and the SardiNIA Study of Aging (see companion manuscript for meta-analytic methods 4 )—and selected an additional 30 SNPs for replication on the basis of the combined evidence (see Supple- mentary Fig. 1 online for study design). The 226 SNPs selected
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