LDL-cholesterol concentrations:: a genome-wide association study

被引:272
作者
Sandhu, Manjinder S. [1 ,2 ]
Waterworth, Dawn M. [3 ]
Debenham, Sally L. [1 ,2 ]
Wheeler, Eleanor [4 ]
Papadakis, Konstantinos [8 ]
Zhao, Jing Hua [2 ]
Song, Kijoung [3 ]
Yuan, Xin [3 ]
Johnson, Toby [5 ,6 ,7 ]
Ashford, Sofie [1 ,2 ]
Inouye, Michael [4 ]
Luben, Robert [1 ]
Sims, Matthew [2 ]
Hadley, David [8 ]
McArdle, Wendy [9 ]
Barter, Philip [10 ]
Kesaeniemi, Y. Antero [11 ,12 ]
Mahley, Robert W. [13 ,14 ]
McPherson, Ruth [15 ]
Grundy, Scott M. [16 ]
Bingham, Sheila A. [17 ]
Khaw, Kay-Tee [1 ]
Loos, Ruth J. F. [2 ]
Waeber, Gerard [18 ]
Barroso, Ines [4 ]
Strachan, David P. [8 ]
Deloukas, Panagiotis [4 ]
Vollenweider, Peter [18 ]
Wareham, Nicholas J. [2 ]
Mooser, Vincent [3 ]
机构
[1] Univ Cambridge, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Cambridge CB1 8RN, England
[2] Addenbrookes Hosp, MRC Epidemiol Unit, Inst Metab Sci, Cambridge, England
[3] GlaxoSmithKline, Div Med Genet Clin Pharmacol & Discovery Med, King Of Prussia, PA USA
[4] Wellcome Trust Sanger Inst, Cambridge, England
[5] Univ Lausanne, Dept Med Genet, Lausanne, Switzerland
[6] Univ Lausanne, Univ Inst Social & Prevent Med, Lausanne, Switzerland
[7] CHU Vaudois, Lausanne, Switzerland
[8] Univ London St Georges Hosp, Div Community Hlth Sci, London, England
[9] Univ Bristol, Avon Longitudinal Study Parents & Children, Bristol, Avon, England
[10] Heart Res Inst, Sydney, NSW, Australia
[11] Univ Oulu, Dept Internal Med, SF-90220 Oulu, Finland
[12] Univ Oulu, Bioctr, SF-90220 Oulu, Finland
[13] Gladstone Inst Neurol Dis, San Francisco, CA USA
[14] Gladstone Inst Cardiovasc Dis, San Francisco, CA USA
[15] Univ Ottawa, Ctr Heart, Div Cardiol, Ottawa, ON, Canada
[16] Univ Texas Dallas, SW Med Ctr, Ctr Human Nutr, Dept Clin Nutr, Dallas, TX 75230 USA
[17] MRC Dunn Human Nutr Unit, Cambridge, England
[18] CHU Vaudois, Dept Internal Med, Lausanne, Switzerland
基金
英国惠康基金; 英国医学研究理事会;
关键词
D O I
10.1016/S0140-6736(08)60208-1
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background LDL cholesterol has a causal role in the development of cardiovascular disease. Improved understanding of the biological mechanisms that underlie the metabolism and regulation of LDL cholesterol might help to identify novel therapeutic targets. We therefore did a genome-wide association study of LDL-cholesterol concentrations. Methods We used genome-wide association data from up to 11685 participants with measures of circulating LDL-cholesterol concentrations across five studies, including data for 293461 autosomal single nucleotide polymorphisms (SNPs) with a minor allele frequency of 5% or more that passed our quality control criteria. We also used data from a second genome-wide array in up to 4337 participants from three of these five studies, with data for 290140 SNPs. We did replication studies in two independent populations consisting of up to 4979 participants. Statistical approaches, including meta-analysis and linkage disequilibrium plots, were used to refine association signals; we analysed pooled data from all seven populations to determine the effect of each SNP on variations in circulating LDL-cholesterol concentrations. Findings In our initial scan, we found two SNPs (rs599839 [p=1.7x10(-15)] and rs4970834 [p=3 .0x10(-11)]) that showed genome-wide statistical association with LDL cholesterol at chromosomal locus 1p13.3. The second genome screen found a third statistically associated SNP at the same locus (rs646776 [p=4.3x10(-9)]). Meta-analysis of data from all studies showed an association of SNPs rs599839 (combined p=1.2x10(-33)) and rs646776 (p=4.8x10(-20)) with LDL-cholesterol concentrations. SNPs rs599839 and rs646776 both explained around 1% of the variation in circulating LDL-cholesterol concentrations and were associated with about 15% of an SD change in LDL cholesterol per allele, assuming an SD of 1 mmol/L. Interpretation We found evidence for a novel locus for LDL cholesterol on chromosome 1p13.3. These results potentially provide insight into the biological mechanisms that underlie the regulation of LDL cholesterol and might help in the discovery of novel therapeutic targets for cardiovascular disease.
引用
收藏
页码:483 / 491
页数:9
相关论文
共 28 条
[1]   Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins [J].
Baigent, C ;
Keech, A ;
Kearney, PM ;
Blackwell, L ;
Buck, G ;
Pollicino, C ;
Kirby, A ;
Sourjina, T ;
Peto, R ;
Collins, R ;
Simes, J .
LANCET, 2005, 366 (9493) :1267-1278
[2]   Haploview: analysis and visualization of LD and haplotype maps [J].
Barrett, JC ;
Fry, B ;
Maller, J ;
Daly, MJ .
BIOINFORMATICS, 2005, 21 (02) :263-265
[3]   Association of apolipoprotein E genotypes with lipid levels and coronary risk [J].
Bennet, Anna M. ;
Di Angelantonio, Emanuele ;
Ye, Zheng ;
Wensley, Frances ;
Dahlin, Anette ;
Ahlbom, Anders ;
Keavney, Bernard ;
Collins, Rory ;
Wiman, Bjoern ;
de Faire, Ulf ;
Danesh, John .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2007, 298 (11) :1300-1311
[4]   Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J].
Burton, Paul R. ;
Clayton, David G. ;
Cardon, Lon R. ;
Craddock, Nick ;
Deloukas, Panos ;
Duncanson, Audrey ;
Kwiatkowski, Dominic P. ;
McCarthy, Mark I. ;
Ouwehand, Willem H. ;
Samani, Nilesh J. ;
Todd, John A. ;
Donnelly, Peter ;
Barrett, Jeffrey C. ;
Davison, Dan ;
Easton, Doug ;
Evans, David ;
Leung, Hin-Tak ;
Marchini, Jonathan L. ;
Morris, Andrew P. ;
Spencer, Chris C. A. ;
Tobin, Martin D. ;
Attwood, Antony P. ;
Boorman, James P. ;
Cant, Barbara ;
Everson, Ursula ;
Hussey, Judith M. ;
Jolley, Jennifer D. ;
Knight, Alexandra S. ;
Koch, Kerstin ;
Meech, Elizabeth ;
Nutland, Sarah ;
Prowse, Christopher V. ;
Stevens, Helen E. ;
Taylor, Niall C. ;
Walters, Graham R. ;
Walker, Neil M. ;
Watkins, Nicholas A. ;
Winzer, Thilo ;
Jones, Richard W. ;
McArdle, Wendy L. ;
Ring, Susan M. ;
Strachan, David P. ;
Pembrey, Marcus ;
Breen, Gerome ;
St Clair, David ;
Caesar, Sian ;
Gordon-Smith, Katherine ;
Jones, Lisa ;
Fraser, Christine ;
Green, Elain K. .
NATURE, 2007, 447 (7145) :661-678
[5]   Genetics of cardiovascular diseases - From single mutations to the whole genome [J].
Cambien, Francois ;
Tiret, Laurence .
CIRCULATION, 2007, 116 (15) :1714-1724
[6]   Replicating genotype-phenotype associations [J].
Chanock, Stephen J. ;
Manolio, Teri ;
Boehnke, Michael ;
Boerwinkle, Eric ;
Hunter, David J. ;
Thomas, Gilles ;
Hirschhorn, Joel N. ;
Abecasis, Goncalo ;
Altshuler, David ;
Bailey-Wilson, Joan E. ;
Brooks, Lisa D. ;
Cardon, Lon R. ;
Daly, Mark ;
Donnelly, Peter ;
Fraumeni, Joseph F., Jr. ;
Freimer, Nelson B. ;
Gerhard, Daniela S. ;
Gunter, Chris ;
Guttmacher, Alan E. ;
Guyer, Mark S. ;
Harris, Emily L. ;
Hoh, Josephine ;
Hoover, Robert ;
Kong, C. Augustine ;
Merikangas, Kathleen R. ;
Morton, Cynthia C. ;
Palmer, Lyle J. ;
Phimister, Elizabeth G. ;
Rice, John P. ;
Roberts, Jerry ;
Rotimi, Charles ;
Tucker, Margaret A. ;
Vogan, Kyle J. ;
Wacholder, Sholom ;
Wijsman, Ellen M. ;
Winn, Deborah M. ;
Collins, Francis S. .
NATURE, 2007, 447 (7145) :655-660
[7]  
Day N, 1999, BRIT J CANCER, V80, P95
[8]   Genomic control for association studies [J].
Devlin, B ;
Roeder, K .
BIOMETRICS, 1999, 55 (04) :997-1004
[9]  
FRIEDEWALD WT, 1972, CLIN CHEM, V18, P499
[10]   The structure of haplotype blocks in the human genome [J].
Gabriel, SB ;
Schaffner, SF ;
Nguyen, H ;
Moore, JM ;
Roy, J ;
Blumenstiel, B ;
Higgins, J ;
DeFelice, M ;
Lochner, A ;
Faggart, M ;
Liu-Cordero, SN ;
Rotimi, C ;
Adeyemo, A ;
Cooper, R ;
Ward, R ;
Lander, ES ;
Daly, MJ ;
Altshuler, D .
SCIENCE, 2002, 296 (5576) :2225-2229