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

TitleLDL-cholesterol concentrations: a genome-wide association study.
Publication TypeJournal Article
Year of Publication2008
AuthorsSandhu, MS, Waterworth, DM, Debenham, SL, Wheeler, E, Papadakis, K, Zhao, JHua, Song, K, Yuan, X, Johnson, T, Ashford, S, Inouye, M, Luben, R, Sims, M, Hadley, D, McArdle, W, Barter, P, Y Kesäniemi, A, Mahley, RW, McPherson, R, Grundy, SM, Bingham, SA, Khaw, K-T, Loos, RJF, Waeber, G, Barroso, I, Strachan, DP, Deloukas, P, Vollenweider, P, Wareham, NJ, Mooser, V
Corporate Authors
JournalLancet
Volume371
Issue9611
Pagination483-91
Date Published2008 Feb 09
ISSN1474-547X
KeywordsAdult, Aged, Cardiovascular Diseases, Cholesterol, LDL, Chromosomes, Human, Pair 1, Cohort Studies, Europe, European Continental Ancestry Group, Female, Genetic Variation, Genome, Human, Humans, Linear Models, Linkage Disequilibrium, Male, Middle Aged, Polymorphism, Single Nucleotide, Seroepidemiologic Studies
Abstract

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 11,685 participants with measures of circulating LDL-cholesterol concentrations across five studies, including data for 293 461 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 290,140 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.

DOI10.1016/S0140-6736(08)60208-1
Alternate JournalLancet
Citation Key10.1016/S0140-6736(08)60208-1
PubMed ID18262040
PubMed Central IDPMC2292820
Grant ListG0000934 / / Medical Research Council / United Kingdom
MC_U105630924 / / Medical Research Council / United Kingdom
G0701863 / / Medical Research Council / United Kingdom
068545/Z/02 / / Wellcome Trust / United Kingdom
MC_QA137934 / / Medical Research Council / United Kingdom
MC_U106188470 / / Medical Research Council / United Kingdom