LDL-cholesterol concentrations: a genome-wide association study

Sandhu, M. S., Wellcome Trust Case Control Consortium, Brown, Matthew A. and Bradbury, Linda A. (2008) LDL-cholesterol concentrations: a genome-wide association study. The Lancet, 371 9611: 483-491. doi:10.1016/S0140-6736(08)60208-1


Author Sandhu, M. S.
Wellcome Trust Case Control Consortium
Brown, Matthew A.
Bradbury, Linda A.
Title LDL-cholesterol concentrations: a genome-wide association study
Journal name The Lancet   Check publisher's open access policy
ISSN 0140-6736
1474-547X
Publication date 2008-02-09
Sub-type Article (original research)
DOI 10.1016/S0140-6736(08)60208-1
Volume 371
Issue 9611
Start page 483
End page 491
Total pages 9
Editor Richard Horton
Place of publication London, U.K.
Publisher Lancet Publishing Group
Language eng
Subject 1103 Clinical Sciences
Formatted 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=1·7×10-15] and rs4970834 [p=3·0×10-11]) 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=4·3×10-9]). Meta-analysis of data from all studies showed an association of SNPs rs599839 (combined p=1·2×10-33) and rs646776 (p=4·8×10-20) 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.
© 2008 Elsevier Ltd. All rights reserved.
Keyword Cardiovascular diseases
Cholesterol, LDL
Chromosomes, Human, Pair 1
European continental ancestry group
Linkage disequilibrium
Polymorphism
Single nucleotide
Seroepidemiologic studies
Q-Index Code C1
Q-Index Status Provisional Code

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
UQ Diamantina Institute Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 215 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 222 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Thu, 01 Apr 2010, 10:37:41 EST by June Temby on behalf of UQ Diamantina Institute