TY - JOUR
T1 - LDL-cholesterol concentrations
T2 - a genome-wide association study
AU - Sandhu, Manjinder S.
AU - Waterworth, Dawn M.
AU - Debenham, Sally L.
AU - Wheeler, Eleanor
AU - Papadakis, Konstantinos
AU - Zhao, Jing Hua
AU - Song, Kijoung
AU - Yuan, Xin
AU - Johnson, Toby
AU - Ashford, Sofie
AU - Inouye, Michael
AU - Luben, Robert
AU - Sims, Matthew
AU - Hadley, David
AU - McArdle, Wendy
AU - Barter, Philip
AU - Kesäniemi, Y. Antero
AU - Mahley, Robert W.
AU - McPherson, Ruth
AU - Grundy, Scott M
AU - Bingham, Sheila A.
AU - Khaw, Kay Tee
AU - Loos, Ruth JF
AU - Waeber, Gérard
AU - Barroso, Inês
AU - Strachan, David P.
AU - Deloukas, Panagiotis
AU - Vollenweider, Peter
AU - Wareham, Nicholas J.
AU - Mooser, Vincent
N1 - Funding Information:
We acknowledge the support of the UK Medical Research Council, Wellcome Trust, British Heart Foundation (BHF), European Commission, and GlaxoSmithKline. Specifically, we acknowledge use of genotype data from the 1958 British birth cohort DNA collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. IB and EW acknowledge support from EU FP6 funding (contract no LSHM-CT-2003-503041). SLD is funded by the BHF. MI, IB, and PD are funded by the Wellcome Trust. Some computation was done on the Vital-IT system at the Swiss Institute of Bioinformatics. The Lausanne and GEMS study were sponsored in part by GlaxoSmithKline. The support of Allen Roses, Lefkos Middleton, and Paul Matthews is greatly appreciated.
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
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U2 - 10.1016/S0140-6736(08)60208-1
DO - 10.1016/S0140-6736(08)60208-1
M3 - Article
C2 - 18262040
AN - SCOPUS:38849166666
SN - 0140-6736
VL - 371
SP - 483
EP - 491
JO - The Lancet
JF - The Lancet
IS - 9611
ER -