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 J F

AU - Waeber, Gérard

AU - Barroso, Inês

AU - Strachan, David P

AU - Deloukas, Panagiotis

AU - Vollenweider, Peter

AU - Wareham, Nicholas J

AU - Mooser, Vincent

AU - Wellcome Trust Case-Control Consortium

PY - 2008/2/9

Y1 - 2008/2/9

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=1.7x10(-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.

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=1.7x10(-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.

KW - Adult

KW - Aged

KW - Cardiovascular Diseases/epidemiology

KW - Cholesterol, LDL/blood

KW - Chromosomes, Human, Pair 1/genetics

KW - Cohort Studies

KW - Europe/epidemiology

KW - European Continental Ancestry Group/genetics

KW - Female

KW - Genetic Variation/genetics

KW - Genome, Human

KW - Humans

KW - Linear Models

KW - Linkage Disequilibrium

KW - Male

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

KW - Seroepidemiologic Studies

U2 - 10.1016/S0140-6736(08)60208-1

DO - 10.1016/S0140-6736(08)60208-1

M3 - Journal article

C2 - 18262040

VL - 371

SP - 483

EP - 491

JO - The Lancet Oncology

JF - The Lancet Oncology

SN - 1470-2045

IS - 9611

ER -