LDL-cholesterol concentrations: a genome-wide association study
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LDL-cholesterol concentrations : a genome-wide association study. / Wellcome Trust Case-Control Consortium.
I: Lancet Oncology, Bind 371, Nr. 9611, 09.02.2008, s. 483-91.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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 -
ID: 258453158