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LDL-cholesterol concentrations: a genome-wide association study

Summary 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 assoc... Full description

Journal Title: Lancet 2008, Vol.371 (9611), p.483-491
Main Author: Sandhu, Manjinder S, Dr
Other Authors: Waterworth, Dawn M, PhD , Debenham, Sally L, PhD , Wheeler, Eleanor, PhD , Papadakis, Konstantinos, MSc , Zhao, Jing Hua, PhD , Song, Kijoung, PhD , Yuan, Xin, PhD , Johnson, Toby, PhD , Ashford, Sofie, BSc , Inouye, Michael, MSc , Luben, Robert, BSc , Sims, Matthew, BSc , Hadley, David, MSc , McArdle, Wendy, PhD , Barter, Philip, Prof , Kesäniemi, Y Antero, Prof , Mahley, Robert W, Prof , McPherson, Ruth, Prof , Grundy, Scott M, Prof , Bingham, Sheila A, Prof , Khaw, Kay-Tee, Prof , Loos, Ruth JF, PhD , Waeber, Gérard, Prof , Barroso, Inês, PhD , Strachan, David P, Prof , Deloukas, Panagiotis, PhD , Vollenweider, Peter, MD , Wareham, Nicholas J, Prof , Mooser, Vincent, MD
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
Publisher: England: Elsevier Ltd
ID: ISSN: 0140-6736
Link: https://www.ncbi.nlm.nih.gov/pubmed/18262040
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recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2292820
title: LDL-cholesterol concentrations: a genome-wide association study
format: Article
creator:
  • Sandhu, Manjinder S, Dr
  • Waterworth, Dawn M, PhD
  • Debenham, Sally L, PhD
  • Wheeler, Eleanor, PhD
  • Papadakis, Konstantinos, MSc
  • Zhao, Jing Hua, PhD
  • Song, Kijoung, PhD
  • Yuan, Xin, PhD
  • Johnson, Toby, PhD
  • Ashford, Sofie, BSc
  • Inouye, Michael, MSc
  • Luben, Robert, BSc
  • Sims, Matthew, BSc
  • Hadley, David, MSc
  • McArdle, Wendy, PhD
  • Barter, Philip, Prof
  • Kesäniemi, Y Antero, Prof
  • Mahley, Robert W, Prof
  • McPherson, Ruth, Prof
  • Grundy, Scott M, Prof
  • Bingham, Sheila A, Prof
  • Khaw, Kay-Tee, Prof
  • Loos, Ruth JF, PhD
  • Waeber, Gérard, Prof
  • Barroso, Inês, PhD
  • Strachan, David P, Prof
  • Deloukas, Panagiotis, PhD
  • Vollenweider, Peter, MD
  • Wareham, Nicholas J, Prof
  • Mooser, Vincent, MD
subjects:
  • Abridged Index Medicus
  • Adult
  • Aged
  • Cardiovascular disease
  • Cardiovascular Diseases
  • Cardiovascular Diseases - epidemiology
  • Cardiovascular Diseases - genetics
  • Cholesterol
  • Cholesterol, LDL - blood
  • Cholesterol, LDL - genetics
  • Cholesterol, LDL - physiology
  • Chromosomes
  • Chromosomes, Human, Pair 1 - genetics
  • Cohort Studies
  • Colaus Study
  • Diet
  • Europe
  • Europe - epidemiology
  • European Continental Ancestry Group
  • European Continental Ancestry Group - genetics
  • Fast track
  • Fast track — Articles
  • Female
  • Genetic Variation
  • Genetic Variation - genetics
  • Genome
  • Genome, Human
  • Genomics
  • Human
  • Humans
  • Internal Medicine
  • Linear Models
  • Linkage Disequilibrium
  • lipids (amino acids
  • Male
  • Medical research
  • Middle Aged
  • Pair 1
  • peptides
  • Polymorphism
  • Polymorphism, Single Nucleotide
  • proteins
  • Seroepidemiologic Studies
  • Single Nucleotide
  • Studies
  • Systematic review
ispartof: Lancet, 2008, Vol.371 (9611), p.483-491
description: Summary 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.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0140-6736
fulltext: fulltext
issn:
  • 0140-6736
  • 1474-547X
url: Link


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creatorSandhu, Manjinder S, Dr ; Waterworth, Dawn M, PhD ; Debenham, Sally L, PhD ; Wheeler, Eleanor, PhD ; Papadakis, Konstantinos, MSc ; Zhao, Jing Hua, PhD ; Song, Kijoung, PhD ; Yuan, Xin, PhD ; Johnson, Toby, PhD ; Ashford, Sofie, BSc ; Inouye, Michael, MSc ; Luben, Robert, BSc ; Sims, Matthew, BSc ; Hadley, David, MSc ; McArdle, Wendy, PhD ; Barter, Philip, Prof ; Kesäniemi, Y Antero, Prof ; Mahley, Robert W, Prof ; McPherson, Ruth, Prof ; Grundy, Scott M, Prof ; Bingham, Sheila A, Prof ; Khaw, Kay-Tee, Prof ; Loos, Ruth JF, PhD ; Waeber, Gérard, Prof ; Barroso, Inês, PhD ; Strachan, David P, Prof ; Deloukas, Panagiotis, PhD ; Vollenweider, Peter, MD ; Wareham, Nicholas J, Prof ; Mooser, Vincent, MD
creatorcontribSandhu, Manjinder S, Dr ; Waterworth, Dawn M, PhD ; Debenham, Sally L, PhD ; Wheeler, Eleanor, PhD ; Papadakis, Konstantinos, MSc ; Zhao, Jing Hua, PhD ; Song, Kijoung, PhD ; Yuan, Xin, PhD ; Johnson, Toby, PhD ; Ashford, Sofie, BSc ; Inouye, Michael, MSc ; Luben, Robert, BSc ; Sims, Matthew, BSc ; Hadley, David, MSc ; McArdle, Wendy, PhD ; Barter, Philip, Prof ; Kesäniemi, Y Antero, Prof ; Mahley, Robert W, Prof ; McPherson, Ruth, Prof ; Grundy, Scott M, Prof ; Bingham, Sheila A, Prof ; Khaw, Kay-Tee, Prof ; Loos, Ruth JF, PhD ; Waeber, Gérard, Prof ; Barroso, Inês, PhD ; Strachan, David P, Prof ; Deloukas, Panagiotis, PhD ; Vollenweider, Peter, MD ; Wareham, Nicholas J, Prof ; Mooser, Vincent, MD ; Wellcome Trust Case Control Consortium
descriptionSummary 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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languageeng
publisherEngland: Elsevier Ltd
subjectAbridged Index Medicus ; Adult ; Aged ; Cardiovascular disease ; Cardiovascular Diseases ; Cardiovascular Diseases - epidemiology ; Cardiovascular Diseases - genetics ; Cholesterol ; Cholesterol, LDL - blood ; Cholesterol, LDL - genetics ; Cholesterol, LDL - physiology ; Chromosomes ; Chromosomes, Human, Pair 1 - genetics ; Cohort Studies ; Colaus Study ; Diet ; Europe ; Europe - epidemiology ; European Continental Ancestry Group ; European Continental Ancestry Group - genetics ; Fast track ; Fast track — Articles ; Female ; Genetic Variation ; Genetic Variation - genetics ; Genome ; Genome, Human ; Genomics ; Human ; Humans ; Internal Medicine ; Linear Models ; Linkage Disequilibrium ; lipids (amino acids ; Male ; Medical research ; Middle Aged ; Pair 1 ; peptides ; Polymorphism ; Polymorphism, Single Nucleotide ; proteins ; Seroepidemiologic Studies ; Single Nucleotide ; Studies ; Systematic review
ispartofLancet, 2008, Vol.371 (9611), p.483-491
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1Waterworth, Dawn M, PhD
2Debenham, Sally L, PhD
3Wheeler, Eleanor, PhD
4Papadakis, Konstantinos, MSc
5Zhao, Jing Hua, PhD
6Song, Kijoung, PhD
7Yuan, Xin, PhD
8Johnson, Toby, PhD
9Ashford, Sofie, BSc
10Inouye, Michael, MSc
11Luben, Robert, BSc
12Sims, Matthew, BSc
13Hadley, David, MSc
14McArdle, Wendy, PhD
15Barter, Philip, Prof
16Kesäniemi, Y Antero, Prof
17Mahley, Robert W, Prof
18McPherson, Ruth, Prof
19Grundy, Scott M, Prof
20Bingham, Sheila A, Prof
21Khaw, Kay-Tee, Prof
22Loos, Ruth JF, PhD
23Waeber, Gérard, Prof
24Barroso, Inês, PhD
25Strachan, David P, Prof
26Deloukas, Panagiotis, PhD
27Vollenweider, Peter, MD
28Wareham, Nicholas J, Prof
29Mooser, Vincent, MD
30Wellcome Trust Case Control Consortium
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descriptionSummary 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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1Adult
2Aged
3Cardiovascular disease
4Cardiovascular Diseases
5Cardiovascular Diseases - epidemiology
6Cardiovascular Diseases - genetics
7Cholesterol
8Cholesterol, LDL - blood
9Cholesterol, LDL - genetics
10Cholesterol, LDL - physiology
11Chromosomes
12Chromosomes, Human, Pair 1 - genetics
13Cohort Studies
14Colaus Study
15Diet
16Europe
17Europe - epidemiology
18European Continental Ancestry Group
19European Continental Ancestry Group - genetics
20Fast track
21Fast track — Articles
22Female
23Genetic Variation
24Genetic Variation - genetics
25Genome
26Genome, Human
27Genomics
28Human
29Humans
30Internal Medicine
31Linear Models
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35Medical research
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37Pair 1
38peptides
39Polymorphism
40Polymorphism, Single Nucleotide
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43Single Nucleotide
44Studies
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titleLDL-cholesterol concentrations: a genome-wide association study
authorSandhu, Manjinder S, Dr ; Waterworth, Dawn M, PhD ; Debenham, Sally L, PhD ; Wheeler, Eleanor, PhD ; Papadakis, Konstantinos, MSc ; Zhao, Jing Hua, PhD ; Song, Kijoung, PhD ; Yuan, Xin, PhD ; Johnson, Toby, PhD ; Ashford, Sofie, BSc ; Inouye, Michael, MSc ; Luben, Robert, BSc ; Sims, Matthew, BSc ; Hadley, David, MSc ; McArdle, Wendy, PhD ; Barter, Philip, Prof ; Kesäniemi, Y Antero, Prof ; Mahley, Robert W, Prof ; McPherson, Ruth, Prof ; Grundy, Scott M, Prof ; Bingham, Sheila A, Prof ; Khaw, Kay-Tee, Prof ; Loos, Ruth JF, PhD ; Waeber, Gérard, Prof ; Barroso, Inês, PhD ; Strachan, David P, Prof ; Deloukas, Panagiotis, PhD ; Vollenweider, Peter, MD ; Wareham, Nicholas J, Prof ; Mooser, Vincent, MD
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0Sandhu, Manjinder S, Dr
1Waterworth, Dawn M, PhD
2Debenham, Sally L, PhD
3Wheeler, Eleanor, PhD
4Papadakis, Konstantinos, MSc
5Zhao, Jing Hua, PhD
6Song, Kijoung, PhD
7Yuan, Xin, PhD
8Johnson, Toby, PhD
9Ashford, Sofie, BSc
10Inouye, Michael, MSc
11Luben, Robert, BSc
12Sims, Matthew, BSc
13Hadley, David, MSc
14McArdle, Wendy, PhD
15Barter, Philip, Prof
16Kesäniemi, Y Antero, Prof
17Mahley, Robert W, Prof
18McPherson, Ruth, Prof
19Grundy, Scott M, Prof
20Bingham, Sheila A, Prof
21Khaw, Kay-Tee, Prof
22Loos, Ruth JF, PhD
23Waeber, Gérard, Prof
24Barroso, Inês, PhD
25Strachan, David P, Prof
26Deloukas, Panagiotis, PhD
27Vollenweider, Peter, MD
28Wareham, Nicholas J, Prof
29Mooser, Vincent, MD
aucorpWellcome Trust Case Control Consortium
formatjournal
genrearticle
ristypeJOUR
atitleLDL-cholesterol concentrations: a genome-wide association study
jtitleLancet
addtitleLancet
date2008
risdate2008
volume371
issue9611
spage483
epage491
pages483-491
issn0140-6736
eissn1474-547X
codenLANCAO
notes
0Members listed at end of paper
1Contributed equally
abstractSummary 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.
copEngland
pubElsevier Ltd
pmid18262040
doi10.1016/S0140-6736(08)60208-1
oafree_for_read