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PMID: 19060906 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Common variants at 30 loci contribute to polygenic dyslipidemia.

Nature genetics ·Vol. 41 ·No. 1 ·2009-01-00 ·Pages 56-65

Kathiresan S, Willer CJ, Peloso GM, Demissie S, Musunuru K, Schadt EE, Kaplan L, Bennett D, Li Y, Tanaka T, Voight BF, Bonnycastle LL, Jackson AU, Crawford G, Surti A, Guiducci C, Burtt NP, Parish S, Clarke R, Zelenika D, Kubalanza KA, Morken MA, Scott LJ, Stringham HM, Galan P, Swift AJ, Kuusisto J, Bergman RN, Sundvall J, Laakso M, Ferrucci L, Scheet P, Sanna S, Uda M, Yang Q, Lunetta KL, Dupuis J, de Bakker PI, O'Donnell CJ, Chambers JC, Kooner JS, Hercberg S, Meneton P, Lakatta EG, Scuteri A, Schlessinger D, Tuomilehto J, Collins FS, Groop L, Altshuler D, Collins R, Lathrop GM, Melander O, Salomaa V, Peltonen L, Orho-Melander M, Ordovas JM, Boehnke M, Abecasis GR, Mohlke KL, Cupples LA

Abstract

Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.

MeSH Terms
Adult Alleles Cholesterol, HDL/blood Cholesterol, LDL/blood Delta-5 Fatty Acid Desaturase Dyslipidemias/blood,genetics Female Gene Expression Regulation Genome-Wide Association Study Humans Liver/metabolism Male Meta-Analysis as Topic Middle Aged Multifactorial Inheritance/genetics Phenotype Polymorphism, Single Nucleotide/genetics Quantitative Trait Loci/genetics RNA, Messenger/genetics,metabolism Reproducibility of Results Syndrome Triglycerides/blood
Chemicals
Cholesterol, HDL Cholesterol, LDL Delta-5 Fatty Acid Desaturase RNA, Messenger Triglycerides FADS1 protein, human
Authors & Affiliations
61 authors, click to expand affiliations / ORCID
Kathiresan Sekar
Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Willer Cristen J
Peloso Gina M
Demissie Serkalem
Musunuru Kiran
Schadt Eric E
Kaplan Lee
Bennett Derrick
Li Yun
Tanaka Toshiko
Voight Benjamin F
Bonnycastle Lori L
Jackson Anne U
Crawford Gabriel
Surti Aarti
Guiducci Candace
Burtt Noel P
Parish Sarah
Clarke Robert
Zelenika Diana
Kubalanza Kari A
Morken Mario A
Scott Laura J
Stringham Heather M
Galan Pilar
Swift Amy J
Kuusisto Johanna
Bergman Richard N
Sundvall Jouko
Laakso Markku
Ferrucci Luigi
Scheet Paul
Sanna Serena
Uda Manuela
Yang Qiong
Lunetta Kathryn L
Dupuis Josée
de Bakker Paul I W
O'Donnell Christopher J
Chambers John C
Kooner Jaspal S
Hercberg Serge
Meneton Pierre
Lakatta Edward G
Scuteri Angelo
Schlessinger David
Tuomilehto Jaakko
Collins Francis S
Groop Leif
Altshuler David
Collins Rory
Lathrop G Mark
Melander Olle
Salomaa Veikko
Peltonen Leena
Orho-Melander Marju
Ordovas Jose M
Boehnke Michael
Abecasis Gonçalo R
Mohlke Karen L
Cupples L Adrienne
References (50)
50 references, click to expand
  1. Cardiovascular risk factor changes in Finland, 1972-1997.
    Int J Epidemiol. 2000 Feb;29(1):49-56 PMID: 10750603
  2. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9.
    Nat Genet. 2005 Feb;37(2):161-5 PMID: 15654334
  3. ATP binding cassette transporter G5 and G8 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin.
    J Lipid Res. 2004 Apr;45(4):653-6 PMID: 14703505
  4. Studies on the mechanism of fatty acid synthesis. XVI. Preparation and general properties of acyl-malonyl acyl carrier protein-condensing enzyme from Escherichia coli.
    J Biol Chem. 1966 Mar 10;241(5):1159-65 PMID: 5327099
  5. Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL.
    Nat Genet. 2007 Apr;39(4):513-6 PMID: 17322881
  6. NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol.
    J Biol Chem. 2004 Nov 19;279(47):48865-75 PMID: 15358785
  7. Common genetic variants of the FADS1 FADS2 gene cluster and their reconstructed haplotypes are associated with the fatty acid composition in phospholipids.
    Hum Mol Genet. 2006 Jun 1;15(11):1745-56 PMID: 16670158
  8. The Malmo Diet and Cancer Study. Design and feasibility.
    J Intern Med. 1993 Jan;233(1):45-51 PMID: 8429286
  9. Control of pancreas and liver gene expression by HNF transcription factors.
    Science. 2004 Feb 27;303(5662):1378-81 PMID: 14988562
  10. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.
    Science. 2007 Jun 1;316(5829):1331-6 PMID: 17463246
  11. ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial infarction. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group.
    Lancet. 1992 Mar 28;339(8796):753-70 PMID: 1347801
  12. The functional Thr130Ile and Val255Met polymorphisms of the hepatocyte nuclear factor-4alpha (HNF4A): gene associations with type 2 diabetes or altered beta-cell function among Danes.
    J Clin Endocrinol Metab. 2005 May;90(5):3054-9 PMID: 15728204
  13. Identification of Tim4 as a phosphatidylserine receptor.
    Nature. 2007 Nov 15;450(7168):435-9 PMID: 17960135
  14. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment.
    Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):2069-74 PMID: 15677715
  15. Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis.
    Mol Cell Biol. 2001 Feb;21(4):1393-403 PMID: 11158324
  16. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans.
    Nat Genet. 2008 Feb;40(2):189-97 PMID: 18193044
  17. Polymorphisms associated with cholesterol and risk of cardiovascular events.
    N Engl J Med. 2008 Mar 20;358(12):1240-9 PMID: 18354102
  18. Mapping the genetic architecture of gene expression in human liver.
    PLoS Biol. 2008 May 6;6(5):e107 PMID: 18462017
  19. Newly identified loci that influence lipid concentrations and risk of coronary artery disease.
    Nat Genet. 2008 Feb;40(2):161-9 PMID: 18193043
  20. Low-density lipoprotein receptor-related protein interacts with MafB, a regulator of hindbrain development.
    FEBS Lett. 2004 May 7;565(1-3):23-7 PMID: 15135046
  21. An investigation of coronary heart disease in families. The Framingham offspring study.
    Am J Epidemiol. 1979 Sep;110(3):281-90 PMID: 474565
  22. A polymorphism in the protease-like domain of apolipoprotein(a) is associated with severe coronary artery disease.
    Arterioscler Thromb Vasc Biol. 2007 Sep;27(9):2030-6 PMID: 17569884
  23. LDL-cholesterol concentrations: a genome-wide association study.
    Lancet. 2008 Feb 9;371(9611):483-91 PMID: 18262040
  24. Genetic analysis of 103 candidate genes for coronary artery disease and associated phenotypes in a founder population reveals a new association between endothelin-1 and high-density lipoprotein cholesterol.
    Am J Hum Genet. 2007 Apr;80(4):673-82 PMID: 17357073
  25. Reduction of plasma lipids, lipoproteins, and apoproteins by dietary fish oils in patients with hypertriglyceridemia.
    N Engl J Med. 1985 May 9;312(19):1210-6 PMID: 3990714
  26. Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.
    Am J Hum Genet. 2008 Jan;82(1):139-49 PMID: 18179892
  27. Targeted mutation of plasma phospholipid transfer protein gene markedly reduces high-density lipoprotein levels.
    J Clin Invest. 1999 Mar;103(6):907-14 PMID: 10079112
  28. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.
    Science. 2007 Jun 1;316(5829):1341-5 PMID: 17463248
  29. A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study.
    BMC Med Genet. 2007 Sep 19;8 Suppl 1:S17 PMID: 17903299
  30. A molecular defect causing fish eye disease: an amino acid exchange in lecithin-cholesterol acyltransferase (LCAT) leads to the selective loss of alpha-LCAT activity.
    Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4855-9 PMID: 2052566
  31. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.
    Nat Genet. 2003 Jun;34(2):154-6 PMID: 12730697
  32. The private hepatocyte nuclear factor-1alpha G319S variant is associated with plasma lipoprotein variation in Canadian Oji-Cree.
    Arterioscler Thromb Vasc Biol. 2000 Jan;20(1):217-22 PMID: 10634821
  33. Estimation of the multiple testing burden for genomewide association studies of nearly all common variants.
    Genet Epidemiol. 2008 May;32(4):381-5 PMID: 18348202
  34. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.
    N Engl J Med. 2006 Mar 23;354(12):1264-72 PMID: 16554528
  35. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol.
    Am J Hum Genet. 2006 Mar;78(3):410-22 PMID: 16465619
  36. Mechanism of hypertriglyceridemia in human apolipoprotein (apo) CIII transgenic mice. Diminished very low density lipoprotein fractional catabolic rate associated with increased apo CIII and reduced apo E on the particles.
    J Clin Invest. 1992 Nov;90(5):1889-900 PMID: 1430212
  37. Extensions to pedigree analysis. IV. Covariance components models for multivariate traits.
    Am J Med Genet. 1983 Mar;14(3):513-24 PMID: 6859102
  38. Angiopoietin-like protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase.
    J Lipid Res. 2002 Nov;43(11):1770-2 PMID: 12401877
  39. The tetratricopeptide repeat: a structural motif mediating protein-protein interactions.
    Bioessays. 1999 Nov;21(11):932-9 PMID: 10517866
  40. Hepatocyte nuclear factor-1alpha is an essential regulator of bile acid and plasma cholesterol metabolism.
    Nat Genet. 2001 Apr;27(4):375-82 PMID: 11279518
  41. The -514 C->T hepatic lipase promoter region polymorphism and plasma lipids: a meta-analysis.
    J Clin Endocrinol Metab. 2004 Aug;89(8):3858-63 PMID: 15292318
  42. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters.
    Science. 2000 Dec 1;290(5497):1771-5 PMID: 11099417
  43. The Third Generation Cohort of the National Heart, Lung, and Blood Institute's Framingham Heart Study: design, recruitment, and initial examination.
    Am J Epidemiol. 2007 Jun 1;165(11):1328-35 PMID: 17372189
  44. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III).
    JAMA. 2001 May 16;285(19):2486-97 PMID: 11368702
  45. Increased prebeta-high density lipoprotein, apolipoprotein AI, and phospholipid in mice expressing the human phospholipid transfer protein and human apolipoprotein AI transgenes.
    J Clin Invest. 1996 Nov 15;98(10):2373-80 PMID: 8941656
  46. Common single-nucleotide polymorphisms act in concert to affect plasma levels of high-density lipoprotein cholesterol.
    Am J Hum Genet. 2007 Dec;81(6):1298-303 PMID: 17952847
  47. A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease.
    Nat Genet. 2007 Aug;39(8):995-9 PMID: 17632509
  48. A HapMap harvest of insights into the genetics of common disease.
    J Clin Invest. 2008 May;118(5):1590-605 PMID: 18451988
  49. Factors of risk in the development of coronary heart disease--six year follow-up experience. The Framingham Study.
    Ann Intern Med. 1961 Jul;55:33-50 PMID: 13751193
  50. Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver.
    J Biol Chem. 2004 Nov 26;279(48):50630-8 PMID: 15385538
Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.291
Published
2009-01-00
Epub
2008-00-07
Pages
56-65
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC2881676
Subset
IM
Grants
NHLBI NIH HHS · N01-HC-25195 · United States
NIDDK NIH HHS · P30 DK040561 · United States
NHLBI NIH HHS · U01 HL084729 · United States
NIDDK NIH HHS · R01 DK072193 · United States
Department of Health · United Kingdom
NHLBI NIH HHS · K23 HL083102 · United States
Medical Research Council · MC_U137686857 · United Kingdom
NIDDK NIH HHS · R01 DK062370 · United States
NIDDK NIH HHS · R01 DK029867 · United States
Intramural NIH HHS · Z01 HG000024 · United States
NHLBI NIH HHS · N01HC25195 · United States
Wellcome Trust · 089061 · United Kingdom
NHLBI NIH HHS · R01 HL054776 · United States
Cancer Research UK · United Kingdom
NIDDK NIH HHS · P30 DK040561-13 · United States
NIDDK NIH HHS · R56 DK062370 · United States
NHGRI NIH HHS · N01HG65403 · United States
NHGRI NIH HHS · R01 HG002651 · United States
British Heart Foundation · United Kingdom
NIDDK NIH HHS · DK072193 · United States
NHLBI NIH HHS · HL-54776 · United States
NHLBI NIH HHS · HL084729 · United States
NIDDK NIH HHS · U01 DK062370 · United States
NHGRI NIH HHS · HG02651 · United States
NIDDK NIH HHS · DK062370 · United States
NIDDK NIH HHS · R01 DK075030 · United States
NHLBI NIH HHS · K23 HL083102-03 · United States
PHS HHS · 53-K06-5-10 · United States
Corrections
CommentIn
PMID: 19112455
External Links
PubMed source DOI: 10.1038/ng.291 PMC Full Text View journal details
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