Common variants at 30 loci contribute to polygenic dyslipidemia

Nature Genetics

Volumn 41, Issue 1, 2009, Pages 56-65

  Kathiresan, Sekar ^a,b,c,d   Willer, Cristen J ^e   Peloso, Gina M ^c,f   Demissie, Serkalem ^c,f   Musunuru, Kiran ^a   Schadt, Eric E ^g   Kaplan, Lee ^a   Bennett, Derrick ^h   Li, Yun ^e   Tanaka, Toshiko ⁱ   Voight, Benjamin F ^a,b   Bonnycastle, Lori L ^j   Jackson, Anne U ^e   Crawford, Gabriel ^b   Surti, Aarti ^b   Guiducci, Candace ^b   Burtt, Noel P ^b   Parish, Sarah ^h   Clarke, Robert ^h   Zelenika, Diana ^k   Kubalanza, Kari A ^j   Morken, Mario A ^j   Scott, Laura J ^e   Stringham, Heather M ^e   Galan, Pilar ^l   Swift, Amy J ^j   Kuusisto, Johanna ^m   Bergman, Richard N ⁿ   Sundvall, Jouko ^o   Laakso, Markku ^m   Ferrucci, Luigi ⁱ   Scheet, Paul ^e   Sanna, Serena ^p   Uda, Manuela ^p   Yang, Qiong ^c,f   Lunetta, Kathryn L ^c,f   Dupuis, Josée ^c,f   De Bakker, Paul I W ^q   O'Donnell, Christopher J ^c,r   Chambers, John C ^s   Kooner, Jaspal S ^t   Hercberg, Serge ^l   Meneton, Pierre ^u   Lakatta, Edward G ^v   Scuteri, Angelo ^w   Schlessinger, David ^v   Tuomilehto, Jaakko ^o   Collins, Francis S ^j   Groop, Leif ^x,y   Altshuler, David ^a,b,d   Collins, Rory ^h   Lathrop, G Mark ^k   Melander, Olle ^x   Salomaa, Veikko ^o   Peltonen, Leena ^b,z,aa   Orho Melander, Marju ^x   Ordovas, Jose M ^ab   Boehnke, Michael ^e   Abecasis, Gonçalo R ^e   Mohlke, Karen L ^ac   Cupples, L Adrienne ^c,f   more..

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

^b MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

^c BOSTON UNIVERSITY   (United States)

^d HARVARD MEDICAL SCHOOL   (United States)

^e UNIVERSITY OF MICHIGAN   (United States)

^f BOSTON UNIVERSITY SCHOOL OF PUBLIC HEALTH   (United States)

^g ROSETTA INPHARMATICS   (United States)

^h UNIVERSITY OF OXFORD   (United Kingdom)

ⁱ NATIONAL INSTITUTE ON AGING   (United States)

^j NATIONAL HUMAN GENOME RESEARCH INSTITUTE   (United States)

^k CENTRE NATIONAL DE GÉNOTYPAGE   (France)

^l Paris 13 SMBH ^*  (France)

^m UNIVERSITY OF EASTERN FINLAND   (Finland)

ⁿ UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

^o NATIONAL PUBLIC HEALTH INSTITUTE   (Finland)

^p CNR   (Italy)

^q BRIGHAM AND WOMEN S HOSPITAL   (United States)

^r NATIONAL INSTITUTES OF HEALTH   (United States)

^s IMPERIAL COLLEGE LONDON   (United Kingdom)

^t HAMMERSMITH HOSPITAL   (United Kingdom)

^u CENTRE DE RECHERCHE DES CORDELIERS   (France)

^v NATIONAL INSTITUTE ON AGING   (United States)

^w INRCA   (Italy)

^x LUND UNIVERSITY HOSPITAL   (Sweden)

^y HELSINKI UNIVERSITY CENTRAL HOSPITAL   (Finland)

^z UNIVERSITY OF HELSINKI   (Finland)

^aa WELLCOME TRUST SANGER INSTITUTE   (United Kingdom)

^ab TUFTS UNIVERSITY   (United States)

^ac UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

more..

Author keywords

[No Author keywords available]

Indexed keywords

ABC TRANSPORTER; ACYL COENZYME A DESATURASE; AMAC1L2 ENZYME; CITRATE SYNTHASE; FADS1 ENZYME; FADS2 ENZYME; FADS3 ENZYME; HEPATOCYTE NUCLEAR FACTOR 1ALPHA; HEPATOCYTE NUCLEAR FACTOR 4ALPHA; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; LIPOPROTEIN; LOW DENSITY LIPOPROTEIN CHOLESTEROL; MEMBRANE PROTEIN; PEPTIDE DERIVATIVE; PHOSPHATIDYLCHOLINE STEROL ACYLTRANSFERASE; PHOSPHOLIPID TRANSFER PROTEIN; PROTEIN ABCG8; PROTEIN ANGPTL4; PROTEIN TIMD4; PROTEIN TTC39B; REGULATOR PROTEIN; TRANSCRIPTION FACTOR MAFB; TRIACYLGLYCEROL; UNCLASSIFIED DRUG;

ALLELE; ARTICLE; CONTROLLED STUDY; DYSLIPIDEMIA; GENE EXPRESSION; GENE LOCATION; GENE LOCUS; GENETIC ASSOCIATION; GENETIC SCREENING; GENOME; HUMAN; HUMAN TISSUE; LIPOPROTEIN BLOOD LEVEL; LIVER; MULTIFACTORIAL INHERITANCE; POLYGENIC DYSLIPIDEMIA; PRIORITY JOURNAL; SINGLE NUCLEOTIDE POLYMORPHISM;

ADULT; ALLELES; CHOLESTEROL, HDL; CHOLESTEROL, LDL; DYSLIPIDEMIAS; FEMALE; GENE EXPRESSION REGULATION; GENOME-WIDE ASSOCIATION STUDY; HUMANS; LIVER; MALE; META-ANALYSIS AS TOPIC; MIDDLE AGED; MULTIFACTORIAL INHERITANCE; PHENOTYPE; POLYMORPHISM, SINGLE NUCLEOTIDE; QUANTITATIVE TRAIT LOCI; REPRODUCIBILITY OF RESULTS; RNA, MESSENGER; SYNDROME; TRIGLYCERIDES;

EID: 58149163149     PISSN: 10614036     EISSN: 15461718     Source Type: Journal    
DOI: 10.1038/ng.291     Document Type: Article

References (50)

1. Manolio, T.A., Brooks, L.D. & Collins, F.S.A. HapMap harvest of insights into the genetics of common disease. J. Clin. Invest. 118, 1590-1605 (2008).
2. Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316, 1331-1336 (2007).
3. Kathiresan, S. et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat. Genet. 40, 189-197 (2008).
4. Willer, C.J. et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat. Genet. 40, 161-169 (2008).
5. Wallace, C. et al. Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia. Am. J. Hum. Genet. 82, 139-149 (2008).
6. Sandhu, M.S. et al. LDL-cholesterol concentrations: a genome-wide association study. Lancet 371, 483-491 (2008).
7. Kannel, W.B., Dawber, T.R., Kagan, A., Revotskie, N. & Stokes, J. III. Factors of risk in the development of coronary heart disease-six year follow-up experience. The Framingham Study. Ann. Intern. Med. 55, 33-50 (1961).
8. Kannel, W.B., Feinleib, M., McNamara, P.M., Garrison, R.J. & Castelli, W.P. An investigation of coronary heart disease in families. The Framingham offspring study. Am. J. Epidemiol. 110, 281-290 (1979).
9. Splansky, G.L. et al. The Third Generation Cohort of the National Heart, Lung, and Blood Institute's Framingham Heart Study: design, recruitment, and initial examination. Am. J. Epidemiol. 165, 1328-1335 (2007).
10. Pe'er, I., Yelensky, R., Altshuler, D. & Daly, M.J. Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet. Epidemiol. 32, 381-385 (2008).
11. Berglund, G., Elmstahl, S., Janzon, L. & Larsson, S.A. The Malmo Diet and Cancer Study. Design and feasibility. J. Intern. Med. 233, 45-51 (1993).
12. Vartiainen, E. et al. Cardiovascular risk factor changes in Finland, 1972-1997. Int. J. Epidemiol. 29, 49-56 (2000).
13. Scott, L.J. et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316, 1341-1345 (2007).
14. 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 339, 753-770 (1992).
15. Kajinami, K., Brousseau, M.E., Nartsupha, C., Ordovas, J.M. & Schaefer, E.J. ATP binding cassette transporter G5 and G8 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin. J. Lipid Res. 45, 653-656 (2004).
16. Romeo, S. et al. Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. Nat. Genet. 39, 513-516 (2007).
17. Schaeffer, L. et al. 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. 15, 1745-1756 (2006).
18. Ek, J. et al. 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. 90, 3054-3059 (2005).
19. Pare, G. et al. 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. 80, 673-682 (2007).
20. Spirin, V. et al. Common single-nucleotide polymorphisms act in concert to affect plasma levels of high-density lipoprotein cholesterol. Am. J. Hum. Genet. 81, 1298-1303 (2007).
21. Hegele, R.A. et al. The private hepatocyte nuclear factor-1alpha G319S variant is associated with plasma lipoprotein variation in Canadian Oji-Cree. Arterioscler. Thromb. Vasc. Biol. 20, 217-222 (2000).
22. Schadt, E.E. et al. Mapping the genetic architecture of gene expression in human liver. PLoS Biol. 6, e107 (2008).
23. Jiang, X. et al. 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. 98, 2373-2380 (1996).
24. Jiang, X.C. et al. Targeted mutation of plasma phospholipid transfer protein gene markedly reduces high-density lipoprotein levels. J. Clin. Invest. 103, 907-914 (1999).
25. Isaacs, A., Sayed-Tabatabaei, F.A., Njajou, O.T., Witteman, J.C. & van Duijn, C.M. The - 514 C->T hepatic lipase promoter region polymorphism and plasma lipids: a meta-analysis. J. Clin. Endocrinol. Metab. 89, 3858-3863 (2004).
26. Phillipson, B.E., Rothrock, D.W., Connor, W.E., Harris, W.S. & Illingworth, D.R. Reduction of plasma lipids, lipoproteins, and apoproteins by dietary fish oils in patients with hypertriglyceridemia. N. Engl. J. Med. 312, 1210-1216 (1985).
27. Blatch, G.L. & Lassle, M. The tetratricopeptide repeat: a structural motif mediating protein-protein interactions. Bioessays 21, 932-939 (1999).
28. Berge, K.E. et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 290, 1771-1775 (2000).
29. Funke, H. et al. 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. USA 88, 4855-4859 (1991).
30. Buch, S. et al. A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease. Nat. Genet. 39, 995-999 (2007).
31. Odom, D.T. et al. Control of pancreas and liver gene expression by HNF transcription factors. Science 303, 1378-1381 (2004).
32. Hayhurst, G.P., Lee, Y.H., Lambert, G., Ward, J.M. & Gonzalez, F.J. Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol. Cell. Biol. 21, 1393-1403 (2001).
33. Shih, D.Q. et al. Hepatocyte nuclear factor-1alpha is an essential regulator of bile acid and plasma cholesterol metabolism. Nat. Genet. 27, 375-382 (2001).
34. Yoshida, K., Shimizugawa, T., Ono, M. & Furukawa, H. Angiopoietin-like protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase. J. Lipid Res. 43, 1770-1772 (2002).
35. Toomey, R.E. & Wakil, S.J. 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. 241, 1159-1165 (1966).
36. Miyanishi, M. et al. Identification of Tim4 as a phosphatidylserine receptor. Nature 450, 435-439 (2007).
37. Petersen, H.H. et al. Low-density lipoprotein receptor-related protein interacts with MafB, a regulator of hindbrain development. FEBS Lett. 565, 23-27 (2004).
38. Aalto-Setala, K. et al. 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. 90, 1889-1900 (1992).
39. Luke, M.M. et al. A polymorphism in the protease-like domain of apolipoprotein(a) is associated with severe coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 27, 2030-2036 (2007).
40. 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 285, 2486-2497 (2001).
41. Cohen, J. et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet. 37, 161-165 (2005).
42. Abifadel, M. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34, 154-156 (2003).
43. Kotowski, I.K. et al. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am. J. Hum. Genet. 78, 410-422 (2006).
44. Maxwell, K.N., Fisher, E.A. & Breslow, J.L. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc. Natl. Acad. Sci. USA 102, 2069-2074 (2005).
45. Park, S.W., Moon, Y.A. & Horton, J.D. Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J. Biol. Chem. 279, 50630-50638 (2004).
46. Benjannet, S. et al. NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. J. Biol. Chem. 279, 48865-48875 (2004).
47. Cohen, J.C., Boerwinkle, E., Mosley, T.H. Jr & Hobbs, H.H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354, 1264-1272 (2006).
48. Kathiresan, S. et al. Polymorphisms associated with cholesterol and risk of cardiovascular events. N. Engl. J. Med. 358, 1240-1249 (2008).
49. Kathiresan, S. et al. A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study. BMC Med. Genet. 8 Suppl 1, S17 (2007).
50. Lange, K. & Boehnke, M. Extensions to pedigree analysis. IV. Covariance components models for multivariate traits. Am. J. Med. Genet. 14, 513-524 (1983).