Common variants at 30 loci contribute to polygenic dyslipidemia

被引：1076

作者：

Kathiresan, Sekar ^{[1
,2
,3
,4
,5
,6
,7
]}

Willer, Cristen J. ^{[8
]}

Peloso, Gina M. ^{[5
,6
]}

Demissie, Serkalem ^{[5
,6
]}

Musunuru, Kiran ^{[1
,2
,3
]}

Schadt, Eric E. ^{[10
]}

Kaplan, Lee ^{[11
]}

Bennett, Derrick ^{[12
]}

Li, Yun ^{[8
]}

Tanaka, Toshiko ^{[13
]}

Voight, Benjamin F. ^{[3
,4
,14
]}

Bonnycastle, Lori L. ^{[9
]}

Jackson, Anne U. ^{[8
]}

Crawford, Gabriel ^{[4
]}

Surti, Aarti ^{[4
]}

Guiducci, Candace ^{[4
]}

Burtt, Noel P. ^{[4
]}

Parish, Sarah ^{[12
]}

Clarke, Robert ^{[12
]}

Zelenika, Diana ^{[16
]}

Kubalanza, Kari A. ^{[9
,15
]}

Morken, Mario A. ^{[9
,15
]}

Scott, Laura J. ^{[8
]}

Stringham, Heather M. ^{[8
]}

Galan, Pilar ^{[17
]}

Swift, Amy J. ^{[9
,15
]}

Kuusisto, Johanna ^{[18
]}

Bergman, Richard N. ^{[19
]}

Sundvall, Jouko ^{[20
]}

Laakso, Markku ^{[18
]}

Ferrucci, Luigi ^{[13
]}

Scheet, Paul ^{[8
]}

Sanna, Serena ^{[21
]}

Uda, Manuela ^{[21
]}

Yang, Qiong ^{[5
,6
]}

Lunetta, Kathryn L. ^{[5
,6
]}

Dupuis, Josee ^{[5
,6
]}

de Bakker, Paul I. W. ^{[22
]}

O'Donnell, Christopher J. ^{[5
,6
,23
]}

Chambers, John C. ^{[24
]}

Kooner, Jaspal S. ^{[25
]}

Hercberg, Serge ^{[17
]}

Meneton, Pierre ^{[26
]}

Lakatta, Edward G. ^{[27
]}

Scuteri, Angelo ^{[28
]}

Schlessinger, David ^{[29
]}

Tuomilehto, Jaakko ^{[20
]}

Collins, Francis S. ^{[9
,15
]}

Groop, Leif ^{[30
,31
]}

Altshuler, David ^{[4
,7
,14
,32
]}

机构：

[1] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA

[2] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA

[3] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[4] Harvard & Massachusetts Inst, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02142 USA

[5] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA

[6] Boston Univ, Framingham, MA 01702 USA

[7] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[8] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[9] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA

[10] Merck & Co Inc, Rosetta Inpharmat LLC, Seattle, WA 98109 USA

[11] Massachusetts Gen Hosp, Weight Ctr, Boston, MA 02114 USA

[12] Univ Oxford, Clin Trial Serv Unit, Oxford OX3 7LF, England

[13] NIA, Clin Res Branch, NIH, Baltimore, MD 21225 USA

[14] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA

[15] NHGRI, NIH, Bethesda, MD 20892 USA

[16] Inst Genom Commissariat Energie Atom, Ctr Natl Genotypage, F-91057 Evry, France

[17] Paris 13 SMBH, CNAM, INRA, INSERM,U557,U1125, Bobigny, France

[18] Univ Kuopio, Dept Med, SF-70210 Kuopio, Finland

[19] Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90033 USA

[20] Natl Publ Hlth Inst, Dept Hlth Promot & Chron Dis Prevent, Diabet Unit, SF-00300 Helsinki, Finland

[21] CNR, Ist Neurogenet & Neurofarmacol, I-08045 Cagliari, Italy

[22] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA

[23] Natl Lung & Blood Inst, NIH, Framingham, MA 01702 USA

[24] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London W2 1PG, England

[25] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Hammersmith Hosp, London W12 0NN, England

[26] Ctr Rech Cordeliers, INSERM, U872, F-75270 Paris 06, France

[27] NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, Baltimore, MD 21224 USA

[28] Ist Nazl Ricovero & Cura Anziani, Unita Operat Geriatria, I-00189 Rome, Italy

[29] NIA, Genet Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA

[30] Lund Univ, Malmo Univ Hosp, Dept Clin Sci Diabet & Endocrinol, S-20502 Malmo, Sweden

[31] Helsinki Univ Hosp, Dept Med, Helsinki 00029, Finland

[32] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[33] Lund Univ, Malmo Univ Hosp, Dept Clin Sci Hypertens & Cardiovasc Dis, S-20502 Malmo, Sweden

[34] Univ Helsinki, Inst Mol Med, Helsinki 00029, Finland

[35] Natl Publ Hlth Inst, Chron Dis Epidemiol Unit, Dept Hlth Promot & Chron Dis Prevent, SF-00300 Helsinki, Finland

[36] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[37] Tufts Univ, Human Nutr Res Ctr Aging, Jean Mayer US Dept Agr, Nutr & Genom Lab, Boston, MA 02111 USA

[38] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA

来源：

NATURE GENETICS | 2009年 / 41卷 / 01期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

HIGH-DENSITY-LIPOPROTEIN; GENOME-WIDE ASSOCIATION; HEPATOCYTE NUCLEAR FACTOR-1-ALPHA; PHOSPHOLIPID TRANSFER PROTEIN; CORONARY-HEART-DISEASE; GENE-EXPRESSION; PLASMA-LIPIDS; CHOLESTEROL; RECEPTOR; PCSK9;

D O I：

10.1038/ng.291

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：56 / 65

页数：10

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