Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study

被引：1731

作者：

Voight, Benjamin F. ^{[3
,4
,7
]}

Peloso, Gina M. ^{[8
,9
]}

Orho-Melander, Marju

Frikke-Schmidt, Ruth ^{[11
]}

Barbalic, Maja ^{[12
]}

Jensen, Majken K. ^{[13
]}

Hindy, George

Holm, Hilma ^{[16
]}

Ding, Eric L. ^{[14
,15
]}

Johnson, Toby ^{[17
]}

Schunkert, Heribert ^{[18
]}

Samani, Nilesh J. ^{[20
,22
]}

Clarke, Robert ^{[27
,28
]}

Hopewell, Jemma C. ^{[27
,28
]}

Thompson, John F. ^{[21
]}

Li, Mingyao

Thorleifsson, Gudmar ^{[16
]}

Newton-Cheh, Christopher ^{[6
,7
]}

Musunuru, Kiran ^{[7
]}

Pirruccello, James P. ^{[7
]}

Saleheen, Danish ^{[25
]}

Chen, Li ^{[26
]}

Stewart, Alexandre F. R. ^{[26
]}

Schillert, Arne ^{[19
]}

Thorsteinsdottir, Unnur ^{[16
,30
]}

Thorgeirsson, Gudmundur ^{[30
,31
]}

Anand, Sonia ^{[32
,33
,34
]}

Engert, James C. ^{[35
,36
]}

Morgan, Thomas ^{[37
]}

Spertus, John ^{[38
,39
]}

Stoll, Monika ^{[40
]}

Berger, Klaus ^{[41
]}

Martinelli, Nicola ^{[42
]}

Girelli, Domenico ^{[42
]}

McKeown, Pascal P. ^{[43
]}

Patterson, Christopher C. ^{[43
]}

Epstein, Stephen E. ^{[44
]}

Devaney, Joseph ^{[44
]}

Burnett, Mary-Susan ^{[44
]}

Mooser, Vincent ^{[45
,46
]}

Ripatti, Samuli ^{[47
]}

Surakka, Ida ^{[47
]}

Nieminen, Markku S. ^{[47
,48
]}

Sinisalo, Juha ^{[48
]}

Lokki, Marja-Liisa ^{[49
]}

Perola, Markus ^{[50
]}

Havulinna, Aki ^{[50
]}

de Faire, Ulf ^{[52
,53
]}

Gigante, Bruna ^{[52
,53
]}

Ingelsson, Erik ^{[54
]}

机构：

[1] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA 02114 USA

[2] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA 02114 USA

[3] Univ Penn, Dept Pharmacol, Philadelphia, PA 19104 USA

[4] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA

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

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

[7] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

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

[9] NHLBI, Framingham Heart Study, Framingham, MA USA

[10] Lund Univ, Skania Univ Hosp, Dept Clin Sci Hypertens & Cardiovasc Dis, Malmo, Sweden

[11] Copenhagen Univ Hosp, Rigshosp, Dept Clin Biochem, Mol Genet Sect, Copenhagen, Denmark

[12] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA

[13] Harvard Univ, Sch Publ Hlth, Dept Nutr & Epidemiol, Boston, MA 02115 USA

[14] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA

[15] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA

[16] deCODE Genet, Reykjavik, Iceland

[17] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, Genome Ctr, London, England

[18] Med Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany

[19] Med Univ Lubeck, Inst Med Biometrie & Stat, D-23538 Lubeck, Germany

[20] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England

[21] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England

[22] Glenfield Gen Hosp, Leicester Natl Inst Hlth Res Biomed Res Unit Card, Leicester LE3 9QP, Leics, England

[23] Univ Penn, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA

[24] Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA

[25] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England

[26] Univ Ottawa, Inst Heart, John & Jennifer Ruddy Canadian Cardiovasc Genet C, Ottawa, ON, Canada

[27] Univ Oxford, Clin Trial Serv Unit, Oxford, England

[28] Univ Oxford, Epidemiol Studies Unit, Oxford, England

[29] Univ Oxford, Dept Cardiovasc Med, Oxford, England

[30] Univ Iceland, Fac Med, Reykjavik, Iceland

[31] Landspitali Univ Hosp, Div Cardiol, Dept Internal Med, Reykjavik, Iceland

[32] McMaster Univ, Populat Hlth Res Inst, Hamilton Hlth Sci, Hamilton, ON, Canada

[33] McMaster Univ, Dept Med, Hamilton, ON, Canada

[34] McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada

[35] McGill Univ, Dept Med, Montreal, PQ, Canada

[36] McGill Univ, Dept Human Genet, Montreal, PQ, Canada

[37] Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37212 USA

[38] St Lukes Hosp, Mid Amer Heart Inst, Kansas City, MO 64111 USA

[39] Univ Missouri, Kansas City, MO 64110 USA

[40] Univ Munster, Leibniz Inst Arteriosclerosis Res, Munster, Germany

[41] Univ Munster, Inst Epidemiol & Social Med, Munster, Germany

[42] Univ Verona, Dept Med, I-37100 Verona, Italy

[43] Queens Univ Belfast, Inst Clin Sci, Ctr Publ Hlth, Belfast, Antrim, North Ireland

[44] Washington Hosp Ctr, MedStar Res Inst, Cardiovasc Res Inst, Washington, DC 20010 USA

[45] GlaxoSmithKline, Div Genet, King Of Prussia, PA USA

[46] GlaxoSmithKline, Drug Discovery, King Of Prussia, PA USA

[47] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland

[48] Univ Helsinki, Cent Hosp, Dept Med, Div Cardiol, Helsinki, Finland

[49] Univ Helsinki, Transplantat Lab, Haartman Inst, Helsinki, Finland

[50] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Chron Dis Epidemiol & Prevent Unit, Helsinki, Finland

来源：

LANCET | 2012年 / 380卷 / 9841期

基金：

英国惠康基金; 美国国家卫生研究院;

关键词：

HIGH-DENSITY-LIPOPROTEIN; ENDOTHELIAL LIPASE; CARDIOVASCULAR-DISEASE; GENETIC-VARIANTS; LOCI; ASSOCIATION; ATHEROSCLEROSIS; SUSCEPTIBILITY; CONTRIBUTE;

D O I：

10.1016/S0140-6736(12)60312-2

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal. Methods We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. Findings Carriers of the LIPG 396Ser allele (2.6% frequency) had higher HDL cholesterol (0.14 mmol/L higher, p=8x10(-13)) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0.87, 95% CI 0.84-0.91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0.99, 95% CI 0.88-1.11, p=0.85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0.62, 95% CI 0.58-0.66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0.93, 95% CI 0.68-1.26, p=0.63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1.54, 95% CI 1.45-1.63) was concordant with that from genetic score (OR 2.13, 95% CI 1.69-2.69, p=2x10(-10)). Interpretation Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.

引用

页码：572 / 580

页数：9

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