Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.[Erratum appears in Lancet. 2012 Aug 11;380(9841):564]

MedStar author(s):
Citation: Lancet. 380(9841):572-80, 2012 Aug 11.PMID: 22607825Institution: MedStar Health Research InstituteForm of publication: Journal ArticleMedline article type(s): Journal Article | Meta-Analysis | Research Support, N.I.H., Extramural | Research Support, Non-U.S. Gov'tSubject headings: *Cholesterol, HDL/bl [Blood] | *Mendelian Randomization Analysis/mt [Methods] | *Myocardial Infarction/bl [Blood] | Biological Markers/bl [Blood] | Case-Control Studies | Cholesterol, LDL/bl [Blood] | Gene Frequency | Genetic Predisposition to Disease | Humans | Lipase/ge [Genetics] | Myocardial Infarction/ep [Epidemiology] | Myocardial Infarction/et [Etiology] | Myocardial Infarction/ge [Genetics] | Polymorphism, Single Nucleotide | Prospective Studies | Risk FactorsLocal holdings: Available online from MWHC library: 1995 - present, Available in print through MWHC library: 1983 - 2007ISSN:
  • 0140-6736
Name of journal: LancetAbstract: 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.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)).FUNDING: US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research. Copyright 2012 Elsevier Ltd. All rights reserved.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.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.All authors: Abecasis GR, Altshuler D, Anand S, Ardissino D, Barbalic M, Berger K, Blankenberg S, Boehnke M, Boer JM, Boerwinkle E, Burnett MS, Burtt NP, Buysschaert I, Chen L, Clarke R, Cupples LA, Daly MJ, Danesh J, de Bakker PI, de Boer A, de Faire U, Demissie S, Deneer VH, Devaney J, Diemert P, Ding EL, Do R, El Mokhtari NE, Elbers CC, Elosua R, Engert JC, Epstein SE, Erdmann J, Fischer M, Fox KA, Frikke-Schmidt R, Frossard P, Gabriel S, Gigante B, Girelli D, Gonzalez E, Grobbee DE, Guiducci C, Hall AS, Havulinna A, Hengstenberg C, Hindy G, Hofker MH, Holm H, Hopewell JC, Ingelsson E, Jensen MK, Johnson T, Kamphuisen PW, Kathiresan S, Klungel OH, Konig IR, Lambrechts D, Li M, Lokki ML, Maitland-van der Zee AH, Mannucci PM, Marrugat J, Martinelli N, McKeown PP, McPherson R, Melander O, Mohlke KL, Mooser V, Morgan T, Musunuru K, Newton-Cheh C, Nieminen MS, O'Donnell CJ, Onland-Moret NC, Ordovas JM, Orho-Melander M, Overvad K, Patterson CC, Peden J, Peloso GM, Peltonen L, Perola M, Peters BJ, Pirruccello JP, Purcell S, Rader DJ, Rasheed A, Reilly MP, Rimm E, Ripatti S, Roberts R, Rubin D, Saleheen D, Salomaa V, Samani NJ, Schafer A, Schillert A, Schreiber S, Schrezenmeir J, Schunkert H, Schwartz SM, Sinisalo J, Siscovick D, Spertus J, Stefansson K, Stewart A, Stoll M, Surakka I, Surti A, Thompson JF, Thorgeirsson G, Thorleifsson G, Thorsteinsdottir U, Tybjaerg-Hansen A, Van de Werf F, van der Schouw YT, Verschuren WM, Voight BF, Watkins H, Wijmenga C, Wild P, Willenborg C, Willer C, Zeller T, Ziegler ADigital Object Identifier: Date added to catalog: 2013-09-17
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Item type Current library Collection Call number Status Date due Barcode
Journal Article MedStar Authors Catalog Article Available 22607825

Available online from MWHC library: 1995 - present, Available in print through MWHC library: 1983 - 2007

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.

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)).

FUNDING: US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research. Copyright 2012 Elsevier Ltd. All rights reserved.

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.

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.

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