Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study
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Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. / Voight, Benjamin F; Peloso, Gina M; Orho-Melander, Marju; Frikke-Schmidt, Ruth; Barbalic, Maja; Jensen, Majken K; Hindy, George; Hólm, Hilma; Ding, Eric L; Johnson, Toby; Schunkert, Heribert; Samani, Nilesh J; Clarke, Robert; Hopewell, Jemma C; Thompson, John F; Li, Mingyao; Thorleifsson, Gudmar; Newton-Cheh, Christopher; Musunuru, Kiran; Pirruccello, James P; Saleheen, Danish; Chen, Li; Stewart, Alexandre F R; Schillert, Arne; Thorsteinsdottir, Unnur; Thorgeirsson, Gudmundur; Anand, Sonia; Engert, James C; Morgan, Thomas; Spertus, John; Stoll, Monika; Berger, Klaus; Martinelli, Nicola; Girelli, Domenico; McKeown, Pascal P; Patterson, Christopher C; Epstein, Stephen E; Devaney, Joseph; Burnett, Mary-Susan; Mooser, Vincent; Ripatti, Samuli; Surakka, Ida; Nieminen, Markku S; Sinisalo, Juha; Lokki, Marja-Liisa; Perola, Markus; Havulinna, Aki; de Faire, Ulf; Gigante, Bruna; Ingelsson, Erik; Zeller, Tanja; Wild, Philipp; de Bakker, Paul I W; Klungel, Olaf H; Maitland-van der Zee, Anke-Hilse; Peters, Bas J M; de Boer, Anthonius; Grobbee, Diederick E; Kamphuisen, Pieter W; Deneer, Vera H M; Elbers, Clara C; Onland-Moret, N Charlotte; Hofker, Marten H; Wijmenga, Cisca; Verschuren, W M Monique; Boer, Jolanda M A; van der Schouw, Yvonne T; Rasheed, Asif; Frossard, Philippe; Demissie, Serkalem; Willer, Cristen; Do, Ron; Ordovas, Jose M; Abecasis, Gonçalo R; Boehnke, Michael; Mohlke, Karen L; Daly, Mark J; Guiducci, Candace; Burtt, Noël P; Surti, Aarti; Gonzalez, Elena; Purcell, Shaun; Gabriel, Stacey; Marrugat, Jaume; Peden, John; Erdmann, Jeanette; Diemert, Patrick; Willenborg, Christina; König, Inke R; Fischer, Marcus; Hengstenberg, Christian; Ziegler, Andreas; Buysschaert, Ian; Lambrechts, Diether; Van de Werf, Frans; Fox, Keith A; El Mokhtari, Nour Eddine; Rubin, Diana; Schrezenmeir, Jürgen; Schreiber, Stefan; Schäfer, Arne; Danesh, John; Blankenberg, Stefan; Roberts, Robert; McPherson, Ruth; Watkins, Hugh; Hall, Alistair S; Overvad, Kim; Rimm, Eric; Boerwinkle, Eric; Tybjaerg-Hansen, Anne; Cupples, L Adrienne; Reilly, Muredach P; Melander, Olle; Mannucci, Pier M; Ardissino, Diego; Siscovick, David; Elosua, Roberto; Stefansson, Kari; O'Donnell, Christopher J; Salomaa, Veikko; Rader, Daniel J; Peltonen, Leena; Schwartz, Stephen M; Altshuler, David; Kathiresan, Sekar.
in: LANCET, Jahrgang 380, Nr. 9841, 11.08.2012, S. 572-580.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study
AU - Voight, Benjamin F
AU - Peloso, Gina M
AU - Orho-Melander, Marju
AU - Frikke-Schmidt, Ruth
AU - Barbalic, Maja
AU - Jensen, Majken K
AU - Hindy, George
AU - Hólm, Hilma
AU - Ding, Eric L
AU - Johnson, Toby
AU - Schunkert, Heribert
AU - Samani, Nilesh J
AU - Clarke, Robert
AU - Hopewell, Jemma C
AU - Thompson, John F
AU - Li, Mingyao
AU - Thorleifsson, Gudmar
AU - Newton-Cheh, Christopher
AU - Musunuru, Kiran
AU - Pirruccello, James P
AU - Saleheen, Danish
AU - Chen, Li
AU - Stewart, Alexandre F R
AU - Schillert, Arne
AU - Thorsteinsdottir, Unnur
AU - Thorgeirsson, Gudmundur
AU - Anand, Sonia
AU - Engert, James C
AU - Morgan, Thomas
AU - Spertus, John
AU - Stoll, Monika
AU - Berger, Klaus
AU - Martinelli, Nicola
AU - Girelli, Domenico
AU - McKeown, Pascal P
AU - Patterson, Christopher C
AU - Epstein, Stephen E
AU - Devaney, Joseph
AU - Burnett, Mary-Susan
AU - Mooser, Vincent
AU - Ripatti, Samuli
AU - Surakka, Ida
AU - Nieminen, Markku S
AU - Sinisalo, Juha
AU - Lokki, Marja-Liisa
AU - Perola, Markus
AU - Havulinna, Aki
AU - de Faire, Ulf
AU - Gigante, Bruna
AU - Ingelsson, Erik
AU - Zeller, Tanja
AU - Wild, Philipp
AU - de Bakker, Paul I W
AU - Klungel, Olaf H
AU - Maitland-van der Zee, Anke-Hilse
AU - Peters, Bas J M
AU - de Boer, Anthonius
AU - Grobbee, Diederick E
AU - Kamphuisen, Pieter W
AU - Deneer, Vera H M
AU - Elbers, Clara C
AU - Onland-Moret, N Charlotte
AU - Hofker, Marten H
AU - Wijmenga, Cisca
AU - Verschuren, W M Monique
AU - Boer, Jolanda M A
AU - van der Schouw, Yvonne T
AU - Rasheed, Asif
AU - Frossard, Philippe
AU - Demissie, Serkalem
AU - Willer, Cristen
AU - Do, Ron
AU - Ordovas, Jose M
AU - Abecasis, Gonçalo R
AU - Boehnke, Michael
AU - Mohlke, Karen L
AU - Daly, Mark J
AU - Guiducci, Candace
AU - Burtt, Noël P
AU - Surti, Aarti
AU - Gonzalez, Elena
AU - Purcell, Shaun
AU - Gabriel, Stacey
AU - Marrugat, Jaume
AU - Peden, John
AU - Erdmann, Jeanette
AU - Diemert, Patrick
AU - Willenborg, Christina
AU - König, Inke R
AU - Fischer, Marcus
AU - Hengstenberg, Christian
AU - Ziegler, Andreas
AU - Buysschaert, Ian
AU - Lambrechts, Diether
AU - Van de Werf, Frans
AU - Fox, Keith A
AU - El Mokhtari, Nour Eddine
AU - Rubin, Diana
AU - Schrezenmeir, Jürgen
AU - Schreiber, Stefan
AU - Schäfer, Arne
AU - Danesh, John
AU - Blankenberg, Stefan
AU - Roberts, Robert
AU - McPherson, Ruth
AU - Watkins, Hugh
AU - Hall, Alistair S
AU - Overvad, Kim
AU - Rimm, Eric
AU - Boerwinkle, Eric
AU - Tybjaerg-Hansen, Anne
AU - Cupples, L Adrienne
AU - Reilly, Muredach P
AU - Melander, Olle
AU - Mannucci, Pier M
AU - Ardissino, Diego
AU - Siscovick, David
AU - Elosua, Roberto
AU - Stefansson, Kari
AU - O'Donnell, Christopher J
AU - Salomaa, Veikko
AU - Rader, Daniel J
AU - Peltonen, Leena
AU - Schwartz, Stephen M
AU - Altshuler, David
AU - Kathiresan, Sekar
N1 - Copyright © 2012 Elsevier Ltd. All rights reserved.
PY - 2012/8/11
Y1 - 2012/8/11
N2 - 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=8×10(-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=2×10(-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.FUNDING: US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.
AB - 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=8×10(-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=2×10(-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.FUNDING: US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.
KW - Biomarkers/blood
KW - Case-Control Studies
KW - Cholesterol, HDL/blood
KW - Cholesterol, LDL/blood
KW - Gene Frequency
KW - Genetic Predisposition to Disease
KW - Humans
KW - Lipase/genetics
KW - Mendelian Randomization Analysis/methods
KW - Myocardial Infarction/blood
KW - Polymorphism, Single Nucleotide
KW - Prospective Studies
KW - Risk Factors
U2 - 10.1016/S0140-6736(12)60312-2
DO - 10.1016/S0140-6736(12)60312-2
M3 - SCORING: Journal article
C2 - 22607825
VL - 380
SP - 572
EP - 580
JO - LANCET
JF - LANCET
SN - 0140-6736
IS - 9841
ER -