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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 LU ; Frikke-Schmidt, Ruth ; Barbalic, Maja ; Jensen, Majken K. ; Hindy, George ; Holm, Hilma ; Ding, Eric L. and Johnson, Toby , et al. (2012) In The Lancet 380(9841). p.572-580
Abstract
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
The Lancet
volume
380
issue
9841
pages
572 - 580
publisher
Elsevier
external identifiers
  • wos:000307511400030
  • scopus:84864845456
ISSN
1474-547X
DOI
10.1016/S0140-6736(12)60312-2
language
English
LU publication?
yes
id
8618e123-43cb-463a-8012-8c056d31bebd (old id 3069536)
date added to LUP
2016-04-01 10:14:34
date last changed
2024-01-06 10:19:18
@article{8618e123-43cb-463a-8012-8c056d31bebd,
  abstract     = {{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.}},
  author       = {{Voight, Benjamin F. and Peloso, Gina M. and Orho-Melander, Marju and Frikke-Schmidt, Ruth and Barbalic, Maja and Jensen, Majken K. and Hindy, George and Holm, Hilma and Ding, Eric L. and Johnson, Toby and Schunkert, Heribert and Samani, Nilesh J. and Clarke, Robert and Hopewell, Jemma C. and Thompson, John F. and Li, Mingyao and Thorleifsson, Gudmar and Newton-Cheh, Christopher and Musunuru, Kiran and Pirruccello, James P. and Saleheen, Danish and Chen, Li and Stewart, Alexandre F. R. and Schillert, Arne and Thorsteinsdottir, Unnur and Thorgeirsson, Gudmundur and Anand, Sonia and Engert, James C. and Morgan, Thomas and Spertus, John and Stoll, Monika and Berger, Klaus and Martinelli, Nicola and Girelli, Domenico and McKeown, Pascal P. and Patterson, Christopher C. and Epstein, Stephen E. and Devaney, Joseph and Burnett, Mary-Susan and Mooser, Vincent and Ripatti, Samuli and Surakka, Ida and Nieminen, Markku S. and Sinisalo, Juha and Lokki, Marja-Liisa and Perola, Markus and Havulinna, Aki and de Faire, Ulf and Gigante, Bruna and Ingelsson, Erik and Zeller, Tanja and Wild, Philipp and de Bakker, Paul I. W. and Klungel, Olaf H. and Maitland-van der Zee, Anke-Hilse and Peters, Bas J. M. and de Boer, Anthonius and Grobbee, Diederick E. and Kamphuisen, Pieter W. and Deneer, Vera H. M. and Elbers, Clara C. and Onland-Moret, N. Charlotte and Hofker, Marten H. and Wijmenga, Cisca and Verschuren, W. M. Monique and Boer, Jolanda M. A. and van der Schouw, Yvonne T. and Rasheed, Asif and Frossard, Philippe and Demissie, Serkalem and Willer, Cristen and Do, Ron and Ordovas, Jose M. and Abecasis, Goncalo R. and Boehnke, Michael and Mohlke, Karen L. and Daly, Mark J. and Guiducci, Candace and Burtt, Noel P. and Surti, Aarti and Gonzalez, Elena and Purcell, Shaun and Gabriel, Stacey and Marrugat, Jaume and Peden, John and Erdmann, Jeanette and Diemert, Patrick and Willenborg, Christina and Koenig, Inke R. and Fischer, Marcus and Hengstenberg, Christian and Ziegler, Andreas and Buysschaert, Ian and Lambrechts, Diether and Van de Werf, Frans and Fox, Keith A. and El Mokhtari, Nour Eddine and Rubin, Diana and Schrezenmeir, Juergen and Schreiber, Stefan and Schaefer, Arne and Danesh, John and Blankenberg, Stefan and Roberts, Robert and McPherson, Ruth and Watkins, Hugh and Hall, Alistair S. and Overvad, Kim and Rimm, Eric and Boerwinkle, Eric and Tybjaerg-Hansen, Anne and Cupples, L. Adrienne and Reilly, Muredach P. and Melander, Olle and Mannucci, Pier M. and Ardissino, Diego and Siscovick, David and Elosua, Roberto and Stefansson, Kari and O'Donnell, Christopher J. and Salomaa, Veikko and Rader, Daniel J. and Peltonen, Leena and Schwartz, Stephen M. and Altshuler, David and Kathiresan, Sekar}},
  issn         = {{1474-547X}},
  language     = {{eng}},
  number       = {{9841}},
  pages        = {{572--580}},
  publisher    = {{Elsevier}},
  series       = {{The Lancet}},
  title        = {{Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study}},
  url          = {{http://dx.doi.org/10.1016/S0140-6736(12)60312-2}},
  doi          = {{10.1016/S0140-6736(12)60312-2}},
  volume       = {{380}},
  year         = {{2012}},
}