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

Benjamin F. Voight; Gina M. Peloso; Marju Orho-Melander; Ruth Frikke-Schmidt; Maja Barbalic; Majken K. Jensen; George Hindy; Hilma Hólm; Eric L. Ding; Toby Johnson; Heribert Schunkert; Nilesh J. Samani; Robert Clarke; Jemma C. Hopewell; John F. Thompson; Mingyao Li; Gudmar Thorleifsson; Christopher Newton-Cheh; Kiran Musunuru; James P. Pirruccello; Danish Saleheen; Li Chen; Alexandre F. R. Stewart; Arne Schillert; Unnur Thorsteinsdottir; Gudmundur Thorgeirsson; Sonia Anand; James C. Engert; Thomas Morgan; John Spertus; Monika Stoll; Klaus Berger; Nicola Martinelli; Domenico Girelli; Pascal P. McKeown; Christopher C. Patterson; Stephen E. Epstein; Joseph Devaney; Mary-Susan Burnett; Vincent Mooser; Samuli Ripatti; Ida Surakka; Markku S. Nieminen; Juha Sinisalo; Marja-Liisa Lokki; Markus Perola; Aki Havulinna; Ulf de Faire; Bruna Gigante; Erik Ingelsson; Tanja Zeller; Philipp Wild; Paul I. W. de Bakker; Olaf H. Klungel; Anke-Hilse Maitland-van der Zee; Bas J. M. Peters; Anthonius de Boer; Diederick E. Grobbee; Pieter W. Kamphuisen; Vera H. M. Deneer; Clara C. Elbers; N. Charlotte Onland-Moret; Marten H. Hofker; Cisca Wijmenga; W. M. Monique Verschuren; Jolanda M. A. Boer; Yvonne T. van der Schouw; Asif Rasheed; Philippe Frossard; Serkalem Demissie; Cristen Willer; Ron Do; Jose M. Ordovas; Gonçalo R. Abecasis; Michael Boehnke; Karen L. Mohlke; Mark J. Daly; Candace Guiducci; Noël P. Burtt; Aarti Surti; Elena Gonzalez; Shaun Purcell; Stacey Gabriel; Jaume Marrugat; John Peden; Jeanette Erdmann; Patrick Diemert; Christina Willenborg; Inke R. König; Marcus Fischer; Christian Hengstenberg; Andreas Ziegler; Ian Buysschaert; Diether Lambrechts; Frans van de Werf; Keith A. Fox; Nour Eddine El Mokhtari; Diana Rubin; Jürgen Schrezenmeir; Stefan Schreiber; Arne Schäfer; John Danesh; Stefan Blankenberg; Robert Roberts; Ruth McPherson; Hugh Watkins; Alistair S. Hall; Kim Overvad; Eric Rimm; Eric Boerwinkle; Anne Tybjaerg-Hansen; L. Adrienne Cupples; Muredach P. Reilly; Olle Melander; Pier M. Mannucci; Diego Ardissino; David Siscovick; Roberto Elosua; Kari Stefansson; Christopher J. O'Donnell; Veikko Salomaa; Daniel J. Rader; Leena Peltonen; Stephen M. Schwartz; David Altshuler; Sekar Kathiresan

doi:https://doi.org/10.1016/S0140-6736(12)60312-2

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

Benjamin F. Voight, Gina M. Peloso, Marju Orho-Melander, Ruth Frikke-Schmidt, Maja Barbalic, Majken K. Jensen, George Hindy, Hilma Hólm, Eric L. Ding, Toby Johnson, Heribert Schunkert, Nilesh J. Samani, Robert Clarke, Jemma C. Hopewell, John F. Thompson, Mingyao Li, Gudmar Thorleifsson, Christopher Newton-Cheh, Kiran Musunuru, James P. PirruccelloDanish Saleheen, Li Chen, Alexandre F. R. Stewart, Arne Schillert, Unnur Thorsteinsdottir, Gudmundur Thorgeirsson, Sonia Anand, James C. Engert, Thomas Morgan, John Spertus, Monika Stoll, Klaus Berger, Nicola Martinelli, Domenico Girelli, Pascal P. McKeown, Christopher C. Patterson, Stephen E. Epstein, Joseph Devaney, Mary-Susan Burnett, Vincent Mooser, Samuli Ripatti, Ida Surakka, Markku S. Nieminen, Juha Sinisalo, Marja-Liisa Lokki, Markus Perola, Aki Havulinna, Ulf de Faire, Bruna Gigante, Erik Ingelsson, Tanja Zeller, Philipp Wild, Paul I. W. de Bakker, Olaf H. Klungel, Anke-Hilse Maitland-van der Zee, Bas J. M. Peters, Anthonius de Boer, Diederick E. Grobbee, Pieter W. Kamphuisen, Vera H. M. Deneer, Clara C. Elbers, N. Charlotte Onland-Moret, Marten H. Hofker, Cisca Wijmenga, W. M. Monique Verschuren, Jolanda M. A. Boer, Yvonne T. van der Schouw, Asif Rasheed, Philippe Frossard, Serkalem Demissie, Cristen Willer, Ron Do, Jose M. Ordovas, Gonçalo R. Abecasis, Michael Boehnke, Karen L. Mohlke, Mark J. Daly, Candace Guiducci, Noël P. Burtt, Aarti Surti, Elena Gonzalez, Shaun Purcell, Stacey Gabriel, Jaume Marrugat, John Peden, Jeanette Erdmann, Patrick Diemert, Christina Willenborg, Inke R. König, Marcus Fischer, Christian Hengstenberg, Andreas Ziegler, Ian Buysschaert, Diether Lambrechts, Frans van de Werf, Keith A. Fox, Nour Eddine El Mokhtari, Diana Rubin, Jürgen Schrezenmeir, Stefan Schreiber, Arne Schäfer, John Danesh, Stefan Blankenberg, Robert Roberts, Ruth McPherson, Hugh Watkins, Alistair S. Hall, Kim Overvad, Eric Rimm, Eric Boerwinkle, Anne Tybjaerg-Hansen, L. Adrienne Cupples, Muredach P. Reilly, Olle Melander, Pier M. Mannucci, Diego Ardissino, David Siscovick, Roberto Elosua, Kari Stefansson, Christopher J. O'Donnell, Veikko Salomaa, Daniel J. Rader, Leena Peltonen, Stephen M. Schwartz, David Altshuler, Sekar Kathiresan

Research output: Contribution to journal › Article › Academic › peer-review

1816 Citations (Scopus)

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

Original language	English
Pages (from-to)	572-580
Journal	Lancet
Volume	380
Issue number	9841
DOIs	https://doi.org/10.1016/S0140-6736(12)60312-2
Publication status	Published - 2012
Externally published	Yes

Access to Document

https://doi.org/10.1016/S0140-6736(12)60312-2

Cite this

Voight, B. F., Peloso, G. M., Orho-Melander, M., Frikke-Schmidt, R., Barbalic, M., Jensen, M. K., Hindy, G., Hólm, H., Ding, E. L., Johnson, T., Schunkert, H., Samani, N. J., Clarke, R., Hopewell, J. C., Thompson, J. F., Li, M., Thorleifsson, G., Newton-Cheh, C., Musunuru, K., ... Kathiresan, S. (2012). Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet, 380(9841), 572-580. https://doi.org/10.1016/S0140-6736(12)60312-2

@article{28dad6c628c543f7801ecb2604b293cb,

title = "Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study",

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 Marju Orho-Melander and Ruth Frikke-Schmidt and Maja Barbalic and Jensen, {Majken K.} and George Hindy and Hilma H{\'o}lm and Ding, {Eric L.} and Toby Johnson and Heribert Schunkert and Samani, {Nilesh J.} and Robert Clarke and Hopewell, {Jemma C.} and Thompson, {John F.} and Mingyao Li and Gudmar Thorleifsson and Christopher Newton-Cheh and Kiran Musunuru and Pirruccello, {James P.} and Danish Saleheen and Li Chen and Stewart, {Alexandre F. R.} and Arne Schillert and Unnur Thorsteinsdottir and Gudmundur Thorgeirsson and Sonia Anand and Engert, {James C.} and Thomas Morgan and John Spertus and Monika Stoll and Klaus Berger and Nicola Martinelli and Domenico Girelli and McKeown, {Pascal P.} and Patterson, {Christopher C.} and Epstein, {Stephen E.} and Joseph Devaney and Mary-Susan Burnett and Vincent Mooser and Samuli Ripatti and Ida Surakka and Nieminen, {Markku S.} and Juha Sinisalo and Marja-Liisa Lokki and Markus Perola and Aki Havulinna and {de Faire}, Ulf and Bruna Gigante and Erik Ingelsson and Tanja Zeller and Philipp Wild 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 Cisca Wijmenga and Verschuren, {W. M. Monique} and Boer, {Jolanda M. A.} and {van der Schouw}, {Yvonne T.} and Asif Rasheed and Philippe Frossard and Serkalem Demissie and Cristen Willer and Ron Do and Ordovas, {Jose M.} and Abecasis, {Gon{\c c}alo R.} and Michael Boehnke and Mohlke, {Karen L.} and Daly, {Mark J.} and Candace Guiducci and Burtt, {No{\"e}l P.} and Aarti Surti and Elena Gonzalez and Shaun Purcell and Stacey Gabriel and Jaume Marrugat and John Peden and Jeanette Erdmann and Patrick Diemert and Christina Willenborg and K{\"o}nig, {Inke R.} and Marcus Fischer and Christian Hengstenberg and Andreas Ziegler and Ian Buysschaert and Diether Lambrechts and {van de Werf}, Frans and Fox, {Keith A.} and {El Mokhtari}, {Nour Eddine} and Diana Rubin and J{\"u}rgen Schrezenmeir and Stefan Schreiber and Arne Sch{\"a}fer and John Danesh and Stefan Blankenberg and Robert Roberts and Ruth McPherson and Hugh Watkins and Hall, {Alistair S.} and Kim Overvad and Eric Rimm and Eric Boerwinkle and Anne Tybjaerg-Hansen and Cupples, {L. Adrienne} and Reilly, {Muredach P.} and Olle Melander and Mannucci, {Pier M.} and Diego Ardissino and David Siscovick and Roberto Elosua and Kari Stefansson and O'Donnell, {Christopher J.} and Veikko Salomaa and Rader, {Daniel J.} and Leena Peltonen and Schwartz, {Stephen M.} and David Altshuler and Sekar Kathiresan",

year = "2012",

doi = "https://doi.org/10.1016/S0140-6736(12)60312-2",

language = "English",

volume = "380",

pages = "572--580",

journal = "Lancet",

issn = "0140-6736",

publisher = "Elsevier Limited",

number = "9841",

}

Voight, BF, Peloso, GM, Orho-Melander, M, Frikke-Schmidt, R, Barbalic, M, Jensen, MK, Hindy, G, Hólm, H, Ding, EL, Johnson, T, Schunkert, H, Samani, NJ, Clarke, R, Hopewell, JC, Thompson, JF, Li, M, Thorleifsson, G, Newton-Cheh, C, Musunuru, K, Pirruccello, JP, Saleheen, D, Chen, L, Stewart, AFR, Schillert, A, Thorsteinsdottir, U, Thorgeirsson, G, Anand, S, Engert, JC, Morgan, T, Spertus, J, Stoll, M, Berger, K, Martinelli, N, Girelli, D, McKeown, PP, Patterson, CC, Epstein, SE, Devaney, J, Burnett, M-S, Mooser, V, Ripatti, S, Surakka, I, Nieminen, MS, Sinisalo, J, Lokki, M-L, Perola, M, Havulinna, A, de Faire, U, Gigante, B, Ingelsson, E, Zeller, T, Wild, P, de Bakker, PIW, Klungel, OH, Maitland-van der Zee, A-H, Peters, BJM, de Boer, A, Grobbee, DE, Kamphuisen, PW, Deneer, VHM, Elbers, CC, Onland-Moret, NC, Hofker, MH, Wijmenga, C, Verschuren, WMM, Boer, JMA, van der Schouw, YT, Rasheed, A, Frossard, P, Demissie, S, Willer, C, Do, R, Ordovas, JM, Abecasis, GR, Boehnke, M, Mohlke, KL, Daly, MJ, Guiducci, C, Burtt, NP, Surti, A, Gonzalez, E, Purcell, S, Gabriel, S, Marrugat, J, Peden, J, Erdmann, J, Diemert, P, Willenborg, C, König, IR, Fischer, M, Hengstenberg, C, Ziegler, A, Buysschaert, I, Lambrechts, D, van de Werf, F, Fox, KA, El Mokhtari, NE, Rubin, D, Schrezenmeir, J, Schreiber, S, Schäfer, A, Danesh, J, Blankenberg, S, Roberts, R, McPherson, R, Watkins, H, Hall, AS, Overvad, K, Rimm, E, Boerwinkle, E, Tybjaerg-Hansen, A, Cupples, LA, Reilly, MP, Melander, O, Mannucci, PM, Ardissino, D, Siscovick, D, Elosua, R, Stefansson, K, O'Donnell, CJ, Salomaa, V, Rader, DJ, Peltonen, L, Schwartz, SM, Altshuler, D & Kathiresan, S 2012, 'Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study', Lancet, vol. 380, no. 9841, pp. 572-580. https://doi.org/10.1016/S0140-6736(12)60312-2

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

PY - 2012

Y1 - 2012

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=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

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=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

U2 - https://doi.org/10.1016/S0140-6736(12)60312-2

DO - https://doi.org/10.1016/S0140-6736(12)60312-2

M3 - Article

C2 - 22607825

SN - 0140-6736

VL - 380

SP - 572

EP - 580

JO - Lancet

JF - Lancet

IS - 9841

ER -