Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study
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 A, 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 MS, Mooser V, Ripatti S, Surakka I, Nieminen MS, Sinisalo J, Lokki ML, Perola M, Havulinna A, de Faire U, Gigante B, Ingelsson E, Zeller T, Wild P, de Bakker PI, Klungel OH, Maitland-van der Zee AH, Peters BJ, de Boer A, Grobbee DE, Kamphuisen PW, Deneer VH, Elbers CC, Onland-Moret NC, Hofker MH, Wijmenga C, Verschuren WM, Boer JM, 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
Lancet (London, England) · 1,798 citas
Etiquetas de revisión
Vínculos de autores con la industriaDatos neutrales que nuestra revisión registró sobre cómo se hizo este estudio. Describen el método, nunca si nos gusta el resultado.
Cómo se estudió
- Diseño
- Metaanálisis (indexado por PubMed)
- Estudiado en
- Personas
- Resultado principal
- Eventos clínicos como enfermedad o muerte
Quién lo pagó
- Financiación
- Posiblemente financiado por la industria
- Organización sin fines de lucro
- Wellcome Trust
- Organización sin fines de lucro
- British Heart Foundation
- Gobierno
- National Heart, Lung, and Blood Institute
- Gobierno
- NHLBI NIH HHS
- Gobierno
- Medical Research Council
- Autores
- Al menos un autor declara un vínculo económico con la industria
- Subvenciones
- National Heart, Lung, and Blood Institute (N01-HC-025195); Wellcome Trust (090532); British Heart Foundation (RG/08/014/24067)
Según 5 financiadores declarados y la declaración de financiación del texto completo.
Publicación
- Publicado
- 2012-05-16 · Lancet · vol. 380 · número 9841 · págs. 572–580
- Editorial
- Elsevier BV
- Citado
- 127 citas · más que el 94% de estudios similares · 4.1× el promedio de su campo
- Impacto
- Entre el 10 % más citado de su campo
- Referencias
- 37 trabajos
- Acceso
- Acceso abierto (copia en repositorio) · OTHER-OA
- Áreas de investigación
- Genetic Associations and Epidemiology · Lipoproteins and Cardiovascular Health · Paraoxonase enzyme and polymorphisms
- Palabras clave
- HDL cholesterol, myocardial infarction, causal inference, endothelial lipase, genetic score, LDL cholesterol, cardiovascular risk, genetic instruments, single nucleotide polymorphisms, lipid biomarkers, confounding by indication, reverse causality
- MeSH
- humans, myocardial infarction, genetic predisposition to disease, lipase, risk factors, case-control studies, prospective studies, gene frequency, polymorphism, single nucleotide, cholesterol, ldl, cholesterol, hdl, mendelian randomization analysis, biomarkers
100 autores
- Benjamin F. Voight🇺🇸University of Pennsylvania
- Gina Marie Peloso🇺🇸Boston University; National Heart, Lung, and Blood Institute; Framingham Heart Study
- Marju Orho‐Melander🇸🇪Lund University; Skåne University Hospital
- Ruth Frikke‐Schmidt
- Maja Barbalić🇺🇸The University of Texas Health Science Center at Houston
- Majken K. Jensen🇺🇸Harvard University
- George Hindy🇸🇪Lund University; Skåne University Hospital
- Hilma Hólm🇮🇸deCODE Genetics (Iceland)
- Eric L. Ding
- Toby Johnson🇬🇧Queen Mary University of London; William Harvey Research Institute
- Heribert Schunkert🇩🇪University of Lübeck
- Nilesh J. Samani🇬🇧University of Leicester; Glenfield Hospital; NIHR Leicester Cardiovascular Biomedical Research Unit
- Robert Clarke🇬🇧University of Oxford
- Jemma C. Hopewell🇬🇧University of Oxford
- John F. Thompson🇬🇧University of Leicester
- Mingyao Li🇺🇸University of Pennsylvania
- Guðmar Þorleifsson🇮🇸deCODE Genetics (Iceland)
- Christopher Newton‐Cheh🇺🇸Broad Institute; Massachusetts General Hospital
- Kiran Musunuru🇺🇸Broad Institute; Massachusetts General Hospital
- James P. Pirruccello
- Danish Saleheen
- Li Chen🇨🇦Ottawa Heart Institute
- Alexandre F.R. Stewart🇨🇦Ottawa Heart Institute
- Arne Schillert🇩🇪University of Lübeck
- Unnur Arna Thorsteinsdottir🇮🇸deCODE Genetics (Iceland); University of Iceland
- Guðmundur Þorgeirsson🇮🇸University of Iceland; National University Hospital of Iceland
- Sonia S. Anand🇨🇦Population Health Research Institute; Hamilton Health Sciences; McMaster University
- James C. Engert🇨🇦McGill University
- Thomas M. Morgan🇺🇸Vanderbilt University
- John A. Spertus🇺🇸University of Missouri–Kansas City
- Monika Stoll🇩🇪University of Münster
- Klaus Berger🇩🇪University of Münster
- Nicola Martinelli🇮🇹University of Verona
- Domenico Girelli🇮🇹University of Verona
- Pascal McKeown🇬🇧Queen's University Belfast
- Christopher Patterson🇬🇧Queen's University Belfast
- Stephen E. Epstein🇺🇸MedStar Washington Hospital Center; Washington Hospital; MedStar Health Research Institute
- Joseph Devaney🇺🇸MedStar Washington Hospital Center; Washington Hospital; MedStar Health Research Institute
- Mary-Susan Burnett🇺🇸MedStar Washington Hospital Center; Washington Hospital; MedStar Health Research Institute
- Vincent Mooser🇺🇸GlaxoSmithKline (United States)
- Samuli Ripatti🇫🇮University of Helsinki; Institute for Molecular Medicine Finland
- Ida L. Surakka
- Markku S. Nieminen🇫🇮University of Helsinki; Helsinki University Hospital; Institute for Molecular Medicine Finland
- Juha P. Sinisalo🇫🇮Helsinki University Hospital
- Marja‐Liisa Lokki🇫🇮University of Helsinki
- Markus Perola🇫🇮Finnish Institute for Health and Welfare
- Aki Samuli Havulinna🇫🇮Finnish Institute for Health and Welfare
- Ulf dé Fairé🇸🇪Karolinska Institutet
- Bruna Gigante🇸🇪Karolinska Institutet
- Erik Ingelsson🇸🇪Karolinska Institutet
- Tanja Zeller🇩🇪Johannes Gutenberg University Mainz; University Medical Center of the Johannes Gutenberg University Mainz
- Philipp Sebastian Wild🇩🇪Johannes Gutenberg University Mainz; University Medical Center of the Johannes Gutenberg University Mainz
- Paul I. W. de Bakker🇺🇸🇳🇱Broad Institute; Brigham and Women's Hospital; Harvard University; Utrecht University; University Medical Center Utrecht
- Olaf H. Klungel🇳🇱Utrecht University
- Anke H. Maitland‐van der Zee🇳🇱Utrecht University
- Bas J.M. Peters🇳🇱Utrecht University
- Anthonius de Boer🇳🇱Utrecht University
- Diederick E. Grobbee🇳🇱Utrecht University; University Medical Center Utrecht
- Pieter Willem Kamphuisen🇳🇱University Medical Center Groningen
- Vera H.M. Deneer🇳🇱St. Antonius Ziekenhuis
- Clara C. Elbers🇳🇱Utrecht University; University Medical Center Utrecht
- N. Charlotte Onland‐Moret🇳🇱Utrecht University; University Medical Center Utrecht
- Marten H. Hofker🇳🇱University Medical Center Groningen
- Cisca Wijmenga🇳🇱University Medical Center Groningen
- W. M. Monique Verschuren🇳🇱National Institute for Public Health and the Environment
- Jolanda M.A. Boer🇳🇱National Institute for Public Health and the Environment
- Yvonne T. van der Schouw🇳🇱Utrecht University; University Medical Center Utrecht
- Asif Rasheed🇵🇰Center for Non-Communicable Diseases
- Philippe Frossard🇵🇰Center for Non-Communicable Diseases
- Serkalem Demissie🇺🇸Boston University; National Heart, Lung, and Blood Institute; Framingham Heart Study
- Cristen J. Willer🇺🇸University of Michigan
- Ron Do🇺🇸Massachusetts General Hospital
- José María Ordovás🇺🇸🇪🇸Tufts University; United States Department of Agriculture; Spanish National Centre for Cardiovascular Research; Jean Mayer Human Nutrition Research Center on Aging
- Gonçalo R. Abecasis🇺🇸University of Michigan
- Michael Boehnke🇺🇸University of Michigan
- Karen L. Mohlke🇺🇸University of North Carolina at Chapel Hill
- Mark J. Daly🇺🇸Broad Institute; Massachusetts General Hospital
- Candace Guiducci
- Noël P. Burtt
- Aarti Surti
- Elena González
- Shaun Purcell🇺🇸Broad Institute; Massachusetts General Hospital
- Stacey L. Gabriel🇺🇸Broad Institute
- Jaume Marrugat🇪🇸Hospital del Mar Research Institute
- John F. Peden🇬🇧University of Oxford
- Jeanette Erdmann🇩🇪University of Lübeck
- Patrick Diemert🇩🇪University of Lübeck
- Christina Willenborg🇩🇪University of Lübeck
- Inke Regina König🇩🇪University of Lübeck
- Marcus Fischer🇩🇪University Hospital Regensburg
- Christian Hengstenberg🇩🇪University Hospital Regensburg
- Andreas Ziegler🇩🇪University of Lübeck
- Ian Buysschaert🇧🇪Universitair Ziekenhuis Leuven; KU Leuven
- Diether Lambrechts🇧🇪Universitair Ziekenhuis Leuven; KU Leuven
- Frans Van de Werf🇧🇪Universitair Ziekenhuis Leuven; KU Leuven
- Keith A.A. Fox
- Nour Eddine El Mokhtari🇩🇪Christian-Albrechts-Universität zu Kiel
- Diana Rubin🇩🇪University Hospital Schleswig-Holstein
- Jürgen Schrezenmeir🇩🇪Max Rubner Institut
- Stefan Schreiber🇩🇪Christian-Albrechts-Universität zu Kiel
Resumen
El texto original del estudio, en el idioma en que se publicó.
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.
Resumen vía Europe PMC. Los derechos de autor siguen siendo de los autores o la editorial.
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