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

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          Summary

          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.

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          Most cited references20

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          'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease?

          Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading, despite our best efforts to improve the design and analysis of studies. Mendelian randomization-the random assortment of genes from parents to offspring that occurs during gamete formation and conception-provides one method for assessing the causal nature of some environmental exposures. The association between a disease and a polymorphism that mimics the biological link between a proposed exposure and disease is not generally susceptible to the reverse causation or confounding that may distort interpretations of conventional observational studies. Several examples where the phenotypic effects of polymorphisms are well documented provide encouraging evidence of the explanatory power of Mendelian randomization and are described. The limitations of the approach include confounding by polymorphisms in linkage disequilibrium with the polymorphism under study, that polymorphisms may have several phenotypic effects associated with disease, the lack of suitable polymorphisms for studying modifiable exposures of interest, and canalization-the buffering of the effects of genetic variation during development. Nevertheless, Mendelian randomization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to understanding and preventing the adverse effects on human health of modifiable exposures.
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            Newly identified loci that influence lipid concentrations and risk of coronary artery disease.

            To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.
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              • Record: found
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              • Article: not found

              Mendelian randomization: prospects, potentials, and limitations.

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                Author and article information

                Journal
                Lancet
                Lancet
                Lancet
                Lancet Publishing Group
                0140-6736
                1474-547X
                11 August 2012
                11 August 2012
                : 380
                : 9841
                : 572-580
                Affiliations
                [a ]Department of Pharmacology and Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
                [b ]Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA
                [c ]Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
                [d ]Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
                [e ]Cardiology Division, Massachusetts General Hospital, Boston, MA, USA
                [f ]Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA
                [g ]Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
                [h ]Framingham Heart Study of the National, Heart, Lung, and Blood Institute, Framingham, MA, USA
                [i ]Diabetes and Cardiovascular Disease Genetic Epidemiology, Skania University Hospital, Lund University, Malmö, Sweden
                [j ]Department of Clinical Sciences, Hypertension and Cardiovascular Diseases, Skania University Hospital, Lund University, Malmö, Sweden
                [k ]Department of Clinical Biochemistry, Section for Molecular Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
                [l ]Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA
                [m ]Department of Nutrition and Epidemiology, Harvard School of Public Health, Boston, MA, USA
                [n ]Department of Nutrition, Harvard School of Public Health, Boston, MA, USA
                [o ]Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
                [p ]deCODE Genetics, Reykjavik, Iceland
                [q ]Clinical Pharmacology and The Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
                [r ]Medizinische Klinik II, Universität zu Lübeck, Lübeck, Germany
                [s ]Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Lübeck, Germany
                [t ]Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
                [u ]Department of Health Sciences, University of Leicester, Leicester, UK
                [v ]Leicester National Institute of Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, UK
                [w ]Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA
                [x ]The Institute for Translational Medicine and Therapeutics and The Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA
                [y ]Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
                [z ]The John & Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada
                [aa ]The Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Oxford, UK
                [ab ]Department of Cardiovascular Medicine, University of Oxford, Oxford, UK
                [ac ]University of Iceland Faculty of Medicine, Reykjavik, Iceland
                [ad ]Department of Internal Medicine, Division of Cardiology, Landspitali University Hospital, Reykjavik, Iceland
                [ae ]Population Health Research Institute, Hamilton Health Sciences and Department of Medicine and Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada
                [af ]Department of Medicine and Department of Human Genetics, McGill University, Montréal, QC, Canada
                [ag ]Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA
                [ah ]Mid-America Heart Institute and University of Missouri-Kansas City, Kansas City, MO, USA
                [ai ]Leibniz-Institute for Arteriosclerosis Research, University of Münster, Münster, Germany
                [aj ]Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany
                [ak ]Department of Medicine, University of Verona, Verona, Italy
                [al ]Centre for Public Health, Queen's University Belfast, Institute of Clinical Science, Belfast, UK
                [am ]Cardiovascular Research Institute, MedStar Research Institute, Washington Hospital Center, Washington, DC, USA
                [an ]Genetics Division and Drug Discovery, GlaxoSmithKline, King of Prussia, Pennsylvania, PA, USA
                [ao ]Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland
                [ap ]Division of Cardiology Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
                [aq ]Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland
                [ar ]Chronic Disease Epidemiology and Prevention Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
                [as ]Division of Cardiovascular Epidemiology and Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
                [at ]Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
                [au ]der Johannes Gutenberg-Universität Mainz II, Medizinische Klinik und Poliklinik, Mainz, Germany
                [av ]Division of Genetics, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA
                [aw ]Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Netherlands
                [ax ]Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands
                [ay ]Department of Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands
                [az ]Department of Vascular Medicine, University Medical Center Groningen, Groningen, Netherlands
                [ba ]Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, Netherlands
                [bb ]Department of Genetics, University Medical Center Groningen, Groningen, Netherlands
                [bc ]Department of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, Netherlands
                [bd ]Center for Prevention and Health Services Research, National Institute for Public Health and the Environment, Bilthoven, Netherlands
                [be ]Center for Nutrition and Health, National Institute for Public Health and the Environment, Bilthoven, Netherlands
                [bf ]Center for Non-Communicable Diseases, Karachi, Pakistan
                [bg ]Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
                [bh ]Nutrition and Genomics Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
                [bi ]Department of Cardiovascular Epidemiology and Population Genetics, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
                [bj ]Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
                [bk ]Cardiovascular Epidemiology and Genetics, IMIM, Barcelona, Spain
                [bl ]CIBER Epidemiología y Salud Pública, Barcelona, Spain
                [bm ]Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany
                [bn ]Vesalius Research Center, VIB-KU Leuven, Leuven, Belgium
                [bo ]Department of Cardiology, University Hospital Gasthuisberg, Leuven, Belgium
                [bp ]Cardiovascular Research, Division of Medical and Radiological Sciences, The University of Edinburgh, Edinburgh, UK
                [bq ]Institut für Klinische Molekularbiologie, Christian-Albrechts Universität, Kiel, Germany
                [br ]Medizinische Klinik I, Universitätsklinikum Schleswig Holstein, Campus Kiel, Kiel, Germany
                [bs ]Max-Rubner-Institut, Institut für Physiologie und Biochemie der Ernährung, Kiel, Germany
                [bt ]LIGHT and LIMM Research Institutes, Faculty of Medicine and Health, University of Leeds, Leeds, UK
                [bu ]Department of Epidemiology, School of Public Health, Aarhus University, Aarhus, Denmark
                [bv ]The Copenhagen City Heart Study Bispebjerg University Hospital, Copenhagen, Denmark
                [bw ]Department of Internal Medicine and Medical Specialities, IRCCS Fondazione Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
                [bx ]Division of Cardiology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
                [by ]Cardiovascular Health Research Unit, Department of Medicine and Department of Epidemiology, University of Washington, Seattle, WA, USA
                [bz ]Wellcome Trust Sanger Institute Cambridge, UK
                [ca ]Department of Genetics, Harvard Medical School, Boston, MA, USA
                Author notes
                [* ]Correspondence to: Dr Sekar Kathiresan, Center for Human Genetic Research and Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA skathiresan@ 123456partners.org
                [†]

                These authors contributed equally to this work

                Article
                LANCET60312
                10.1016/S0140-6736(12)60312-2
                3419820
                22607825
                33a827d6-4dae-4ef8-861e-e10d2243b412
                © 2012 Elsevier Ltd. All rights reserved.

                This document may be redistributed and reused, subject to certain conditions.

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