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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.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.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)).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.US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.

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 unmodifi ed by disease processes, mendelian random isation 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 noncarriers. This diff erence 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. ; 115770

This is the final version. Available on open access from Nature Research via the DOI in this record. ; Data availability: GWAS summary statistics for FG/FI analyses presented in this manuscript are deposited on https://www.magicinvestigators.org/downloads/ and will be also be available through the NHGRI-EBI GWAS Catalog https://www.ebi.ac.uk/gwas/downloads/summary-statistics. Raw files for RNA-seq mRNA expression in islet donors have been deposited in NCBI GEO database with the accession code GSE50398. Summary-level GWAS results for genetic correlation analysis with glycemic traits were downloaded from the LDHub database (http://ldsc.broadinstitute.org/ldhub/). Islets from 89 cadaver donors were provided by the Nordic Islet Transplantation Programme (http://www.medscinet.com/nordicislets/). The dexseq_count python script for RNA sequencing analysis in human pancreatic islets was downloaded from http://www-huber.embl.de/pub/DEXSeq/analysis/scripts/. Raw files for RNA-seq mRNA expression in islet donors have been deposited in NCBI GEO database with the accession code GSE50398. ; Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes. ; Academy of Finland ; ADA ; Biotechnology and Biological Sciences Research Council (BBSRC) ; BHF ; Clinical Translational Science Institute ; Croatian Ministry of Science ; Directorate C - Public Health and Risk Assessment, Health & Consumer Protection ; Dutch Kidney Foundation ; Estonian Research Council ; European Research Council (ERC) ; European Regional Development Fund (ERDF) ; European Union Horizon 2020 ; Federal Ministry of Education and Research (BMBF), Germany ; Finnish Funding Agency for Technology and Innovation ; German Research Foundation ; Greek General Secretary of Research and Technology ; Icelandic National Bioethics Committee ; IFB Adiposity Diseases ; IngaBritt och Arne Lundberg's Research Foundation ; Italian Ministry of Health ; Knut & Alice Wallenberg foundation ; Kuopio University Hospital from Ministry of Health and Social Affairs ; Affymetrix, Inc ; Lundberg Foundation ; Medical Research Council (MRC) ; Mid-Atlantic Nutrition Obesity Research Center ; Ministry of Education and Culture of Finland ; MRC-GSK pilot programme ; NHLBI ; NIA ; NIH ; Nordic Centre of Excellence on Systems biology in controlled dietary interventions and cohort studies, SYSDIET ; Novo Nordisk Foundation ; NWO/ZonMW ; Spinozapremie ; Rutgers University Cell and DNA Repository ; Stockholm County Council ; Swedish Foundation for Strategic Research ; Swedish Heart-Lung Foundation ; Swedish Research Council ; Swiss National Science Foundation ; TEKES ; Torsten och Ragnar Söderbergs Stiftelser ; Wellcome Trust ; Yrjö Jahnsson Foundation ; Note that the full list of funders and grant numbers is available in the online article and in the PDF in this record