title: Genetically Driven Hyperglycemia Increases Risk of Coronary Artery Disease Separately From Type 2 Diabetes.
abstract: This study tested the hypothesis that genetically raised hyperglycemia increases coronary artery disease (CAD) risk separately from the risk conferred by type 2 diabetes as a whole.
  
  
  
  We conducted a Mendelian randomization (MR) analysis using summary-level statistics from the largest published meta-analyses of genome-wide association studies (GWAS) for fasting glucose (FG) (n= 133,010 participants free of diabetes) and CAD (n= 63,746 case subjects and 130,681 control subjects) of predominantly European ancestry. FG-increasing variants associated with type 2 diabetes from the largest GWAS for type 2 diabetes were excluded. Variants with pleiotropic effects on other CAD risk factors (blood lipids, blood pressure, and obesity) were excluded using summary-level data from the largest published GWAS. Data from the Framingham Heart Study were used to validate the MR instrument and to build an FG genetic risk score (GRS).
  
  
  
  In an instrumental variable analysis comprising 12 FG-raising variants, a 1 mmol/L increase in FG revealed an effect-size estimate of 1.43 CAD odds (95% CI 1.14-1.79). The association was preserved after excluding variants for heterogeneity and pleiotropic effects on other CAD risk factors (odds ratio [OR] 1.33 [95% CI 1.02-1.73]). The 12 FG-increasing variants did not significantly increase type 2 diabetes risk (OR 1.05 [95% CI 0.91-1.23]), and its prevalence was constant across FG GRS quintiles (P= 0.72).
  
  
  
  Our data support that genetic predisposition to hyperglycemia raises the odds of CAD separately from type 2 diabetes and other CAD risk factors. These findings suggest that modulating glycemia may provide cardiovascular benefit.
authors.affiliation: Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.|Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA.|Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Institut Investigació Sanitaria Pere VirgiliI, Rovira i Virgili University, CIBERDEM, Reus, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Merino
authors.affiliation: Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA.|Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Leong
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Posner
authors.affiliation: Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA.
authors.forename: Bianca
authors.initials: B
authors.lastname: Porneala
authors.affiliation: Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Institut Investigació Sanitaria Pere VirgiliI, Rovira i Virgili University, CIBERDEM, Reus, Spain.
authors.forename: Lluís
authors.initials: L
authors.lastname: Masana
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA.|National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA.
authors.forename: Josée
authors.initials: J
authors.lastname: Dupuis
authors.affiliation: Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA jcflorez@partners.org.|Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA.|Department of Medicine, Harvard Medical School, Boston, MA.
authors.forename: Jose C
authors.identifier: 0000-0002-1730-9325
authors.initials: JC
authors.lastname: Florez
mesh_terms: D001786:Blood Glucose / Q000378:metabolism; D003324:Coronary Artery Disease / Q000453:epidemiology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications*; D005215:Fasting; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000235:genetics*; D057182:Mendelian Randomization Analysis; D016017:Odds Ratio; D012307:Risk Factors
chemical_list: D001786:Blood Glucose