title: Genetic Predictors of Cardiovascular Mortality During Intensive Glycemic Control in Type 2 Diabetes: Findings From the ACCORD Clinical Trial.
abstract: To identify genetic determinants of increased cardiovascular mortality among subjects with type 2 diabetes who underwent intensive glycemic therapy in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.
  
  
  
  A total of 6.8 million common variants were analyzed for genome-wide association with cardiovascular mortality among 2,667 self-reported white subjects in the ACCORD intensive treatment arm. Significant loci were examined in the entire ACCORD white genetic dataset (n = 5,360) for their modulation of cardiovascular responses to glycemic treatment assignment and in a Joslin Clinic cohort (n = 422) for their interaction with long-term glycemic control on cardiovascular mortality.
  
  
  
  Two loci, at 10q26 and 5q13, attained genome-wide significance as determinants of cardiovascular mortality in the ACCORD intensive arm (P = 9.8 × 10-9and P = 2 × 10-8, respectively). A genetic risk score (GRS) defined by the two variants was a significant modulator of cardiovascular mortality response to treatment assignment in the entire ACCORD white genetic dataset. Participants with GRS = 0 experienced a fourfold reduction in cardiovascular mortality in response to intensive treatment (hazard ratio [HR] 0.24 [95% CI 0.07-0.86]), those with GRS = 1 experienced no difference (HR 0.92 [95% CI 0.54-1.56]), and those with GRS ≥2 experienced a threefold increase (HR 3.08 [95% CI 1.82-5.21]). The modulatory effect of the GRS on the association between glycemic control and cardiovascular mortality was confirmed in the Joslin cohort (P = 0.029).
  
  
  
  Two genetic variants predict the cardiovascular effects of intensive glycemic control in ACCORD. Further studies are warranted to determine whether these findings can be translated into new strategies to prevent cardiovascular complications of diabetes.
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA.|Department of Medicine, Harvard Medical School, Boston, MA.
authors.forename: Hetal S
authors.initials: HS
authors.lastname: Shah
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA.|Department of Medicine, Harvard Medical School, Boston, MA.
authors.forename: He
authors.initials: H
authors.lastname: Gao
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA.|Department of Medicine, Harvard Medical School, Boston, MA.
authors.forename: Mario Luca
authors.initials: ML
authors.lastname: Morieri
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA.|Department of Medicine, Harvard Medical School, Boston, MA.|Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Skupien
authors.affiliation: Bioinformatics Research Center and Department of Statistics, North Carolina State University, Raleigh, NC.
authors.forename: Skylar
authors.initials: S
authors.lastname: Marvel
authors.affiliation: Department of Medicine and the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Ontario, Canada.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Paré
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA.|Department of Medicine, Harvard Medical School, Boston, MA.
authors.forename: Gaia C
authors.initials: GC
authors.lastname: Mannino
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA.|Department of Medicine, Harvard Medical School, Boston, MA.|Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Patinut
authors.initials: P
authors.lastname: Buranasupkajorn
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA.
authors.forename: Christine
authors.initials: C
authors.lastname: Mendonca
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hastings
authors.affiliation: Department of Medicine, University of Washington, and Northwest Lipid Metabolism and Diabetes Research Laboratories, Seattle, WA.
authors.forename: Santica M
authors.initials: SM
authors.lastname: Marcovina
authors.affiliation: Departments of Medicine, Cardiac Sciences, and Community Health Sciences, Cumming School of Medicine, Faculties of Medicine and Kinesiology, University of Calgary, Alberta, Canada.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Sigal
authors.affiliation: Department of Medicine and the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Ontario, Canada.
authors.forename: Hertzel C
authors.initials: HC
authors.lastname: Gerstein
authors.affiliation: Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wagner
authors.affiliation: Bioinformatics Research Center and Department of Statistics, North Carolina State University, Raleigh, NC.
authors.forename: Alison A
authors.initials: AA
authors.lastname: Motsinger-Reif
authors.affiliation: Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC.
authors.forename: John B
authors.initials: JB
authors.lastname: Buse
authors.affiliation: Departments of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA.
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, VA.
authors.forename: Josyf C
authors.initials: JC
authors.lastname: Mychaleckyj
authors.affiliation: Research Division, Joslin Diabetes Center, Boston, MA alessandro.doria@joslin.harvard.edu.|Department of Medicine, Harvard Medical School, Boston, MA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Doria
mesh_terms: D000368:Aged; D001786:Blood Glucose / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000401:mortality; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors
chemical_list: D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents