Prospective association of a genetic risk score and lifestyle intervention with cardiovascular morbidity and mortality among individuals with type 2 diabetes: the Look AHEAD randomised controlled trial

Academic Article


  • Aims/hypothesis: Both obesity and genetics contribute to cardiovascular disease (CVD). We examined whether a genetic risk score (GRS) prospectively predicted cardiovascular morbidity and mortality among overweight/obese individuals with type 2 diabetes and whether behavioural weight loss could diminish this association. Methods: Look AHEAD (Action for Health in Diabetes) is a randomised controlled trial to determine the effects of intensive lifestyle intervention (ILI), including weight loss and physical activity, relative to diabetes support and education, on cardiovascular outcomes among overweight/obese individuals with type 2 diabetes. Of the participants, 4,016 provided consent for genetic analyses and had DNA samples passing quality control procedures. These secondary data analyses focused on whether a GRS derived from 153 single nucleotide polymorphisms (SNPs) associated with coronary artery disease in the most recent genome-wide association study predicted cardiovascular morbidity and mortality over a median of 9.6¬†years of follow-up, and whether ILI would diminish this association. Results: The GRS significantly predicted the primary composite endpoint of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalisation for angina in the full sample (HR, 95% CI per 1 SD increase in GRS: 1.19 [1.10, 1.28]) and among individuals with no known history of CVD at baseline (HR 1.18 [95% CI 1.07, 1.30]). In no case did ILI significantly alter this association. Conclusions/interpretation: A GRS comprised of SNPs significantly predicts cardiovascular morbidity and mortality over 9.6¬†years of follow-up in Look AHEAD. Lifestyle intervention did not alter the genetic association. Clinical Trial Registration: NCT00017953; NCT01270763.
  • Published In

  • Diabetologia  Journal
  • Digital Object Identifier (doi)

    Author List

  • McCaffery JM; Anderson A; Bantle JP; Berkowitz RI; Bray GA; Cheskin L; Clark JM; Curtis JM; Delahanty LM; Evans M
  • Start Page

  • 1803
  • End Page

  • 1813
  • Volume

  • 58
  • Issue

  • 8