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

The Look AHEAD Research Group

Research output: Contribution to journalArticle

11 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1803-1813
Number of pages11
Issue number8
StatePublished - Aug 23 2015



  • Cardiovascular disease
  • Genetics
  • Lifestyle intervention
  • Myocardial infarction
  • Obesity
  • Stroke
  • Type 2 diabetes
  • Weight loss

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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