Prospective Association of GLUL rs10911021 With Cardiovascular Morbidity and Mortality Among Individuals With Type 2 Diabetes: The Look AHEAD Study

Diabetes. 2016 Jan;65(1):297-302. doi: 10.2337/db15-0890. Epub 2015 Sep 22.


Genetic studies have identified a glutamate-ammonia ligase gene (GLUL) polymorphism associated with cardiovascular disease morbidity and mortality among people with type 2 diabetes (T2D). We sought to determine whether GLUL rs10911021 is associated prospectively with adjudicated cardiovascular composite end points among overweight/obese individuals with T2D and whether a lifestyle intervention resulting in weight loss could diminish this association. Look AHEAD is a randomized, 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. Look AHEAD participants included in this report were 3,845 overweight/obese individuals with T2D who provided consent for genetic analyses. Over a median of 9.6 years of follow-up, the risk (C) allele for GLUL rs10911021 was significantly associated with the primary composite end point of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina among individuals with no history of cardiovascular disease (CVD) at baseline using additive genetic models (hazard ratio 1.17 [95% CI 1.01-1.36]; P = 0.032). Results appeared more consistent in recessive models and among individuals with no known history of CVD at baseline; ILI did not alter these associations. These results extend the association of GLUL rs10911021 to incident CVD morbidity and mortality in the setting of T2D.

Trial registration: NCT00017953 NCT01270763.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Angina Pectoris / epidemiology
  • Angina Pectoris / genetics
  • Angina Pectoris / mortality
  • Cardiovascular Diseases / epidemiology
  • Cardiovascular Diseases / genetics*
  • Cardiovascular Diseases / mortality
  • Comorbidity
  • Diabetes Mellitus, Type 2 / epidemiology
  • Diabetes Mellitus, Type 2 / therapy*
  • Female
  • Glutamate-Ammonia Ligase / genetics*
  • Hospitalization / statistics & numerical data
  • Humans
  • Male
  • Middle Aged
  • Motor Activity
  • Myocardial Infarction / epidemiology
  • Myocardial Infarction / genetics
  • Myocardial Infarction / mortality
  • Obesity / epidemiology
  • Obesity / therapy*
  • Overweight / epidemiology
  • Overweight / therapy
  • Proportional Hazards Models
  • Risk Reduction Behavior
  • Stroke / epidemiology
  • Stroke / genetics
  • Stroke / mortality
  • Weight Reduction Programs*


  • Glutamate-Ammonia Ligase

Associated data