Variation in the eNOS Gene Modifies the Association Between Total Energy Expenditure and Glucose Intolerance

  1. Paul W. Franks12,
  2. Jian’an Luan1,
  3. Inês Barroso3,
  4. Søren Brage1,
  5. Jose Luis Gonzalez Sanchez4,
  6. Ulf Ekelund1,
  7. Manuel Serrano Ríos4,
  8. Alan J. Schafer5,
  9. Stephen O’Rahilly6 and
  10. Nicholas J. Wareham1
  1. 1Medical Research Council Epidemiology Unit, Cambridge, U.K
  2. 2Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona
  3. 3Wellcome Trust Sanger Institute, Metabolic Disease Group, Cambridge, U.K
  4. 4Departamento de Medicina Interna II, Hospital Universitario Clínico San Carlos, Madrid, Spain
  5. 5Incyte Genomics, Cambridge, U.K
  6. 6Departments of Clinical Biochemistry and Medicine, Addenbrooke’s Hospital, Cambridge, U.K
  1. Address correspondence and reprint requests to Dr. Paul Franks, National Institute of DiabetesDigestiveKidney Diseases, 1550 E. Indian School Rd., Phoenix, AZ 85014. E-mail: pfranks{at}niddk.nih.gov. Or Dr. Nicholas Wareham, Medical Research Council Epidemiology Unit, University of Cambridge, U.K. E-mail: njw1004{at}medschl.cam.ac.uk

Abstract

Endothelium-derived nitric oxide (NO) facilitates skeletal muscle glucose uptake. Energy expenditure induces the endothelial NO synthase (eNOS) gene, providing a mechanism for insulin-independent glucose disposal. The object was to test 1) the association of genetic variation in eNOS, as assessed by haplotype-tagging single nucleotide polymorphisms (htSNPs) with type 2 diabetes, and 2) the interaction between eNOS haplotypes and total energy expenditure on glucose intolerance. Using multivariate models, we tested associations between eNOS htSNPs and diabetes (n = 461 and 474 case and control subjects, respectively) and glucose intolerance (two cohorts of n = 706 and 738 U.K. and Spanish Caucasians, respectively), and we tested eNOS × total energy expenditure interactions on glucose intolerance. An overall association between eNOS haplotype and diabetes was observed (P = 0.004). Relative to the most common haplotype (111), two haplotypes (121 and 212) tended to increase diabetes risk (OR 1.22, 95% CI 0.96–1.55), and one (122) was associated with decreased risk (0.58, 0.39–0.86). In the cohort studies, no association was observed between haplotypes and 2-h glucose (P > 0.10). However, we observed a significant total energy expenditure–haplotype interaction (P = 0.007). Genetic variation at the eNOS locus is associated with diabetes, which may be attributable to an enhanced effect of total energy expenditure on glucose disposal in individuals with specific eNOS haplotypes. Gene-environment interactions such as this may help explain why replication of genetic association frequently fails.

Footnotes

  • I.B. and A.J.S. hold stock in Incyte and GlaxoSmithKline, and A.J.S. is employed by GlaxoSmithKline.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted June 16, 2005.
    • Received March 22, 2005.
« Previous | Next Article »Table of Contents

This Article

  1. doi: 10.2337/diabetes.54.9.2795 Diabetes September 2005 vol. 54 no. 9 2795-2801
  1. » Abstract
  2. Full Text
  3. Full Text (PDF)

Current Issue

  1. December 2009, 58 (12)
    Current Issue
  1. Alert me to new issues of Diabetes