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

¹ Medical Research Council Epidemiology Unit, Cambridge, U.K
² Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona
³ Wellcome Trust Sanger Institute, Metabolic Disease Group, Cambridge, U.K
⁴ Departamento de Medicina Interna II, Hospital Universitario Clínico San Carlos, Madrid, Spain
⁵ Incyte Genomics, Cambridge, U.K
⁶ Departments of Clinical Biochemistry and Medicine, Addenbrooke’s Hospital, Cambridge, U.K

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 x 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.

Abbreviations: CCS, Cambridgeshire Case-Control Study; eNOS, endothelial nitric oxide synthase; htSNP, haplotype-tagging single nucleotide polymorphism; MRC, Medical Research Council Ely Study; NOS, nitric oxide synthase; SNP, single nucleotide polymorphism

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