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

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. Diabetes 54:2795-2801, 2005

Renin–angiotensin and endothelial nitric oxide synthase gene polymorphisms are not associated with the risk of incident type 2 diabetes mellitus: a prospective cohort study

“…Thus, we were unable to confirm a relationship between the rs1799983 genotype and type 2 diabetes, previously described in a small European study [38]. Furthermore, we could not replicate an association between NOS3 haplotypes and the prevalence of type 2 diabetes [39]. Again, selective reporting of positive findings amongst small studies is the most plausible explanation of these discrepancies.…”

Endothelial nitric oxide synthase Glu298Asp, 4b/a, and T‐786C polymorphisms in type 2 diabetic retinopathy

“…On the other hand, de Syllos suggested that haplotype 112 was protective of T2DM, as it was present at low frequencies among T2DM patients 14 . While not addressing DR, Franks demonstrated the select association between specific eNOS haplotypes and T2DM and associated conditions (energy metabolism) 19 . The differences in eNOS haplotype distribution among Tunisian Arabs with other populations may be explained by ethnic variation in the eNOS haplotype distribution, highlighted by the high prevalence of the 111 haplotype among Asians (77%) compared to other ethnic groups (46%) 20 …”

Anti-Inflammatory and Cardioprotective Effects of Tadalafil in Diabetic Mice

“…obesity, elevated fasting glucose levels, dyslipidemia, hypertension) and urinary cGMP excretion, suggesting that a reduction of NO bioactivity concurs with these CV risk factors [33]. Moreover, genetic variations of eNOS gene influenced energy expenditure, severity of glucose intolerance and risk of developing type II diabetes [34]. Chronic (alternate-day) administration of TAD in men with ED had improved endothelial function as indicated by marked changes in serum markers of endothelial function, increased insulin levels and a robust decrease in the inflammatory marker, high sensitivity C-reactive protein (hs-CRP) [35].…”