Investigation of eNOS gene polymorphism exposes a genetic association between endothelial dysfunction and osteoporosis in postmenopausal women.

Objectives: To investigate the association of genetic polymorphisms of endothelial nitric oxide synthase (eNOS) gene with endothelial dysfunction associated osteoporosis in postmenopausal women of Punjab, India. Methods: The study involved 456 postmenopausal women having endothelial dysfunction categorized according to women with (n = 236) and without osteoporosis (n = 220). Bone mineral density (BMD) and reactive hyperemia index (RHI) were evaluated together with six single-nucleotide polymorphisms (SNPs) within the eNOS gene (rs2070744, rs1799983, rs1800780, rs3918181, rs891512, and rs1808593). Results: A moderate association between RHI and BMD at femoral neck (r(2) = 0.213,P = 0.002) and lumbar spine (r(2) = 0.267,P < 0.001) was observed. Minor alleles C and T of SNPs rs2070744 and rs1799983 were associated with chances of osteoporosis in both co-dominant (odds ratio [OR] 2.13,P = 0.017; OR 2.77,P = 0.009) and dominant (OR 2.10,P = 0.011; OR 2.45,P = 0.007) modes, whereas minor allele A of SNP rs891512 showed marginal probability in dominant model (OR 1.68,P = 0.047). A susceptibility haplotype (CTAAAT) was observed within the eNOS gene which conferred 2.32 times higher chances of osteoporosis (OR 2.32, 95% confidence interval 1.18-4.54,P = 0.021) after adjusting for the effect of confounders. Genetic model analysis revealed that each copy of susceptibility haplotype increased the possibility of osteoporosis by a factor of 2.11 +/- 0.63 (P < 0.001). RHI was significantly associated with susceptibility haplotype CTAAAT in a dose-dependent manner, whereby the severity of endothelial dysfunction increased significantly in women having two copies over women having one copy or no copy (beta = 2.13,P < 0.001) of susceptibility haplotype. Conclusion: A susceptibility haplotype CTAAAT within the eNOS gene is associated with double the possibility of endothelial dysfunction affiliated osteoporosis in postmenopausal women of Punjab, India.