Significance of haplotype analysis versus single-nucleotide polymorphisms:Association of endothelial nitric oxide synthase gene haplotypes with essential hypertension and plasma nitric oxide levels

Nitric Oxide (NOx) a potent vasodilator plays a key role in blood pressure regulation.Reduced NO synthesis could be the result of endothelial nitric oxide synthase gene (NOS3) polymorphisms. We investigated the role of 922A/G, 786T/C, 894G/T and 4b/4a polymorphisms of the NOS3 and plasma NOx levels in susceptibility to essential hypertension. Methods: We recruited 800 consecutive unrelated subjects comprising of 455 never-treated patients and345 controls. The polymorphisms were investigated independently and in combination with haplotype analysis. Plasma NOx levels were estimated by Griess method. Association was determined by logisticregression analysis. Results: Genotype frequencies for the –786TC, 4b/4a and 894G/T polymorphisms differed significantly (P < 0.001) between patients and controls and were associated with an increased risk of hypertension(OR = 2, OR = 3.8, OR = 1.6, respectively). NOx levels were higher in controls than patients (P < 0.0001). The individual polymorphisms showed marginal association with plasma NOx level (P =0.06). The novel susceptible haplotypes 786C4a, 786T4a, 786T4a894T, 922A786T4a894T (P < 0.001)associated with lower plasma NOx levels and hypertension while 786T4b, 4b894G, 786T4b894G, 922A786T4b894G as protective haplotypes (P < 0.001) with higher plasma NOx in controls. Conclusion: We found significant difference in NOx levels between patients and controls. The 4b/4aand 786T/C polymorphisms, individually and as haplotypes, associated significantly with risk of hypertension. Of interest, the 4b/4a and 786T/C polymorphisms were considered as the determinants modifying the risk of hypertension suggesting the importance of these variants as a potent risk factor for hypertension.

Keywords:

Essential hypertension , NOS3 , polymorphisms , haplotypes , NOx levels