Nejatizadeh Azim, Kumar Rahul, Stobdan Tsering, Goyal A K, Sikdar Sunandan, Gupta Mohit, Javed Saleem, Pasha M A Qadar
Institute of Genomics and Integrative Biology, Delhi, India.
Free Radic Biol Med. 2008 Jun 1;44(11):1912-8. doi: 10.1016/j.freeradbiomed.2008.02.004. Epub 2008 Feb 20.
Nitric oxide (NO), a potent vasodilator, plays a pivotal role in blood pressure regulation. Endothelial NO synthase gene (NOS3) polymorphisms influence NO levels. Here, we investigated the role of the -922A/G, -786T/C, 4b/4a, and 894G/T polymorphisms of the NOS3 and NO(x) levels in 800 consecutive unrelated subjects comprising 455 patients of essential hypertension and 345 controls. The polymorphisms were investigated independently and as haplotypes. Plasma NO(x) levels (nitrate and nitrite) were estimated by the Griess method. Genotype frequencies for the -786T/C, 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=2.0, OR=3.8, OR=1.6, respectively). The 4-locus haplotypes ATaG (H1), ATaT (H2), and GCaG (H3) were significantly associated with essential hypertension and served as susceptible haplotypes (P<or=0.0001). On the other hand, haplotypes ATbG (H4) and GTbG (H5) were negatively associated with hypertension and served as protective haplotypes (P<0.0001). NO(x) levels were significantly lower in patients than controls (P<0.0001). The individual polymorphisms showed marginal association with NO(x) level; however, the susceptible haplotype H2 associated significantly with lower NO(x) levels in patients (P<0.001) and conversely the haplotype H4 with higher NO(x) levels in controls (P<0.001). In conclusion, the 4b/4a and likely -786T/C polymorphisms were identified as the determinants modifying the risk of hypertension. This study identifies the NOS3 variants and haplotypes as genetic risk factors and as useful markers of increased susceptibility to the risk of essential hypertension.
一氧化氮（NO）是一种强效血管舒张剂，在血压调节中起关键作用。内皮型一氧化氮合酶基因（NOS3）多态性会影响NO水平。在此，我们对800名连续的无亲缘关系个体进行研究，其中包括455例原发性高血压患者和345名对照，以探究NOS3的 -922A/G、-786T/C、4b/4a和894G/T多态性与NO(x)水平的作用。这些多态性分别及作为单倍型进行研究。采用格里斯方法估算血浆NO(x)水平（硝酸盐和亚硝酸盐）。患者与对照之间，-786T/C、4b/4a和894G/T多态性的基因型频率存在显著差异（P<0.001），且与高血压风险增加相关（OR分别为2.0、3.8、1.6）。4位点单倍型ATaG（H1）、ATaT（H2）和GCaG（H3）与原发性高血压显著相关，为易感单倍型（P≤0.0001）。另一方面，单倍型ATbG（H4）和GTbG（H5）与高血压呈负相关，为保护性单倍型（P<0.0001）。患者的NO(x)水平显著低于对照（P<0.0001）。各多态性与NO(x)水平呈边缘性关联；然而，易感单倍型H2与患者较低的NO(x)水平显著相关（P<0.001），相反，单倍型H4与对照中较高的NO(x)水平相关（P<0.001）。总之，4b/4a以及可能的 -786T/C多态性被确定为改变高血压风险的决定因素。本研究将NOS3变异体和单倍型确定为遗传风险因素以及原发性高血压风险易感性增加的有用标志物。
