Institute of Genomics and Integrative Biology, India.
J Renin Angiotensin Aldosterone Syst. 2011 Jun;12(2):93-101. doi: 10.1177/1470320310387177. Epub 2011 Mar 10.
The genes of the renin--angiotensin system (RAS) play an important role in the regulation of pulmonary vascular tone. Although studies on individual genes polymorphisms have reported association with high-altitude pulmonary oedema (HAPE), studies on multiple genes or epistasis are lacking. We therefore investigated the association of the RAS polymorphisms with HAPE. In a case-control design, we screened 163 HAPE-resistant/controls (HAPE-r) and 160 HAPEpatients (HAPE-p) of Indian origin for eight polymorphisms of four RAS genes, ACE, AGT, AGTR1 and AGTR2. Significant difference in genotype and allele frequencies of the ACE I/D and AGT M235T polymorphisms was observed between HAPE-p and HAPE-r (p < 0.05). In three-locus haplotype analysis of AGT the haplotype GTM was significantly higher in HAPE-p (29%) and haplotype GTT in HAPE-r (27%) after Bonferroni correction (p < 0.006). The differences were insignificant for polymorphisms from AGTR1 and AGTR2. The MDR (multifactor dimensional reduction) approach for gene--gene interaction depicted individual polymorphism M235T as the best disease predicting model (cross validation consistency, CVC = 10/10). We found a significant association of D allele of ACE and M allele of AGT with HAPE. The findings are supported at the haplotypic level as well as through nested genetic interaction between the RAS gene polymorphisms using the MDR approach.
肾素-血管紧张素系统（RAS）的基因在调节肺血管张力方面发挥着重要作用。虽然对个别基因多态性的研究报告了与高原肺水肿（HAPE）的相关性，但缺乏对多个基因或上位性的研究。因此，我们研究了 RAS 基因多态性与 HAPE 的相关性。在病例对照设计中，我们筛选了 163 名印度裔 HAPE 抗性/对照（HAPE-r）和 160 名 HAPE 患者（HAPE-p），用于四个 RAS 基因 ACE、AGT、AGTR1 和 AGTR2 的 8 个多态性。ACE I/D 和 AGT M235T 多态性的基因型和等位基因频率在 HAPE-p 和 HAPE-r 之间存在显著差异（p<0.05）。在 AGT 的三基因座单体型分析中，经过 Bonferroni 校正（p<0.006）后，HAPE-p 中 GTM 单体型显著升高（29%），HAPE-r 中 GTT 单体型显著升高（27%）。来自 AGTR1 和 AGTR2 的多态性差异不显著。基因-基因相互作用的 MDR（多因素维度减少）方法表明，单体型 M235T 是最佳疾病预测模型（交叉验证一致性，CVC=10/10）。我们发现 ACE 的 D 等位基因和 AGT 的 M 等位基因与 HAPE 显著相关。这些发现得到了单体型水平以及通过 MDR 方法对 RAS 基因多态性之间嵌套遗传相互作用的支持。
