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.