CYBA and GSTP 1 variants associate with oxidative stress under hypobaric hypoxia as observed in high-altitude pulmonary oedema

HAPE (high-altitude pulmonary oedema) is characterized by pulmonary hypertension, vasoconstriction and an imbalance in oxygen-sensing redox switches. Excess ROS (reactive oxygen species) contribute to endothelial damage under hypobaric hypoxia, hence the oxidative-stress-related genes CYBA (cytochrome b-245 alpha polypeptide) and GSTP 1 (glutathione transferase Pi 1) are potential candidate genes for HAPE. In the present study, we investigated the polymorphisms - 930A/G and H72Y (C/T) of CYBA and 1105V (A/G) and Al 14V (C/T) of GSTP 1, individually and in combination, in 150 HAPE-p (HAPE patients), 180 HAPE-r (HAPE-resistant lowland natives) and 180 HLs (healthy highland natives). 8-Iso-PGF(2 alpha) (8-iso-prostaglandin F-2 alpha) levels were determined in plasma and were correlated with individual alleles, genotype, haplotype and gene-gene interactions. The relative expression of CYBA and GSTP 1 were determined in peripheral blood leucocytes. The genotype distribution of - 930A/G, H72Y (C/T) and 1105V (A/G) differed significantly in HAPE-p compared with HAPE-r and HLs (P <= 0.01). The haplotypes G-C of - 930A/G and H72Y (C/T) in CYBA and G-C and G-T of 1105V (A/G) and Al 14V (C/T) in GSTP 1 were over-represented in HAPE-p; in contrast, haplotypes A-T of - 930A/G and H72Y (C/T) in CYBA and A-C of 1105V (A/G) and Al 14V (C/T) in GSTP 1 were over-represented in HAPE-r and HLs. 8-Iso-PGF(2 alpha) levels were significantly higher in HAPE-p and in HLs than in HAPE-r (P = 2.2 x 10(-16) and 1.2 x 10(-14) respectively) and the expression of CYBA and GSTP 1 varied differentially (P < 0.05). Regression analysis showed that the risk alleles G, C, G and T of - 930A/G, H72Y (C/T), 1105V (A/G) and Al 14V (C/T) were associated with increased 8-iso-PGF(2)alpha, levels (P < 0.05). Interaction between the two genes revealed over-representation of most of the risk-allele-associated genotype combinations in HAPE-p and protective-allele-associated genotype combinations in HLs. In conclusion, the risk alleles of CYBA and GSTP1, their haplotypes and gene-gene interactions are associated with imbalanced oxidative stress and, thereby, with high-altitude adaptation and mal-adaptation.