title: CYBA and GSTP1 variants associate with oxidative stress under hypobaric hypoxia as observed in high-altitude pulmonary oedema.
abstract: 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 α polypeptide) and GSTP1 (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 I105V (A/G) and A114V (C/T) of GSTP1, 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-PGF2α (8-iso-prostaglandin F2α) levels were determined in plasma and were correlated with individual alleles, genotype, haplotype and gene-gene interactions. The relative expression of CYBA and GSTP1 were determined in peripheral blood leucocytes. The genotype distribution of -930A/G, H72Y (C/T) and I105V (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 I105V (A/G) and A114V (C/T) in GSTP1 were over-represented in HAPE-p; in contrast, haplotypes A-T of -930A/G and H72Y (C/T) in CYBA and A-C of I105V (A/G) and A114V (C/T) in GSTP1 were over-represented in HAPE-r and HLs. 8-Iso-PGF2α levels were significantly higher in HAPE-p and in HLs than in HAPE-r (P=2.2×10(-16) and 1.2×10(-14) respectively) and the expression of CYBA and GSTP1 varied differentially (P<0.05). Regression analysis showed that the risk alleles G, C, G and T of -930A/G, H72Y (C/T), I105V (A/G) and A114V (C/T) were associated with increased 8-iso-PGF2α 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.
authors.affiliation: Institute of Genomics and Integrative Biology, Delhi, India.
authors.forename: Aastha
authors.initials: A
authors.lastname: Mishra
authors.forename: Zahara
authors.initials: Z
authors.lastname: Ali
authors.forename: Arpana
authors.initials: A
authors.lastname: Vibhuti
authors.forename: Rahul
authors.initials: R
authors.lastname: Kumar
authors.forename: Perwez
authors.initials: P
authors.lastname: Alam
authors.forename: Rekhbala
authors.initials: R
authors.lastname: Ram
authors.forename: Tashi
authors.initials: T
authors.lastname: Thinlas
authors.forename: Ghulam
authors.initials: G
authors.lastname: Mohammad
authors.forename: M A Qadar
authors.initials: MA
authors.lastname: Pasha
mesh_terms: D000532:Altitude Sickness / Q000235:genetics* / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood; D004843:Epistasis, Genetic; D005787:Gene Frequency; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism*; D015810:Linkage Disequilibrium; D019255:NADPH Oxidases / Q000235:genetics*; D018384:Oxidative Stress; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis
chemical_list: C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D019255:NADPH Oxidases; C086986:CYBA protein, human; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi