a. Genomic markers Genes/Pathways/Biomolecules Involved Polymorphisms/SNPs/ Diplotype Effects on HAPE Ref.. Na-K ATPase, ENaC, CLNCK, Caveolae -- Reduction of caveolae may prove to be prophylactic. [50] Nitric oxide synthase genes G894T, –A 922G and –T 786C, Glu289Asp and 27-bp VNTR (eNOS4a) Increased susceptibility. [37] RAAS system ACE-I/D(27-bp intron), CYP11B2(-240AA, 2350GG and -344TT),AT1R( G1517T) ACE-I confers adaptation, CYP11B2 polymorphisms deviating from wild type cause susceptibility, AT1R polymorphisms increase susceptibility. [46, 47] Hsp70 gene family Dip5 (Hap1–Hap7), Increased susceptibility. But wild type helps in hypoxia tolerance. [14] β-adrenergic receptors haplotype 46G_79C_523C Confers resistance. [55] SP-A1 & SP-A2 1101 T, 3192C, 3234C alleles of SP-A1; SP-A2 allele 3265C Increased susceptibility. [39] ET-1 & ECE-1 G2288T(rs2070699) Increased susceptibility. [22] EPAS-1 (A/rs13419896-G/rs4953354-A/rs4953388) Confers resistance. [16] EGLN-1 TT genotype of rs479200 Increased susceptibility. [34] AQP5 -- Knockouts have increased lung injury and edema. [32] Mitochondrial haplogroups D4 & B B4b, B4c and D4 D & B4b confers resistance and B4c increased susceptibility. [15] TIMP3/MMP derived allele C of rs130293 in TIMP3 gene; haplotype CAC Confer resistance. [13]

b. Proteomic and Metabolomic markers Proteins Mechanism of Action in hypoxia Physiological effects   Pur-α transcriptional activator responsible forcoordinated induction of β-2 integrin family Pur-α expression leads to increasedangiogenesis. Also found in lungs of patients with idiopathic PAH. [56] Chloride intracellular channel protein-4 (CLIC-4) supports the acidification of vacuoles along the intracellular tubulogenic pathway May play a role in angiogenesis. Also implicated in PAH pathogenesis. [57] Periostin TGF-β inducible; advances the atherosclerotic and rheumatic cardiac valve degeneration by inducing angiogenesis Up-regulation of this protein has also been reported in patients with idiopathic PAH [57] Macrophage migration inhibitory factor (MIF) one of the mediators of hypoxia-induced pulmonary hypertension Hypoxia stimulates the expression of MIF in human vascular smooth muscles via HIF-α dependent pathway. [58] HSP-70 HSP-70 protects intestinal epithelial cells from hypoxia/reoxygenation injury via a mechanism involving mitochondrial pathways Promotes hypoxic tolerance and facilitates acclimatization to acute hypobaric hypoxia in rat and mouse models. [59] Rho-A Rho-A activation promotes VEGF secretion but the activation mechanism of Rho-A not clear. Prolonged hypoxia increases Rho-A and ROS signaling and activation in pulmonary artery smooth muscles and endothelial cells [60]

Table 2: Summary of Putative Biomarkers for HAPE.