Gene-gene Interaction Between EPAS 1 and EGLN 1 in Patients with High-Altitude Pulmonary Edema

Objective:Endothelial PER-ARNT-SIM (PAS)domain protein 1(EPAS1,also known as HIF2α)and egl nine homolog 1 (EFLN1),also known as prolyl hydroxylase domain protein 2 (PHD2),have key functions in the upstream of the hypoxia-inducible factor(HIF)pathway.In order to dissect the genetic biology of susceptibility to high-altitude pulmonary edema(HAPE)from the viewpoint of the HIF pathway,we identified the allelic discriminations of three significant tag single-nucleotide polymorphisms(SNPs)in EPAS1 and three tag SNPs in EGLN1 in HAPE-susceptible(HAPE-s)Japanese subjects. Methods: Alleles were determined for the six SNPs (rs13419896, rs4953354, and rs4953388 in EPAS1; rs1435166, rs7542797, and rs2153364 in EGLN1)by the TaqMan SNP Genotyping Assay in a group of 59 HAPE-s subjects and a control group of 67 HAPE resistant(HAPE-r)subjects.In addition to the case-control analysis,multi-dimensional reduction(MDR)methodology was applied to a gene-gene interaction analysis to evaluate the association of HAPE-s with gene-gene interactions. Results:The EGLN1 rs2153364(A/G)x EPAS1 rs13419896(G/A)interaction was significantly associated with HAPE-s in the pairwise model(P=0.0049)based on the balanced accuracy of 63.23% in MDR.However,no significance was detected for the association with HAPE-s in the single gene model. Conclusion :The EPAS1-EGLN1 interaction appears to be associated with HAPE-s in the Japanese population despite the individual genes not being associated with HAPE-s.Shinshu Med J 63 : 157―165, 2015 (Received for publication January 29,2015;accepted in revised form February 17,2015)