Gene-Gene Interaction between EPAS1 and EGLN1 in Patients with High-Altitude Pulmonary Edema

High-altitude pulmonary edema (HAPE) is a hypoxia-induced, non-cardiogenic pulmonary edema. HAPE occurs within 2–4 days after rapid exposure to high altitudes, and lack of oxygen is the crucial cause of this disease. Although the mechanisms underlying the pathogenesis of HAPE are complex, the inception and progression of HAPE are governed by both genetic and environmental factors. Endothelial PER-ARNT-SIM (PAS) domain protein 1 (EPAS1, also known as HIF2α) and egl nine homolog 1 (EGLN1, also known as PHD2), have key functions in the upstream of the hypoxia-inducible factor (HIF) pathway. In order to understand the genetic biology of susceptibility to 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 Japanese subjects (HAPE-s). The six SNPs (rs13419896, rs4953354, and rs4953388 in EPAS1; rs1435166, rs7542797, and rs2153364 in EGLN1) were determined by TaqMan® SNP genotyping assay in a group of 59 HAPE-s subjects and a control group of 67 HAPE-resistant subjects. In addition, multi-dimensional reduction (MDR) methodology was applied to a gene-gene interaction analysis to evaluate the association of HAPE-s with gene-gene interactions. The EGLN1 rs2153364 (A/G) with 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 SNP model. The EPAS1-EGLN1 interaction appears to be associated with HAPE in the Japanese population.