ASSOCIATION STUDY OF EPAS1 GENE POLYMORPHISMS WITH THE SUSCEPTIBILITY TO HIGH ALTITUDE PULMONARY HYPERTENSION IN TIBETAN RESIDENTS

Objective: Tibetans, mostly adapted to the plateau’s high altitude, still face some chronic hypoxia-related illnesses, including high altitude pulmonary hypertension (HAPH). Research indicates that the EPAS1 gene is key to high-altitude adaptation, with Tibetan-specific variations regulating responses to hypoxia through a hypoxia-inducible pathway. However, there is currently a lack of research on single nucleotide polymorphisms (SNPs) in the EPAS1 gene related to HAPH. Design and method: A case-control study of 94 HAPH patients and 94 healthy controls was conducted. Nine EPAS1 SNPs were genotyped, and linkage disequilibrium was analyzed using Haploview software. Logistic regression was used to assess the roles of SNPs and haplotypes in HAPH. Results: The allele A of EPAS1 rs6735530 was significantly associated with an increased risk of HAPH (81.9% vs. 62.7%, p = 0.000). Analysis using four genetic models revealed significant associations for rs1867785 and rs6735530. Under the codominant model, the GA genotype of rs1867785 was linked to an increased risk (OR = 2.544; p = 0.008), while the GA and GG genotypes of rs6735530 were associated with a decreased risk (OR = 0.509, p = 0.035; OR = 0.081, p = 0.001, respectively). In the dominant model, the AG+GG genotype of rs6735530 (OR=0.382; p=0.001) was linked to a lower HAPH risk. In the recessive model, the GG genotype of rs6735530 (OR = 0.106; p = 0.003) was also associated with a decreased risk of HAPH. These associations remained significant after adjusting for confounders (p< 0.05). Conclusions: In this study, we were the first to establish the association between SNPs in the EPAS1 (rs6735530) and EPAS1 (rs1867785) genes and susceptibility to HAPH in native Tibetans. These findings offer new insights into the mechanisms underlying HAPH and could potentially inform prophylactic and treatment strategies for the condition.