Differences in pathogenetic mechanism between Tibetan and Han high-altitude polycythemia based on a whole genome-wide association study

High-altitude polycythemia (HAPC) is a common and serious chronic disease affecting people of highland and plains ancestry living at high altitudes. This study investigated genetic susceptibility differences for HAPC among ethnic groups, with 2,248 volunteers participating, including 898 HAPC patients (nHan = 450, nTibetan = 448). The study included a GWAS of 198 cases (nHan = 100, nTibetan = 98), which revealed eight Tibetan HAPC-susceptibility single-nucleotide polymorphisms and four Han HAPC-susceptibility VARIANTs. Among them, the common polymorphism locus rs7618658 (SNX4, Pcombine<5e-8) was found and verified in both Tibetans and Han Chinese. Furthermore, the exploration of Tibetan EPAS1 suggested that the rs1374749 locus of EPAS1, along with other locus-linked status changes, may be a prevalence factor for HAPC, and the GGTAC haplotype in which it is located is a risk haplotype for HAPC (P = 5.14E-9, OR = 1.85).The study showed significant genetic susceptibility to HAPC between Tibetans and Han Chinese, with Tibetans mainly susceptible in oxygen-sensing pathways such as EPAS1, which are associated with several phenotypes (Hemoglobin, Hematocrit, and Platelets, etc), while Han Chinese patients exhibited susceptibilities mainly in cell differentiation and angiogenesis, such as in SNX4 and LPAR1, which are similarly significantly associated with hemoglobin, hematocrit, and platelets.