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 prevalent chronic condition affecting individuals at high altitudes, including both highland and plains populations. This study, involving 2248 participants, explored genetic susceptibility to HAPC among ethnic groups, with 898 HAPC patients (450 Han, 448 Tibetan). The Genome-wide Association Study, encompassing 198 cases (100 Han, 98 Tibetan), identified eight Tibetan HAPC-susceptibility single-nucleotide polymorphisms and four in Han individuals. The common polymorphism locus rs7618658 (SNX4, p _combine < 5 × 10^-8) was validated in both populations. The investigation of Tibetan EPAS1 revealed the rs1374749 locus, along with linked loci, as a potential prevalence factor for HAPC. The GGTAC haplotype containing this locus emerged as a Protect haplotype for HAPC (p = 2.461 × 10^-12, OR = 0.344). Enrichment analysis revealed that Tibetans exhibited susceptibility in oxygen-sensing pathways, such as EPAS1, associated with phenotypes like hemoglobin and platelets. In contrast, Han Chinese showed significant sensitivity in cell differentiation and angiogenesis, closely linked to hemoglobin, hematocrit, and platelets.

Supplementary information: The online version contains supplementary material available at 10.1007/s43657-024-00180-y.