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 , P combine<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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement . This work was supported by grants from: The Science and Technology Department of Tibet (08080002), 2019 School-level Cultivation Project of Tibet University (ZDTSJH19-08), and Special Funds from the Central Finance to Support the Development of Local Universities [2018] No. 54; [2019] No. 1-19; [2020] No.79; [2021] No.1; (00060695/003). This research was supported by Shanghai Municipal Science and Technology Major Project (2017SHZDZX01), National Science Foundation of China (32288101, 32200536), and CAMS Innovation Fund for Medical Sciences (2019-I2M-5-066). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Finally, we thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The methods used in this study strictly adhered to relevant guidelines and regulations (such as the Helsinki Declaration). All experimental protocols and procedures were approved by the appropriate Ethics Committee or Institutional Review Board [China Tibet University Ethics Committee], ensuring compliance with ethical standards and protection of participants' rights. Additionally, data collection and usage in this study were conducted with the informed consent of all volunteers, who signed an informed consent form. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data used in this study are available from the corresponding author upon reasonable request. The datasets generated and/or analyzed during the current study are not publicly available due to reason for data restrictions.