Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous region, Key Laboratory of High Altitude Environment and Genes Related to Diseases of Tibet Autonomous Region, School of Medicine, Xizang Minzu University, Xianyang, Shaanxi, 712082, China.
Ministry of Education (MOE) Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center of Genetics and Development, Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai, 200438, China.
BMC Med Genomics. 2023 Jul 28;16(1):174. doi: 10.1186/s12920-023-01613-9.
As a chronic mountain sickness(CMS) with the highest incidence and the greatest harm, the pathogenesis of high altitude polycythemia (HAPC) is still not fully understood.
37 HAPC patients and 42 healthy subjects were selected from plateau, and peripheral venous blood samples were collected for transcriptome sequencing on Illumina NovaSeq platform. The sequenced data were analyzed by bioinformatics and phenotypic association analysis.
The results showed significant differences in multiple clinical indicators including RBC and HGB et al. existed between HAPC and control. Based on the RNA-seq data, 550 genes with significant differential expression were identified in HAPC patients. GO and KEGG pathway enrichment analysis showed that the up-regulated genes were mainly enriched in processes such as erythrocyte differentiation and development and homeostasis of number of cells, while the down-regulated genes were mainly enriched in categories such as immunoglobulin production, classical pathway of complement activation and other biological processes. The coupling analysis of differential expression genes(DEGs) and pathological phenotypes revealed that 91 DEGs were in close correlation with in the phenotype of red blood cell volume distribution (width-CV and width-SD), and they were all up-regulated in HAPC and involved in the process of erythrocyte metabolism. Combined with the functional annotation of DEGs and literature survey, we found that the expression of several potential genes might be responsible for pathogenesis of HAPC. Besides, cell type deconvolution analysis result suggested that the changes in the number of some immune cell types was significantly lower in HAPC patients than control, implying the autoimmune level of HAPC patients was affected to a certain extent.
This study provides an important data source for understanding the pathogenesis and screening pathogenic genes of HAPC. We found for the first time that there was a significant correlation between HAPC and the pathological phenotype of width-CV and width-SD, wherein the enriched genes were all up-regulated expressed and involved in the process of erythrocyte metabolism. Although the role of these genes needs to be further studied, the candidate genes can provide a starting point for functionally pinning down the underlying mechanism of HAPC.
作为一种发病率最高、危害最大的慢性高山病（CMS），高原红细胞增多症（HAPC）的发病机制尚未完全阐明。
从高原地区选取 37 例 HAPC 患者和 42 例健康对照者，采集外周静脉血，用 Illumina NovaSeq 平台进行转录组测序。对测序数据进行生物信息学分析和表型关联分析。
HAPC 组与对照组在 RBC、HGB 等多项临床指标上存在显著差异。基于 RNA-seq 数据，在 HAPC 患者中鉴定出 550 个具有显著差异表达的基因。GO 和 KEGG 通路富集分析显示，上调基因主要富集在红细胞分化和发育以及细胞数量平衡等过程中，而下调基因主要富集在免疫球蛋白产生、经典补体激活途径等生物过程中。差异表达基因（DEGs）与病理表型的耦合分析显示，91 个 DEGs 与红细胞体积分布的表型（宽度-CV 和宽度-SD）密切相关，在 HAPC 中均上调，参与红细胞代谢过程。结合 DEGs 的功能注释和文献调研，发现几个潜在基因的表达可能与 HAPC 的发病机制有关。此外，细胞类型去卷积分析结果表明，HAPC 患者某些免疫细胞类型的数量变化明显低于对照组，提示 HAPC 患者的自身免疫水平受到一定程度的影响。
本研究为了解 HAPC 的发病机制和筛选致病基因提供了重要的数据源。我们首次发现 HAPC 与宽度-CV 和宽度-SD 的病理表型之间存在显著相关性，其中富集的基因均上调表达，参与红细胞代谢过程。尽管这些基因的作用需要进一步研究，但候选基因可以为功能上确定 HAPC 的潜在机制提供起点。
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