PDK1、IL12RB1和TCL1A基因多态性与西藏世居人群高原红细胞增多症易感性分析

Analysis of PDK1,IL12RB1 and TCL1A gene polymorphisms and susceptibility to high altitude polycythemia in Tibetan population

目的西藏世居人群对高原缺氧环境引起高原红细胞增多症(HAPC)的适应机制尚未完全阐明。文中旨在通过对西藏世居人群中HAPC易感基因PDK1、IL12RB1和TCL1A的验证与分析,探讨HAPC易感基因变异谱系及其相互关系。方法选取2016年9月至2018年9月西藏民族大学附属医院和西藏自治区第二人民医院567例就诊的HAPC患者为HAPC组。同时选取360例健康体检人员作为对照组。使用FastTarget测序技术对2组的PDK1、IL12RB1和TCL1A基因进行靶向测序。进行单核苷酸多态性(SNP)位点关联分析、连锁不平衡及单倍型分析。结果IL12RB1基因rs393548、rs436857和rs845380与HAPC有关(P<0.05)。总体样本水平,rs393548和rs436857在显性模型和加性模型分析均与HAPC易感性增加有关(P<0.05)。女性样本水平,HAPC保护因素是SNP rs845380,在隐性模型和加性模型分析均与HAPC保护性增加有关(P<0.05)。男性样本水平,rs393548只在显性模型中显示出对HAPC的危险因素(P<0.05)。IL12RB1基因的SNP位点间存在较高的连锁不平衡,形成了具有统计学意义的单倍型域,rs436857和rs393548(OR=1.41,95%CI=1.03~1.93,P=0.030),及rs393548和SNV00212(OR=1.70,95%CI=1.14~2.15,P=0.009)。单倍型A-A及A--是HAPC的危险因素(P<0.05)。结论IL12RB1基因的SNPsrs393548、rs436857和rs845380与西藏世居人群HAPC的发生有关,为后续探寻HAPC发病机制奠定了基础。

Objective The adaptation mechanism of Tibetan people to high altitude polycythemia(HAPC)induced by hypoxia in the plateau environment have not been fully clarified.This study aims to investigate the genetic lineage and correlation of HAPC susceptibility genes PDK1,IL12RB1 and TCL1A in a large sample of HAPC in Tibetan population.Methods PDK1,IL12RB1 and TCL1A genes of 567 HAPC patients and 360 healthy controls were sequenced using Fast Target sequencing technology in Tibetan plateau population.Software SPSS 23.0,R 3.6.0,Plink and Haploview v4.2 were used for single nucleotide polymorphism(SNP)site association analysis,linkage imbalance and haplotype analysis.Results In this case-control study,we observed significant differences of IL12RB1 rs393548,rs436857 and rs845380 genotypes between the case group and the control group.Through gender stratification,rs845380 in recessive model(OR=0.45,95%CI=0.23-0.86,P=0.015)and additive model(OR=0.61,95%CI=0.41-0.90,P=0.012)was associated with the increase of HAPC protection in female samples,while in male samples,rs393548 was a risk factor for HAPC in dominant model(OR=1.51,95%CI=1.04-2.12,P=0.032).There was no significant difference of SNPs in PDK1 and TCL1A genes.There was a high linkage disequilibrium between the SNP loci of IL12RB1 gene,which formed statistically significant haplotype blocks rs436857 and rs393548(OR=1.41,95%CI=1.03-1.93,P=0.030),and rs393548 and SNV00212(OR=1.70,95%CI=1.14-2.15,P=0.009).Haplotypes A-A and A--were the risk factors for HAPC,respectively.Conclusion The results suggest that three SNPs rs393548,rs436857 and rs845380 in IL12RB1 gene are associated with the occurrence of HAPC in Tibetan population,which lays a foundation for further exploration of the pathogenesis of HAPC.