Chen Yu, Jiang Chunhua, Luo Yongjun, Liu Fuyu, Gao Yuqi
Institute of Medicine and Hygienic Equipment for High Altitude Region, College of High Altitude Military Medicine, Third Military Medical University, Chongqing 400038, China; Key Laboratory of High Altitude Medicine, Third Military Medical University, Ministry of Education, Chongqing 400038, China; Key Laboratory of High Altitude Medicine, PLA, Chongqing 400038, China.
Department of Pathophysiology and High Altitude Pathology, College of High Altitude Military Medicine, Third Military Medical University, Chongqing 400038, China; Key Laboratory of High Altitude Medicine, Third Military Medical University, Ministry of Education, Chongqing 400038, China; Key Laboratory of High Altitude Medicine, PLA, Chongqing 400038, China.
Blood Cells Mol Dis. 2016 Mar;57:13-22. doi: 10.1016/j.bcmd.2015.11.005. Epub 2015 Nov 12.
High altitude polycythemia (HAPC) is a serious public health problem among Han Chinese immigrants to the Qinghai-Tibetan Plateau. This study aims to explore the genetic basis of HAPC in the Han Chinese population. 484 male subjects (234 patients and 250 controls) were enrolled in this study. Genotyping was performed for polymorphisms of I/D in ACE, C1772T and G1790A in exon 12 of HIF-1α, rs2567206 in CYP1B1, rs726354 in SENP1, rs3025033 in VEGFA, rs7251432 in HAMP, rs2075800 in HSPA1L and rs8065364 in CARD14. Gene-gene interaction was assessed by multifactor dimensionality reduction. A significant association was seen between CARD14 polymorphism rs8065364 and risk of HAPC development in male Han Chinese, and the C allele of rs8065364 was a risk factor (odds ratio (OR)=1.59, 95% confidence interval (95% CI)=1.21-2.08). Gene-gene interaction analysis indicated that a synergistic relationship existed between rs3025033 and rs8065364 (1.00%), rs3025033 and rs726354 (0.18%), and rs726354 and rs8065364 (0.17%). The combination of rs8065364 in CARD14, rs3025033 in VEGFA and rs726354 in SENP1 was the best model to predict HAPC development in this study (testing accuracy=0.6183, p=0.0010, cross-validated consistency=10/10). Genetic interactions of SNPs in CARD14, SENP1 and VEGFA might represent a functional mechanism in the pathogenesis of HAPC.
高原红细胞增多症（HAPC）是汉族移民到青藏高原后出现的一个严重公共卫生问题。本研究旨在探索汉族人群中HAPC的遗传基础。本研究纳入了484名男性受试者（234例患者和250例对照）。对ACE基因I/D多态性、低氧诱导因子-1α（HIF-1α）第12外显子的C1772T和G1790A、细胞色素P450 1B1（CYP1B1）基因的rs2567206、泛素特异性蛋白酶1（SENP1）基因的rs726354、血管内皮生长因子A（VEGFA）基因的rs3025033、肝脏抗菌肽（HAMP）基因的rs7251432、热休克蛋白A1L（HSPA1L）基因的rs2075800以及含半胱氨酸的天冬氨酸蛋白水解酶募集结构域蛋白14（CARD14）基因的rs8065364进行基因分型。通过多因素降维法评估基因-基因相互作用。在汉族男性中，发现CARD14基因多态性rs8065364与HAPC发生风险之间存在显著关联，rs8065364的C等位基因是一个风险因素（优势比（OR）=1.59，95%置信区间（95%CI）=1.21 - 2.08）。基因-基因相互作用分析表明，rs3025033与rs8065364之间（1.00%）、rs3025033与rs726354之间（0.18%）以及rs726354与rs8065364之间（0.17%）存在协同关系。在本研究中，CARD14基因的rs8065364、VEGFA基因的rs3025033和SENP1基因的rs726354的组合是预测HAPC发生的最佳模型（检验准确性=0.6183，p = 0.0010，交叉验证一致性=10/10）。CARD14、SENP1和VEGFA基因单核苷酸多态性的遗传相互作用可能代表了HAPC发病机制中的一种功能机制。
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