Gilbert综合征UGT1A1致病变异的连锁关系研究  

Linkage analysis of pathogenic UGT1A1 mutations in Gilbert syndrome: a case-control study of 46 cases

作　　者：李露锋 邓国宏 毛青 LI Lufeng;DENG Guohong;MAO Qing(Department of Infectious Diseases,First Affiliated Hospital,Army Medical University(Third Military Medical university),Chongqing,400038,China)

机构地区：[1]重庆陆军军医大学(第三军医大学)第一附属医院感染科

出　　处：《第三军医大学学报》2020年第2期168-175,共8页Journal of Third Military Medical University

基　　金：西南医院重大创新课题(SWH2016ZDCX3002)~~

摘　　要：目的明确Gilbert综合征患者(Gilbert syndrome,GS)UDP-葡萄糖醛酸基转移酶1A1基因(UDP-glucuronyl transferase 1A1 gene,UGT1A1)致病变异的连锁关系,进一步明确GS的遗传机制。方法对46例GS患者与80名健康对照者UGT1A1基因的增强子PBREM、启动子TATA盒、PE、DE及外显子进行直接测序,把所测得的SNP进行连锁不平衡分析、并构建单体型和单体基因型进行分析。结果共测到c.-3279T>G、c.-1352C>A、c.-40_-39insTA、c.211G>A、c.686C>A、c.1456T>G等6个SNP位点,对该6个SNP位点进行连锁不平衡分析表明c.-3279T>G和c.-1352C>A的D’值和r^2均等于1,呈完全的连锁不平衡;进一步构建单体型表明c.-40_-39insTA和c.-3279T>G呈连锁关系、c.211G>A和c.-1352C>A呈连锁关系,他们所构成的单体基因型在病例组中的频率高达0.717,而在对照组中的频率仅为0.005,两者具有显著的统计学差异,P<0.000。结论 Gilbert综合征的发生与来源于不同同源染色体的c.-40_-39insTA和c.211G>A的两两变异相关,而c.-3279T>G和c.-1352C>A与它们的各自连锁发挥了剂量效应作用。Objective To clarify the linkage of pathogenic mutations in UDP-glucuronyl transferase 1 A1(UGT1 A1) gene with Gilbert syndrome(GS) and explore the genetic mechanism of GS. Methods The genomic DNA was extracted from the peripheral blood samples of 46 unrelated GS patients and 80 healthy control subjects. The enhancer PBREM, the promoter TATA box, PE, DE and the coding regions of UGT1 A1 gene were amplified with PCR, and the amplified DNA fragments were sequenced and analyzed. Results Six single nucleotide polymorphisms(SNPs) were identified in UGT1 A1 gene of GS patients, namely c.-3279 T>G, c.-1352 C>A, c.-40_-39 insTA, c.211 G>A, c.686 C>A, and c.1456 T>G. The D’ and r^2 were both 1 for c.-40_-39 insTA and c.-3279 T>G, demonstrating a complete linkage disequilibrium. Haplotype construction showed that c.-40_-39 insTA was linked to c.-3279 T>G, and c.211 G>A was linked to c.-1352 C>A;the frequency of the diplotypes generated by these haplotypes reached 0.717 in GS, as comparted to 0.005 in the control subjects(P<0.000). Conclusion The occurrence of GS is associated with the variations of c.-40_-39 insTA and c.211 G >A from different homologous chromosomes, and c.-3279 T>G and c.-1352 C>A both have a dose effect in their respective linkage.

关 键 词：GILBERT综合征 UGT1A1 连锁 单体型 单体基因型 

分 类 号：R363.21[医药卫生—病理学] R394.3[医药卫生—基础医学]