尿苷二磷酸葡萄糖醛酸转移酶1A6基因多态性与抗结核药致肝损害的相关性

Relationship between the polymorphisms of UGT1A6 genes and anti-tuberculosis drug induced hepatic-injury

目的探讨尿营二磷酸葡萄糖醛酸转移酶1A6（UGT1A6）基因多态性与中国唐山地区结核患者抗结核药致肝损害的相关性。方法采用病例对照研究，以抗结核治疗导致肝损害患者202例为病例组，无肝损害者239例为对照组，收集环境因素暴露情况及静脉血。UGT1A6基因多态性分析采用聚合酶链反应限制性片段长度多态方法，利用HhaⅠ、DpnⅡ和NsiⅠ内切酶分析其基因多态性，以SPSS13．0软件对各危险因素进行单因素和多因素非条件Logistic回归分析。结果UGT1A6的19T／G、308C／A和541A／G多态性位点均存在3种基因型，UGT1A619T／T、UGT1A619T／G和UGT1A6—19G／G在病例组和对照组的频率分别为51．5％、39．6％、8．9％和71．1％、25．5％、3．3％；UGT1A6—308C／C、UGT1A6308C／A和UGT1A6—308A／A在病例组和对照组的频率分别为52．0％、40．6％、7．4％和79．1％、19．2％、1．7％；UGT1A6541AA、UGT1A6—541A／G和UGT1A6541G／G在病例组和对照组的频率分别为57．9％、33．7％、8．4％和79．5％、19．2％、1．3％，两组问差异均有统计学意义（x^2值分别为17．956、37．385和24．095，P值均〈0．01）。单因素和多凶素分析均显示UGT1A619T／G、308C／A、541A／G3个位点基因多态性与抗结核药致肝损害的发生有关（P值均〈0．05）。结论UGT1A6基因多态性可能与汉族人抗结核药致肝损害的发病有关，且各基因型存在相互作用。

Objective To investigate the relationship between the polymorphisms of UGT1A6 genes and anti-tuberculosis drug induced hepatic-injury （ADIH）. Methods 202 cases and 239 controls were collected and a case-control study was conducted. Information on related risk factors of tuberculosis was collected. The genotypes of UGT 1A6-19T/G, UGT 1A6-308C/A and UGT 1 A6-541A/G genetic polymorphisms were detected by polymerase chain reaction and restriction fragment length polymorphism technique （PCR- RFLP） in patients received anti-tuberculosis therapy. The Hha I, Dpn II and Nsi I enzyme were employed. Univariate and multivariate conditional logistic analyses were conducted using SPSS13.0 for windows software. Results The allele frequency ofgene UGTIA6-19T/T, UGT1A6-19T/G, UGTIA6-19G/G, GT1A6-308C/ C, UGT1A6-308C/A, UGTI A6-308A/A, UGT1 A6-541AA, UGT1A6-541A/G and UGT1A6-541G/G in ADIH group were 51.5%, 39.6%, 8.9%, 52.0%, 40.6%, 7.4%, 57.9%, 33.7%, 8.4% and 71.1%, 25.5%, 3.3%, 79.1%, 19.2%, 1.7%, 79.5%, 19.2%, 1.3% in control group, respectively. Univariate analysis demonstrated that the frequency of UGT1A6-19T/G, UGT1A6-308C/A and UGT1A6-541A/G genotype in cases were significantly higher than that in controls （P 〈 0.05）. Conclusion A positive association is found between UGT1A6 genotype and the occurrence of ADIH. The synergetic effect is proved on susceptibility to pulmonary tuberculosis between UGT1A6 mutant genotypes.