A polymorphism in the integrin αV subunit gene affects the progression of primary biliary cirrhosis in Japanese patients
A polymorphism in the integrin αV subunit gene affects the progression of primary biliary cirrhosis in Japanese patients
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DOI：
10.1007/s00535-010-0351-0
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发表时间：
2011-05-01
影响因子：
6.3
通讯作者：
Tsukamoto, Kazuhiro
中科院分区：
文献类型：
--
作者：
Inamine, Tatsuo;Nakamura, Minoru;Tsukamoto, Kazuhiro
越来越多的证据表明，多种遗传因素参与原发性胆汁性肝硬化（PBC）的发病机制。本研究的目的是研究整合素α V亚基基因（ITGAV）的多态性是否与PBC发病和/或进展的易感性相关。整合素α V β 6是整合素α V β 6的一个组成部分，在纤维化过程中起重要作用。在初步研究中，通过聚合酶链反应(PCR)-限制性片段长度多态性、直接DNA测序或高分辨率融化曲线分析，分析了309名登记在日本国立医院组织肝病研究小组（PBC队列I）的日本PBC患者和293名性别匹配的健康日本志愿者（对照组）中ITGAV的8个标签单核苷酸多态性（snp）。对于重复研究，还分析了35例进展为终末期肝功能衰竭并接受肝移植的PBC患者（PBC队列II）。在最初的研究（PBC队列I）中，ITGAV中的三个标签snp （rs3911238、rs10174098和rs1448427）与PBC的严重进展显著相关，但与PBC发病的易感性无关。在这些snp中，在接受肝移植的PBC患者（PBC队列II）的复制研究中，rs1448427也与严重进展到终末期肝衰竭显著相关。ITGAV是日本患者PBC严重进展的遗传决定因素。ITGAV的遗传多态性可能有助于在最初诊断时识别高风险的日本PBC患者，包括那些需要肝移植的患者。
Accumulating evidence indicates that multiple genetic factors are involved in the pathogenesis of primary biliary cirrhosis (PBC). The aim of this study was to investigate whether polymorphisms of the integrin alpha V subunit gene (ITGAV), a component of integrin alpha V beta 6, which plays an important role in the process of fibrosis, are associated with susceptibility to the onset and/or progression of PBC.In the primary study, eight tag single nucleotide polymorphisms (SNPs) in ITGAV were analyzed by polymerase chain reaction (PCR)-restriction fragment length polymorphism, direct DNA sequencing, or high-resolution melting curve analysis in 309 Japanese patients with PBC who were registered in the National Hospital Organization Study Group for Liver Disease in Japan (PBC cohort I) and 293 gender-matched healthy Japanese volunteers (control subjects). For the replication study, 35 PBC patients who progressed to end-stage hepatic failure and underwent liver transplantation (PBC cohort II) were also analyzed.Three tag SNPs (rs3911238, rs10174098, and rs1448427) in ITGAV were significantly associated with the severe progression of PBC, but not with susceptibility to the onset of PBC, in the primary study (PBC cohort I). Among these SNPs, rs1448427 was also significantly associated with the severe progression to end-stage hepatic failure in the replication study of PBC patients who underwent liver transplantation (PBC cohort II).ITGAV is a genetic determinant for the severe progression of PBC in Japanese patients. Genetic polymorphisms of ITGAV may be useful for identifying high-risk Japanese PBC patients, including those who will require liver transplantation, at the time of initial diagnosis.