Identification of primary biliary cirrhosis-susceptibility genes to the progression and its application to DNA-based diagnosis

原发性胆汁性肝硬化（PBC）是一种慢性缓慢进展的自身免疫性肝病，其组织病理学特征为肝内小胆管的炎症和破坏，从而导致胆汁淤积，进而导致肝损伤、肝硬化，最终导致肝功能衰竭。虽然PBC的确切病因尚不清楚，但多种环境因素和多种遗传因素可能参与PBC的发病和进展。我们对333名日本PBC患者的26个与胆汁酸稳态和正常胆管形成相关的候选基因进行了基于候选基因的PBC进展易感性关联研究，使用26个候选基因中的109个单核苷酸多态性，卡方检验或Fisher精确检验显示，CYP7A1，CYP8B1，HNF 4A，PPARGC1A、RXRB、ASBT和ABCG 8与肝硬化进展的易感性相关，而6种基因CYP7A1、PPARGC1A、RXRB、FGF 19、MDR 3、ABCG 8和ITGAV似乎对黄疸伴触觉衰竭的严重进展易感。此外，CYP8B1和PPARGC1A多态性的组合是用于鉴定进展为肝硬化的高危PBC患者的有用生物标志物。同样，CYP7A1、PPARGC1A、ABCG 8和ITGAV多态性的组合可用作重度进展为触觉衰竭伴黄疸的最佳生物标志物。

Primary biliary cirrhosis (PBC) is a chronic and slowly progressing autoimmune liver disease characterized histopathologically by inflammation and destruction of the intrahepatic small bile ducts, thus resulting in cholestasis and thereby leading to hepatic damage, cirrhosis, and eventually hepatic failure. Although the precise etiology of PBC remains unknown, both several environmental factors and multiple genetic factors may contribute to the pathogenesis as well as progression of PBC. As we focused on 26 candidate genes related with the homeostasis of bile acid and normal bile duct formation, a candidate gene-based association study on susceptibility to the progression of PBC was carried out using 109 single nucleotide polymorphisms in the 26 candidate genes for 333 Japanese PBC patients.Chi-square test or Fisher's exact test revealed that the 7 genes, CYP7A1, CYP8B1, HNF4A, PPARGC1A, RXRB, ASBT, and ABCG8, were associated with susceptibility to the progression to cirrhosis, and that the 6 genes, CYP7A1, PPARGC1A, RXRB, FGF19, MDR3, ABCG8, and ITGAV, appeared to be susceptible to severe progression to haptic failure with jaundice. Furthermore, a combination of polymorphisms of CYP8B1 and PPARGC1A is a useful biomarker for identifying high-risk PBC patients for progression to cirrhosis. Likewise, a combination of polymorphisms of CYP7A1, PPARGC1A, ABCG8, and ITGAV is useful as the best biomarker for severe progression to haptic failure with jaundice.