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）是一种慢性进展缓慢的自身免疫性肝病，其组织病理学特征是肝内小胆管的炎症和破坏，从而导致胆汁淤积，从而导致肝损害、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都可能导致PBC的发病和进展。为了研究与胆汁酸稳态和正常胆管形成相关的26个候选基因，我们对333名日本PBC患者进行了一项基于候选基因的PBC易感性关联研究，使用了26个候选基因的109个单核苷酸多态性。卡方检验或Fisher精确检验显示，CYP7A1、CYP8B1、HNF4A、PPARGC1A、RXRB、ASBT和ABCG8这7个基因与肝硬化进展的易感性相关，CYP7A1、PPARGC1A、RXRB、FGF19、MDR3、ABCG8和ITGAV这6个基因似乎与严重进展为黄疸的感觉衰竭相关。此外，CYP8B1和PPARGC1A多态性的组合是识别高风险PBC患者进展为肝硬化的有用生物标志物。同样，CYP7A1、PPARGC1A、ABCG8和ITGAV的多态性组合也可作为黄疸严重进展到触觉衰竭的最佳生物标志物。

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.