Clinical Features And Genetic Variants Of TNFSF15 Associated With Primary Biliary Cirrhosis In A Han Chinese Population

Primary biliary cirrhosis(PBC)is an autoimmune disease characterized by chronic inflammation and destruction of intrahepatic bile ducts,leading to the fibrosis and liver failure.The etiology of PBC is unknown.There are strong evidences indicating that PBC is caused by the interplay of genetic susceptibility and environmental factors.The studies of PBC started relatively late in China and were far behind western countries.Moreover,there is a lack of solid information of epidemiology and genetic susceptibility about PBC in China.It is necessary to strengthen the research of clinical characteristics,etiology and pathogenesis about PBC,helping in the search for new therapeutic strategies.This study includes two parts.For the first part,we set out to investigate the clinical featuress of 421 PBC patients in Jiangsu province,and characterize the clinical profile among PBC-HBV,PBC and hepatitis B virus(HBV).The subclass distribution as well as the clinical impact of the presence of PBC specific antibodies had been investigated.Three mitochondrial proteins with complete coding sequence were expressed from human source.Enzyme linked immunosorbent assay(ELISA)were used to test the presence of antimitochondrial antibody(AMA)target to three mitochondrial proteins.Among 421 PBC patients,184 patients who receive UDCA at the daily dose of 13 to 15 mg/kg of body weight and have at least 1 year follow-up visit were selected to evaluate the response to UDCA.Biochemical response to treatment was evaluated according to Barcelona and Paris I criteria.The results showed that Han Chinese PBC patients shared common clinical featuress with European counterparts,but also suggested a distinctly different clinical profile.PBC patients have more severe features.PBC patients shared the same disease clinical symptoms with HBV patients.Alkaline phosphatase and glutamine transpeptidase can differential diagnose these diseases at early stage.There maybe ethnic or geographical differences in detection of antibodies to 2-OADC enzyme subunits among different countries and areas.PDC-E2 is a major mitochondrial autoantigens.There is no significant difference in most biochemical indices between the cohorts divided according to the presence of AMA targeted to different antigens.The detection of anti-BCOADC-E2 in our study is higher than it in western countries.The detection of anti-OGDC-E2 AMA always accompanied of anti-PDC-E2 and BCOADC-E2.only one serum reacted with OGDC-E2.The postive rate of BCOADC-E2 reactive antibodies was significantly related to UDCA non-responders.Long-term treatment with UDCA can improve liver function in patients with PBC,biochemical parameters of the responders tend to decline into a normal level whatever the criteria used.For the second parts,we aim to explore genetic variants of TNFSF15 associated with primary biliary cirrhosis in a Han Chinese population.Four exons of TNFSF15 were amplified by PCR to search genetic variants related to PBC.The results showed mutations in the exon of TNFSF15 focused on the first and fourth exon.Two missense mutations were identified in exon 1.They are Lys27Glu and Pro45Ser.Two missense mutations and two synonymous mutations were identified in exon 4.Two missense mutations are Gln 104Lys and Phe110Leu.It is predicted by software that the mutations of Lys27Glu,Pro45Ser and Gln 104Lys have no effect on protein structure and function.These maybe accidental events and not related to the etiology of PBC.Phe110Leu occurred in active fragments while no significant difference have been noted in PBC and control groups.It maybe common mutation in TNFSF15 and not associated with the aetiology of PBC.Further studies are needed to elucidate the exact role of TNFSF15 in the pathogenesis of PBC.