Association Studies Of RUNX3 Polymorphism And Antimitochondrial Antibodies With Primary Biliary Cholangitis In Han Chinese

Aims and Background: The main aim of this work is to investigate the association of runtrelated transcription factor 3(RUNX3)single nucleotide polymorphism(SNP)and the prevalence and clinical significance of anti-mitochondrial antibodies(AMA)in Chinese primary biliary cholangitis(PBC)patients.Susceptibility to PBC is in part genetically determined.The presence of AMA serves as a serological marker of PBC.Method: The tag SNP rs7529070 in RUNX3 was genotyped using a Taq Man assay.Serum samples from 780 PBC patients and 352 healthy controls were used for detection of AMA anti-M2(PDC-E2,BCOADC-E2,and OGDCE2),anti-M4(SUOX),anti M9(PYGL),and anti-nuclear antibodies(ANA)(sp100 and gp210)by using enzyme-linked immunosorbent assay(ELISA)and immunoblotting.Antibody results and biochemical data from PBC patients were analyzed statistically.Results: A meta-analysis with a combined 2553 PBC and 7241 controls,showed that rs7529070 is still nominally associated with PBC(p = 1.7 × 10-4,odds ratio(OR)= 1.18,95% confidence interval(CI)= 1.08-1.28).Bioinformatic analysis with existing expression data showed that the expression of RUNX3 is significantly increased in PBC patients(p = 0.001)and the expression level is correlated with disease severity.Consistently,we also found significantly increased RUNX3 expression(p < 0.01)in the liver tissues of the dominant-negative form of transforming growth factor-beta receptor type II(dn TGFβRII)mice(a PBC mouse model).In PBC patients,the total prevalence of AMAs to PDC-E2,BCOADC-E2,and OGDC-E2 was 86.13%,84.21%,and 40.70%,respectively.There was a significant increase in bilirubin concentration based on the presence of anti-BCOADC-E2 autoantibodies(p < 0.001).A significant decrease in anti-BCOADC-E2 titer was observed in half(5/10)of the PBC patients after ursodeoxycholic acid(UDCA)treatment.Antibodies to SUOX and PYGL were found in 14.23% and 22.94% of PBC patients,respectively,as well as 6.53% and 9.37% of healthy controls.Moreover,antibodies to gp210 and sp100 were found in 27.17% and 44.1% in Han Chinese PBC,respectively.Biochemical data suggested that the PBC disease progression was significantly associated with anti-SUOX and/or-gp210 status.Conclusion: Our genetic association study suggests that the RUNX3 locus may associate with PBC in Han Chinese.Reactivity against the BCOADC antigens was observed more often among Chinese patients compared to the Japanese and Caucasian populations.Anti-BCOADC-E2 antibody titers were lost or significantly decreased in nearly half of PBC patients after UDCA treatment.Anti-SUOX and-PYGL autoantibodies are not disease-specific autoantibody markers,however,their prevalence in Han Chinese PBC patients was significantly associated with ANA status and disease progression.