Replication study and meta-analysis indicate a suggestive association of RUNX3 locus with primary biliary cholangitis.

Susceptibility to primary biliary cholangitis (PBC) is in part genetically determined. In our previous PBC genome-wide association study (GWAS) in 1118 Han Chinese PBC and 4036 controls, we noted that multiple SNPs in the runt-related transcription factor 3 (RUNX3) regions showed a nominally significant association. The tag SNP rs7529070 was genotyped using a TaqMan assay in a separately collected 1435 PBC and 3205 controls. A meta-analysis with a combined 2553 PBC and 7241 controls showed that rs7529070 is still nominally associated with PBC (p = 1.7 × 10, odds ratio (OR) = 1.18, 95% confidence interval (CI) = 1.08-1.28). Further analysis indicated that the risk allele of rs7529070 (G allele) is in complete linkage disequilibrium (LD) (r = 1) with the G allele of rs4648889, which is known to be associated with increased RUNX3 expression. 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 livers of dnTGFβRII mice (a PBC mouse model). This study suggests that the RUNX3 locus may associate with PBC in Han Chinese.