BACKGROUND-Primary biliary cirrhosis is a chronic granulomatous cholangitis, characteristically associated with antimitochondrial antibodies. Twin and family aggregation data suggest that there is a significant genetic predisposition to primary biliary cirrhosis, but the susceptibility loci are unknown.

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Patients with PBC who fail to show a biochemical response to UDCA or who have ductopenia on baseline biopsy progress histologically during extended follow-up. Such patients may benefit from novel treatments, with our exploratory data providing a means of identifying these individuals early in their disease.

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We genotyped individuals with primary biliary cirrhosis and unaffected controls for suggestive risk loci (genome-wide association P < 1 × 10 −4 ) identified in a previous genome-wide association study. Combined analysis of the genome-wide association and replication datasets identified IRF5-TNPO3 (combined P = 8.66 × 10 −13 ), 7q12-21 (combined P = 3.50 × 10 −13 ) and MMEL1 (combined P = 3.15 × 10 −8 ) as new primary biliary cirrhosis susceptibility loci. Fine-mapping studies showed that a single variant accounts for the IRF5-TNPO3 association. As these loci are implicated in other autoimmune conditions, these findings confirm genetic overlap among such diseases. Note: Supplementary information is available on the Nature Genetics website. COMPETING FINANCIAL INTERESTSThe authors declare competing financial interests: details accompany the full-text HTML version of the paper at http://www.nature.com/naturegenetics/. Supplementary Fig. 1); for each locus, association signals at P < 1 × 10 −4 were detected for more than one SNP found in the initial GWAS, with the exception of IRF5-TNPO3, a well-recognized autoimmune disease risk locus. The combination of these replication results and our prior genome-wide association data yielded a genetic dataset derived from 1,351 PBC cases and 4,700 controls (Supplementary Methods). NIH Public AccessFifteen SNPs replicated (P < 1.39 × 10 −3 ) after Bonferroni adjustment (Table 1 and Supplementary Table 1). In addition to HLA, IL12A and IL12RB2, genes at the IRF5-TNPO3 locus, at chromosome 17q12-21 (containing IKZF3, ZPBP2, GSDMB and ORMDL3) and at MMEL1 loci showed significant association with PBC in both the replication analysis and in an analysis combining the replication and initial GWAS datasets ( Fig. 1 and Supplementary Fig. 2).Among the PBC loci confirmed by this analysis, the locus at IRF5-TNPO3 (encoding interferon regulatory factor 5 and transportin 3) is of interest because of the integral immunoregulatory roles for IRF5, the prior association of this locus with systemic lupus erythematosus (SLE) 4, 5 , systemic sclerosis 6 and Sjögrens syndrome 7 , and the strong effect of the disease-associated SNP at this locus on disease risk (rs10488631) in the replication (P = 1.13 × 10 −8 , odds ratio (OR) = 1.58) and combined datasets (P = 8.66 × 10 −13 , OR = 1.57). Association of this locus was thus explored, initially by resequencing the IRF5 locus intronic and exonic regions and the 5′ and 3′ flanking regions of IRF5 in genomic pools of 100 subjects so as to delineate the genetic variation across the locus. This analysis confirmed prior reports of 41 polymorphisms across this region, but it failed to identify any new variants. Among these 41 SNPs, two (rs3807135 and rs3834330) failed repeatedly in genotyping assays and four (rs10275092, rs12537192, rs1727172 and rs754280) showed negligible polymorphism. Thus, for finemapping studies, 1,330 cases and 1,833 controls were geno-typed for 35 SNPs across this region. Among the associations identified (Supplementary Ta...