Primary biliary cholangitis (PBC) is an autoimmune liver disease with a strong hereditary component. Here, we report a genome-wide association study that included 1,122 PBC cases and 4,036 controls of Han Chinese descent, with subsequent replication in a separate cohort of 907 PBC cases and 2,127 controls. Our results show genome-wide association of 14 PBC risk loci including previously identified 6p21 (HLA-DRA and DPB1), 17q12 (ORMDL3), 3q13.33 (CD80), 2q32.3 (STAT1/STAT4), 3q25.33 (IL12A), 4q24 (NF-κB) and 22q13.1 (RPL3/SYNGR1). We also identified variants in IL21, IL21R, CD28/CTLA4/ICOS, CD58, ARID3A and IL16 as novel PBC risk loci. These new findings and histochemical studies showing enhanced expression of IL21 and IL21R in PBC livers (particularly in the hepatic portal tracks) support a disease mechanism in which the deregulation of the IL21 signalling pathway, in addition to CD4 T-cell activation and T-cell co-stimulation are critical components in the development of PBC.

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Aim Pyrrolizidine alkaloids-induced hepatic sinusoidal obstruction syndrome(PA-HSOS) has been reported to have high mortality. We evaluated the efficacy and safety of anticoagulation therapy for the patients with PA-HSOS. Methods We collected clinical data on 249 PA-HSOS patients from January 2012 to December 2017 at four tertiary care hospitals. Among them, 151 patients received anticoagulation therapy, and 98 patients received supportive treatment. The outcomes were analyzed using the Fine and Gray competing risk analysis method and Cox regression model. Results The cumulative complete response rate was higher in the anticoagulation group than in the supportive group (60.9 vs 36.7%; P < 0.0001). The cumulative mortality was 12.6% in the anticoagulation group compared with 43.9% in the supportive group (P < 0.0001). In subgroup analysis, for mild, moderate, severe, and very severe groups, the adjusted hazard ratios [95% confidence interval (CI)] for complete response rates were 7.05 (3.00–16.59), 5.26 (2.31–12.42), 2.59 (0.85–7.87), and 2.05 (0.61–6.92), respectively; and the adjusted hazard ratios (95% CI) for mortalities were 0.02 (0.01–0.09), 0.04 (0.01–0.14), 0.19 (0.01–3.98), and 0.07 (0.02–1.27), respectively (P < 0.0001). There was no significant difference between both groups in the incidence of bleeding events (P = 0.674). Conclusions Anticoagulation therapy improves clinical remission and the survival in selected patients with mild or moderate PA-HSOS. Anticoagulation therapy has a similar safety profile to supportive therapy.

Anti‐nuclear antibodies to speckled 100 kDa (sp100) and glycoprotein 210 (gp210) are specific serologic markers of primary biliary cholangitis (PBC) of uncertain/controversial clinical or prognostic significance. To study the genetic determinants associated with sp100 and gp210 autoantibody subphenotypes, we performed a genome‐wide association analysis of 930 PBC cases based on their autoantibody status, followed by a replication study in 1,252 PBC cases. We confirmed single‐nucleotide polymorphisms rs492899 (P = 3.27 × 10−22; odds ratio [OR], 2.90; 95% confidence interval [CI], 2.34‐3.66) and rs1794280 (P = 5.78 × 10−28; OR, 3.89; 95% CI, 3.05‐4.96) in the human major histocompatibility complex (MHC) region associated with the sp100 autoantibody. However, no genetic variant was identified as being associated with the gp210 autoantibody. To further define specific classical human leukocyte antigen (HLA) alleles or amino acids associated with the sp100 autoantibody, we imputed 922 PBC cases (211 anti‐sp100‐positive versus 711 negative cases) using a Han Chinese MHC reference database. Conditional analysis identified that HLA‐DRβ1‐Asn77/Arg74, DRβ1‐Ser37, and DPβ1‐Lys65 were major determinants for sp100 production. For the classical HLA alleles, the strongest association was with DRB1*03:01 (P = 1.51 × 10−9; OR, 2.97; 95% CI, 2.06‐4.29). Regression analysis with classical HLA alleles identified DRB1*03:01, DRB1*15:01, DRB1*01, and DPB1*03:01 alleles can explain most of the HLA association with sp100 autoantibody. Conclusion: This study indicated significant genetic predisposition to the sp100 autoantibody, but not the gp210 autoantibody, subphenotype in PBC patients. Additional studies will be necessary to determine if these findings have clinical significance to PBC pathogenesis and/or therapeutics.

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