Genome‐wide Association Studies of Specific Antinuclear Autoantibody Subphenotypes in Primary Biliary Cholangitis

Abstract

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.

The Pathogenesis of Primary Biliary Cholangitis: A Comprehensive Review

“…Of note, a recent study performed a genome-wide association analysis of 930 PBC cases based on their autoantibody status and demonstrated a significant genetic predisposition to the sp100 autoantibody, but not the gp210 autoantibody, subphenotype in PBC patients. 96 These results confirm prior reports of distinct HLA associations for sp100 positive patients. Although additional studies will be necessary to determine if these findings have clinical significance to PBC pathogenesis, the striking difference in genetic predisposition observed between the two phenotypes may indicate distinct roles of these two autoantibodies in PBC.…”

Clinical impact of antibodies to Sp100 on a bacterial infection in patients with primary biliary cholangitis

“…We confirmed that the prevalence of anti‐Sp100 antibodies in PBC patients was within the previously reported ranges, 6‐15 but no significant difference in the frequency of anti‐Sp100 was not detected between the AMA‐positive and AMA‐negative PBC patients, indicating that anti‐Sp100 cannot become a complementary serological marker of PBC in AMA‐negative patients. Our analyses also did not elucidate that anti‐Sp100 was associated with the disease severity, which did not support the previous studies 5,11,18 …”

Changes of Serum IgG Glycosylation Patterns in Primary Biliary Cholangitis Patients

“…Several studies have indicated that autoantibodies of gp210 are strong predictors of PBC prognosis (54,55). In addition, faster disease progression, and significantly higher hepatic failure have been found in anti-gp210-positive patients (56,57). In this study, we have observed that the expression of galactose was increased in anti-gp210-positive patients with PBC.…”