A genome-wide association study identifies six novel risk loci for primary biliary cholangitis

Abstract

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.

Genetics and epigenetics in the pathogenesis of primary biliary cholangitis

“…Thus, the IL-12 signaling pathway appears to be a key player in the pathogenesis of PBC worldwide. To support this hypothesis, STAT4, which factors prominently in IL-12 signal transduction polymorphisms, was associated with susceptibility in Japanese and Han Chinese PBC patients [38,43].…”

“…Among the SNPs previously reported to be associated with susceptibility to PBC, only HLA has been consistently linked to the disease in distinct patient cohorts across ethnicities as depicted by many significant dots on genome-wide Manhattan plots of GWASs [34][35][36][37][38][39][40][41][42][43].…”

Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases

“…(10)(11) In addition to the high concordance among monozygotic twins compared with dizygotic twins with PBC (5) , the strong association with human leukocyte antigen alleles, which vary by ethnicity, supports a genetic cause of inherited risk. (12)(13)(14)(15)(16)(17)(18)(19)(20) Despite progress, only an estimated 15% of the variability of the disease has been accounted for by genetic studies. (21) Environmental risks have been suggested by several large case-control cohort studies that have found associations with urinary tract infections, reproductive hormone replacement, nail polish, and past cigarette smoking.…”

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

“…(2) Several large-scale genome-wide association (GWA) studies in European, Japanese, and Han Chinese PBC cohorts have pointed to a strong genetic predisposition to PBC. (3)(4)(5)(6)(7) Specific human leukocyte antigen (HLA) alleles and common polymorphisms in interleukin 12 (IL12), IL12 receptor (IL12R), tumor necrosis factor superfamily member 15 (TNFSF15), IL21, IL21R, and other immune-associated genes have been implicated in PBC pathogenesis. (3,5,6) Although these studies provided many insights in our understanding of PBC pathogenesis, no further studies have examined the genetics of subphenotypes in PBC.…”