Genome‐wide meta‐analysis identifies susceptibility loci for autoimmune hepatitis type 1

Abstract

Background and Aims Autoimmune hepatitis (AIH) is a rare and chronic autoimmune liver disease. While genetic factors are believed to play a crucial role in the etiopathogenesis of AIH, our understanding of these genetic risk factors is still limited. In this study, we aimed to identify susceptibility loci to further understand the pathogenesis of this disease. Approach and Results We conducted a case–control association study of 1,622 Chinese patients with AIH type 1 and 10,466 population controls from two independent cohorts. A meta‐analysis was performed to ascertain variants associated with AIH type 1. A single‐nucleotide polymorphism within the human leukocyte antigen (HLA) region showed the strongest association with AIH (rs6932730: OR = 2.32; p = 9.21 × 10−73). The meta‐analysis also identified two non‐HLA loci significantly associated with AIH: CD28/CTLA4/ICOS on 2q33.3 (rs72929257: OR = 1.31; p = 2.92 × 10−9) and SYNPR on 3p14.2 (rs6809477: OR = 1.25; p = 5.48 × 10−9). In silico annotation, reporter gene assays, and CRISPR activation experiments identified a distal enhancer at 2q33.3 that regulated expression of CTLA4. In addition, variants near STAT1/STAT4 (rs11889341: OR = 1.24; p = 1.34 × 10−7), LINC00392 (rs9564997: OR = 0.81; p = 2.53 × 10−7), IRF8 (rs11117432: OR = 0.72; p = 6.10 × 10−6), and LILRA4/LILRA5 (rs11084330: OR = 0.65; p = 5.19 × 10−6) had suggestive association signals with AIH. Conclusions Our study identifies two novel loci (CD28/CTLA4/ICOS and SYNPR) exceeding genome‐wide significance and suggests four loci as potential risk factors. These findings highlight the importance of costimulatory signaling and neuro‐immune interaction in the pathogenesis of AIH.

Type 2 autoimmune hepatitis: Genetic susceptibility

“…Recently, in another Genome-Wide Association study of 1622 AIH-1 patients, Li et al confirmed the previous association of AIH with HLA, in this case, SNP RS6932730 located in the intronic region of the HLA-B gene, but also found associations with two novel loci, CD28-CTLA4-ICOS and SYNPR ( 29 ). Interestingly, CD28-CTLA4-ICOS is a co-stimulatory receptor gene cluster located on chromosome 2q33 that encodes both the positive (CD28 and ICOS) and negative (CTLA-4) T-cell regulators ( 29 ). Unfortunately, similar Genome-Wide Association studies have not been carried out in patients with AIH-2 since their numbers are much lower ( 28 ).…”

HLA, gut microbiome and hepatic autoimmunity

“…The strong association of AIH-1 with HLA polymorphisms has been confirmed by the two genome-wide association studies (GWAS) performed so far in AIH, both including only AIH-1 adult patients ( 12 , 13 ). The first GWAS, carried out in a Northern European population, identified the class II HLA-DRB1*0301 as the allele with the strongest association with AIH-1, and HLA-DRB1*0401 as the second most strongly AIH-1- associated allele.…”

“…The study also identified two non-HLA loci associated with AIH-1, i.e. the CD28-CTLA4-ICOS and the SYNPR loci, the first coding for proteins involved in T cell activation, and the latter coding for a protein expressed on synaptic membranes ( 13 ).…”

Commentary on “Genome‐wide meta‐analysis identifies novel susceptibility loci for autoimmune hepatitis type 1”

“…In this edition of Hepatology , Li et al [ 3 ] report a genome‐wide meta‐analysis (GWMA) of type 1 AIH involving a total of 1622 cases and 10,466 population controls of Han Chinese descent. In this study, the authors confirmed association with the human leukocyte antigen (HLA) locus and identified genome‐wide significant ( p < 5 × 10 −8 ) association at two non‐HLA loci, harboring CD28 ‐ CTLA4 ‐ ICOS (at 2q33.3) and SYNPR (at 3p14.2), respectively.…”