Genetic risk factors for autoimmune hepatitis: implications for phenotypic heterogeneity and biomarkers for drug response

Abstract

Autoimmune hepatitis (AIH) is a rare chronic progressive liver disease with autoimmune features. It mainly affects middle-aged women. AIH is occasionally complicated with liver cirrhosis that worsens the prognosis. Genetic and environmental factors are involved in the pathogenesis of AIH. Genetic studies of other diseases have been revealing of pathogenesis and drug efficacy. In this review, we summarize the genetic risk factors for AIH, including human leukocyte antigen (HLA) and non-HLA genes. A genome-wide association study (GWAS) on European AIH revealed the strongest associations to be with single nucleotide variants (SNVs) in HLA. Predisposing alleles for AIH were DRB1*03:01 and DRB1*04:01 in Europeans; DRB1*04:04, DRB1*04:05, and DRB1*13:01 in Latin Americans; and DRB1*04:01 and DRB1*04:05 in Japanese. Other risk SNVs in non-HLA genes for AIH were found by a candidate gene approach, but several SNVs were confirmed in replication studies. Some genetic factors of AIH overlapped with those of other autoimmune diseases. Larger-scale GWASs of other ethnic groups are required. The results of genetic studies might provide an explanation for the phenotypic heterogeneity of AIH and biomarkers for drug responses.

Pathogenesis of autoimmune hepatitis

“…HLA-DRB1*13:01 and *03:01 alleles are related to AIH type I. In South America, AIH is mainly related to HLA-DRB1*1301 alleles, while HLA-DRB1*0301-negative type I AIH is mostly related to HLA-DRB1*0401[ 1 , 2 ], and in Japan it is related to HLA-DRB1*0405, *0401, *0802 and *0803. It may be that the amino acid sequence in the binding region of HLA-II molecules of different races differs slightly[ 3 ].…”

“…Patients with HLA-DRB1*0701 have rapid disease progression and poor prognosis. The genetic susceptibility and severity of disease in British and Brazilian type II AIH patients are related to HLA-DRB1*0301 alleles[ 1 - 3 ]. Gene mutations other than HLA are also related to AIH susceptibility or progression: Fas-670a/g and Fas-1377g/a polymorphisms[ 5 ], VDR[ 6 ], and GATA-2[ 7 ] are closely related to the onset of AIH.…”

“…a20 encoded by Tnfaip3 is an inhibitor of the nuclear factor (NF)-kB signaling pathway and a susceptibility gene for autoimmune diseases. The harmful mutations of tnfaip3 and drb1 alleles may be independently related to type I AIH, and are related to AIH and liver cirrhosis in Japan[ 1 ]. GATA2 encodes a transcription factor for hematopoietic cells, and mutations may be manifested as a reduction in monocytes, lack of dendritic cells and B cells, bone marrow dysplasia and immunodeficiency, which are related to the pathogenesis of AIH[ 7 , 11 ].…”

“…Because of the similar clinical manifestations and autoantibodies between this disease and systemic lupus erythematosus, it was originally called lupus-like hepatitis. After 10 years, it was discovered that this disease had obvious differences in clinical manifestations and autoantibodies from systemic lupus erythematosus, and autoimmune liver disease and autoimmune chronic active hepatitis are collectively referred to as AIH[ 1 ]. AIH has a global distribution and can occur in men or women of any age and race.…”

Impact of genetic and environmental factors on autoimmune hepatitis

“…Genetic predisposition in AIH is mainly associated with human leucocyte antigen (HLA) genes [ 1 , 17 ]. Moreover, a significant number of single nucleotide polymorphisms (SNPs) outside the MHC, has been identified and linked to the clinical phenotype of AIH [ 17 ].…”