Role of deleterious single nucleotide variants in the coding regions of TNFAIP3 for Japanese autoimmune hepatitis with cirrhosis

Abstract

Autoimmune hepatitis (AIH) is an autoimmune liver disease and cirrhosis is sometimes complicated with AIH at diagnosis, influencing its prognosis. TNFAIP3 gene encodes A20, an inhibitor of nuclear factor-κB pathway, and is a susceptibility gene for autoimmune diseases. We investigated deleterious variants in the coding regions of TNFAIP3 gene of Japanese AIH patients or those with cirrhosis. The deleterious variants in the coding regions of TNFAIP3 gene were analyzed by the cycle sequencing method and the frequencies of deleterious TNFAIP3 alleles of AIH or AIH with cirrhosis were compared with those of Japanese controls. The deleterious alleles in TNFAIP3 were not associated with AIH. A significant association was shown for the deleterious alleles in TNFAIP3 ( P = 0.0180, odds ratio (OR) 4.28, 95% confidence interval (CI) 1.53–11.95) with AIH with cirrhosis at presentation. The serum IgM levels in AIH patients with deleterious alleles in TNFAIP3 were tended to be lower than those without ( P = 0.0152, Q = 0.1216). The frequency of deleterious alleles in TNFAIP3 was higher in the AIH subset without the DRB1 risk alleles than that with ( P = 0.0052, OR 5.10, 95%CI 1.55–16.74). The deleterious alleles in TNFAIP3 were associated with AIH with cirrhosis.

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

“…Deleterious missense variants change amino acid residues conserved across species. Deleterious SNVs in the exons of the TNFAIP3 gene are associated with AIH patients with cirrhosis in Japanese populations [ 62 ]. In addition, the deleterious allele frequency of TNFAIP3 increases in AIH patients without the DRB1 risk alleles ( DRB1*04:01 , DRB1*04:05 , DRB1*08:02 , or DRB1*08:03 ) [ 42 ].…”

“…However, DRB1 and DQB1 are in strong linkage disequilibrium and the role of DQB1 in predisposition cannot be eliminated [ 42 ]. It is of interest that some SNVs in non- HLA genes are associated with AIH patients without the risk DRB1 alleles [ 62 , 64 ]. These data suggest that the weaker genetic risk factors in non- HLA genes cannot contribute to the predisposition to AIH of individuals with the other genetic risk factor when the gene–gene interaction is observed in AIH patients.…”

“…Some AIH patients present more complicated cases because of the accompaniment of cirrhosis, and their prognoses are worse [ 14 ]. SNVs specifically associated with AIH with cirrhosis have been detected (Supplementary Table S 2 ) [ 62 , 69 ] and may predict the prognosis of the patients. More than 80% of AIH patients respond to conventional treatments with corticosteroid, but less than 20% are refractory [ 13 , 118 ].…”

A20 Haploinsufficiency in a Chinese Patient With Intestinal Behcet's Disease-Like Symptoms: A Case Report

“…TNFAIP3 mutations may lead to a reduced transcription and instability of mutant proteins ( 4 , 7 , 9 ). This mutation causes decreased A20 expression and results in immune dysregulation with increased NF-κB activity in response to TNF-α ( 10 ); it is also proposed as a risk factor for autoimmune disorders ( 11 , 12 ). Additionally, TNFAIP3 is reported to be linked with susceptibility to BD ( 4 , 13 , 14 ).…”

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 ].…”