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 TNFAIP3were associated with AIH with cirrhosis.
Highlights
Autoimmune hepatitis (AIH) is an autoimmune liver disease and cirrhosis is sometimes complicated with AIH at diagnosis, influencing its prognosis
A20 is a negative regulator of the NLRP3 inflammasome and myeloid cell specific deletion of A20 caused spontaneous arthritis in mice[18]
Inflammasome was activated in monocytes of non-transplanted AIH children and liver-transplanted children with de novo autoimmune hepatitis, but increased expression of A20 was observed in monocytes of liver-transplanted children without de novo autoimmune hepatitis[19]
Summary
Autoimmune hepatitis (AIH) is an autoimmune liver disease and cirrhosis is sometimes complicated with AIH at diagnosis, influencing its prognosis. 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. Several candidate-gene approach studies reported weak genetic associations of single nucleotide variants with Japanese AIH in other genes than HLA; STAT49, PTPN2210, ICOS11, TNIP112, and SH2B313. We investigated the variants in the coding regions of TNFAIP3 gene of Japanese AIH patients by the cycle sequencing method and tried to compare the frequencies of deleterious TNFAIP3 alleles of AIH or AIH with cirrhosis with those of Japanese controls
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