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A STAT 4 variant increases liver fibrosis risk in Caucasian patients with chronic hepatitis B
Author(s) -
El Sharkawy R.,
Thabet K.,
Lampertico P.,
Petta S.,
Mangia A.,
Berg T.,
Metwally M.,
Bayoumi A.,
Boonstra A.,
Brouwer W. P.,
Smedile A.,
Abate M. L.,
Loglio A.,
Douglas M. W.,
Khan A.,
Santoro R.,
Fischer J.,
Leeming D. J.,
Liddle C.,
George J.,
Eslam M.
Publication year - 2018
Publication title -
alimentary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.308
H-Index - 177
eISSN - 1365-2036
pISSN - 0269-2813
DOI - 10.1111/apt.14866
Subject(s) - stat4 , medicine , immunology , hepatitis b virus , genetic predisposition , genotype , hepatocellular carcinoma , biology , stat , stat3 , virus , phosphorylation , gene , disease , genetics
Summary Background Host genetic modifiers of the natural history of chronic hepatitis B ( CHB ) remain poorly understood. Recently, a genome‐wide association study ( GWAS )‐identified polymorphism in the STAT 4 gene that contributes to the risk for hepatocellular carcinoma ( HCC ) was shown to be associated with the full spectrum of hepatitis B virus ( HBV ) outcomes in Asian patients. However, the functional mechanisms for this effect are unknown and the role of the variant in modulating HBV disease in Caucasians has not been investigated. Aims To determine whether STAT 4 genetic variation is associated with liver injury in Caucasian patients with CHB and to investigate potential mechanisms mediating this effect. Methods STAT 4 rs7574865 was genotyped in 1085 subjects (830 with CHB and 255 healthy controls). STAT 4 expression in liver, PBMC s and NK cells, STAT 4 phosphorylation and secretion of interferon‐gamma ( IFN ‐γ) according to STAT 4 genetic variation was examined. Results STAT 4 rs7574865 genotype was independently associated with hepatic inflammation ( OR : 1.42, 95% CI : 1.07‐2.06, P = 0.02) and advanced fibrosis ( OR : 1.83, 95% CI : 1.19‐2.83, P = 0.006). The minor allele frequency of rs7574865 was significantly lower than that in healthy controls. rs7574865 GG risk carriers expressed lower levels of STAT 4 in liver, PBMC s and in NK cells, while NK cells from patients with the risk genotype had impaired STAT 4 phosphorylation following stimulation with IL ‐12/ IL ‐18 and a reduction in secretion of IFN ‐γ. Conclusion Genetic susceptibility to HBV persistence, hepatic inflammation and fibrosis in Caucasians associates with STAT 4 rs7574865 variant. Downstream effects on NK cell function through STAT 4 phosphorylation‐dependent IFN ‐γ production likely contribute to these effects.