STAT4变体增加白种人慢性乙型肝炎患者的肝纤维化风险

StephenW

A STAT4 variant increases liver fibrosis risk in Caucasian patients with chronic hepatitis B
R. El Sharkawy
K. Thabet
P. Lampertico
S. Petta
A. Mangia
T. Berg
M. Metwally
A. Bayoumi
A. Boonstra
W. P. Brouwer
A. Smedile
M. L. Abate
A. Loglio
M. W. Douglas
… See all authors
First published: 02 July 2018
https://doi.org/10.1111/apt.14866

Funding informationFlow cytometry was performed in the Flow Cytometry Core Facilities that are supported by the Westmead Research Hub. ME and JG are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; a National Health and Medical Research Council of Australia (NHMRC) Program Grant (1053206) and Project grants (APP1107178 and APP1108422). RE and KT are supported by a Scholarship from the Egyptian Government. AB was supported by the Virgo consortium, funded by the Dutch Government project number FES0908. PL is supported in part by grant RF‐2010‐2317822. AB is supported by an Australian Government Research Training Program (RTP) scholarship.

R. El Sharkawy and K. Thabet contributed equally to this work.

The Handling Editor for this article was Professor Grace Wong, and it was accepted for publication after full peer‐review.
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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 STAT4 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 STAT4 genetic variation is associated with liver injury in Caucasian patients with CHB and to investigate potential mechanisms mediating this effect.
Methods

STAT4 rs7574865 was genotyped in 1085 subjects (830 with CHB and 255 healthy controls). STAT4 expression in liver, PBMCs and NK cells, STAT4 phosphorylation and secretion of interferon‐gamma (IFN‐γ) according to STAT4 genetic variation was examined.
Results

STAT4 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 STAT4 in liver, PBMCs and in NK cells, while NK cells from patients with the risk genotype had impaired STAT4 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 STAT4 rs7574865 variant. Downstream effects on NK cell function through STAT4 phosphorylation‐dependent IFN‐γ production likely contribute to these effects.

StephenW

https://onlinelibrary.wiley.com/doi/full/10.1111/apt.14866