Journal
JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY
Volume 36, Issue 10, Pages 2925-2934Publisher
WILEY
DOI: 10.1111/jgh.15554
Keywords
cytochrome P450 2E1; cytokines; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; single nucleotide polymorphism
Categories
Funding
- National Natural Science Foundation of China [82070588]
- High Level Creative Talents from Department of Public Health in Zhejiang Province [S2032102600032]
- Project of New Century 551 Talent Nurturing in Wenzhou
- University School of Medicine of Verona, Verona, Italy
- Southampton NIHR Biomedical Research Centre, UK [IS-BRC-20004]
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The TA allele of rs2070673 is strongly associated with lobular inflammation and NASH in NAFLD patients, with serum IP-10 levels playing a significant mediating role in this association.
Background and Aim: Cytochrome P450 2E1 (CYP2E1) plays a role in lipid metabolism, and by increasing hepatic oxidative stress and inflammation, the upregulation of CYP2E I is involved in development of nonalcoholic steatohepatitis (NASH). We aimed to explore the relationship between CYP2EI-333A>T (rs2070673) and the histological severity of nonalcoholic fatty liver disease (NAFLD). Methods: We studied 438 patients with biopsy-proven NAFLD. NASH was defined as NAFLD Activity Score >= 5 with existence of steatosis, ballooning, and lobular inflammation. CYP2E1-333A>T (rs2070673) was genotyped by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Serum cytokines related to inflammation were measured by the Bio-plex 200 system to investigate possible mediating factors involved in the process. Results: The TA genotype of rs2070673 had a higher prevalence of moderate/severe lobular inflammation (27.6% vs 20.3% vs 13.3%, P < 0.01) and NASA (55.7% vs 42.4% vs 40.5%, P < 0.01) compared with the AA and TT genotypes, respectively. In multivariable regression modeling, the heterozygote state TA was associated with moderate/severe lobular inflammation (adjusted odds ratio: 2.31, 95% confidence interval 1.41-3.78, P < 0.01) or NASII (adjusted odds ratio: 1.82, 95% confidence interval 1.22-2.69, P < 0.01), independently of age, sex, common metabolic risk factors, and presence of liver fibrosis. Compared with no-NASH, NASH patients had significantly higher levels of serum interleukin-1 receptor antagonist, interleukin-18, and interferon-inducible protein-10 (IP-10), whereas only IP-10 was increased with the rs2070673 TA variant (P = 0.01). Mediation analysis showed that IP-10 was responsible for similar to 60% of the association between the rs2070672 and NASH. Conclusions: The TA allele of rs2070673 is strongly associated with lobular inflammation and NASH, and this effect appears to be largely mediated by serum IP-10 levels.
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