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Polymorphisms in the IL-1 gene cluster influence systemic inflammation in patients at risk for acute-on-chronic liver failure.

Authors :
Alcaraz-Quiles J
Titos E
Casulleras M
Pavesi M
López-Vicario C
Rius B
Lopategi A
de Gottardi A
Graziadei I
Gronbaek H
Ginès P
Bernardi M
Arroyo V
Clària J
Source :
Hepatology (Baltimore, Md.) [Hepatology] 2017 Jan; Vol. 65 (1), pp. 202-216. Date of Electronic Publication: 2016 Nov 28.
Publication Year :
2017

Abstract

Acute-on-chronic liver failure (ACLF) in cirrhosis is an increasingly recognized syndrome characterized by acute decompensation, organ failure(s) and high short-term mortality. Recent findings suggest that an overexuberant systemic inflammation plays a primary role in ACLF progression. In this study, we examined whether genetic factors shape systemic immune responses in patients with decompensated cirrhosis. Six single-nucleotide polymorphisms (SNPs) in inflammation-related genes (interleukin [IL]-1 beta [IL-1β], rs1143623; IL-1 receptor antagonist [IL-1ra], rs4251961; IL-10, rs1800871; suppressor of cytokine signaling-3, rs4969170; nucleotide-binding oligomerization domain-containing protein 2, rs3135500; and chemerin chemokine-like receptor 1, rs1878022) were genotyped in 279 patients with cirrhosis with (n = 178) and without (n = 101) ACLF from the CANONIC study of the CLIF consortium. Among these SNPs, we identified two polymorphisms belonging to the IL-1 gene cluster (IL-1β and IL-1ra) in strong association with ACLF. Both SNPs were protective against ACLF; IL-1β (odds ratio [OR], 0.34, 95% confidence interval [CI], 0.13-0.89; P < 0.05) and IL-1ra (OR, 0.58; 95% CI, 0.35-0.95; P < 0.05) under the recessive and overdominant inheritance models, respectively. These protective SNPs translated into reduced circulating levels of IL-1β, IL-1α, IL-6, granulocyte-colony stimulating factor, granulocyte-macrophage colony-stimulating factor, and C-reactive protein at enrollment as well as after 7-14 days of admission. These findings were confirmed in vitro in leukocytes incubated with plasma from patients with decompensated cirrhosis carrying the protective SNP genotypes. Notably, a higher frequency of the protective genotypes was observed in patients without (80%) than in those with (20%) ACLF. Consistently, patients carrying the combined protective genotypes showed a lower 28-day mortality rate.<br />Conclusion: These data identify two common functional polymorphisms in the IL-1 gene cluster, which are associated with the inflammatory process related to development of ACLF. (Hepatology 2017;65:202-216).<br /> (© 2016 by the American Association for the Study of Liver Diseases.)

Details

Language :
English
ISSN :
1527-3350
Volume :
65
Issue :
1
Database :
MEDLINE
Journal :
Hepatology (Baltimore, Md.)
Publication Type :
Academic Journal
Accession number :
27775822
Full Text :
https://doi.org/10.1002/hep.28896