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

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 over-exuberant 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 (IL-1β: rs1143623, IL-1ra: rs4251961, IL-10: rs1800871, SOCS3: rs4969170, NOD2: rs3135500 and CMKLR1: rs1878022) were genotyped in 279 cirrhotic patients 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 (OR: 0.34, 95% 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, G-CSF, GM-CSF and C-reactive protein at enrolment 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 seen in patients without (80%) than in those with (20%) ACLF. Consistently, patients carrying the combined protective genotypes showed a lower 28-day mortality rate. CONCLUSION: These data identify two common functional polymorphisms in the IL-1 gene cluster which are associated with the inflammatory process related to the development of ACLF. This article is protected by copyright. All rights reserved.