Polymorphisms in the 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 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. 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).