1. Polymorphisms in the IL‐1 gene cluster influence systemic inflammation in patients at risk for acute‐on‐chronic liver failure
- Author
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Vicente Arroyo, Andrea De Gottardi, Esther Titos, Cristina López-Vicario, Bibiana Rius, Henning Grønbæk, Aritz Lopategi, Pere Ginès, Ivo Graziadei, José Alcaraz-Quiles, Joan Clària, Mauro Bernardi, Marco Pavesi, Mireia Casulleras, 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, and Clària, J.
- Subjects
Liver Cirrhosis ,Male ,0301 basic medicine ,medicine.medical_specialty ,Cirrhosis ,medicine.medical_treatment ,Single-nucleotide polymorphism ,Systemic inflammation ,Polymorphism, Single Nucleotide ,polymorphism ,03 medical and health sciences ,Risk Factors ,Internal medicine ,Journal Article ,Humans ,Chemerin ,Medicine ,Decompensation ,610 Medicine & health ,Inflammation ,systemic inflammation ,Hepatology ,biology ,business.industry ,Odds ratio ,Middle Aged ,Interleukin ,medicine.disease ,030104 developmental biology ,Cytokine ,Multigene Family ,Immunology ,biology.protein ,Female ,acute-on-chronic liver failure ,medicine.symptom ,business ,Interleukin-1 ,cirrhosi - 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.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).
- Published
- 2016
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