Genetic Variants of Innate Immunity Receptors Are Associated with Mortality in Cirrhotic Patients with Bacterial Infection

Overview

Journal Liver Int

Specialty Gastroenterology

Date 2020 Jan 29

PMID 31991025

Citations 5

Authors

Jelte J Schaapman

Alex Amoros

Johan J van der Reijden

Wim Laleman

Stefan Zeuzem

Rafael Banares

Rajiv Jalan

Vicente Arroyo

Joan Claria

Hein W Verspaget

Minneke J Coenraad

Affiliations

Soon will be listed here.

Abstract

Background & Aims: Acute-on-chronic liver failure (ACLF) is characterized by acute decompensation of cirrhosis (AD), organ failure(s) and high risk of short-term mortality with bacterial infection frequently as precipitating event. Innate immune pattern recognition receptors and members of the lectin pathway of complement activation are crucial to the innate immune response to pathogens. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) of innate immune components are associated with the occurrence of bacterial infections or mortality in patients with cirrhosis hospitalized for AD or ACLF.

Methods: Twenty-one innate immunity SNPs with known functional implications were genotyped in 826 AD/ACLF patients included in the CANONIC study. Associations between baseline characteristics of the patients, the occurrence of bacterial infections and survival rate at 90 days of follow-up in relation to the innate immunity genetic variants were analysed.

Results: The NOD2-G908R genetic variant was associated with mortality (HR 2.25, P = .004) independently of age and MELD Score. This association was also found in a predefined subgroup analysis in patients with bacterial infections (HR 2.78, P < .001) along with MBL_Yx (HR 1.72, P = .008) and MASP2_371 (HR 1.67, P = .012) genetic variants. None of the analysed SNPs were significantly associated with the occurrence of acute bacterial infections or spontaneous bacterial peritonitis in particular.

Conclusions: Innate immune system-specific NOD2-G908R, MBL_Yx and MASP2_371 genetic variants were independently associated with increased risk of short-term mortality in AD/ACLF patients with bacterial infection.

Citing Articles

Exploring the Relationship Between NOD2 Risk Variants and First Decompensation Events in Cirrhotic Patients With Varices.

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PMID: 39469976 PMC: 11891376. DOI: 10.1111/liv.16143.

Clinical Implications of Inflammation in Patients With Cirrhosis.

Kronsten V, Shawcross D Am J Gastroenterol. 2024; 120(1):65-74.

PMID: 39194320 PMC: 11676607. DOI: 10.14309/ajg.0000000000003056.

Mechanisms of immunity in acutely decompensated cirrhosis and acute-on-chronic liver failure.

Engelmann C, Zhang I, Claria J Liver Int. 2023; 45(3):e15644.

PMID: 37365995 PMC: 11815630. DOI: 10.1111/liv.15644.

Leveraging omics to understand the molecular basis of acute-on-chronic liver failure.

Claria J Adv Lab Med. 2023; 2(4):516-540.

PMID: 37360898 PMC: 10197663. DOI: 10.1515/almed-2021-0023.

Acute-on-Chronic Liver Failure: Pathophysiological Mechanisms and Management.

Khanam A, Kottilil S Front Med (Lausanne). 2021; 8:752875.

PMID: 34820395 PMC: 8606418. DOI: 10.3389/fmed.2021.752875.

References

de Rooij B, van Hoek B, Ten Hove W, Roos A, Bouwman L, Schaapherder A . Lectin complement pathway gene profile of donor and recipient determine the risk of bacterial infections after orthotopic liver transplantation. Hepatology. 2010; 52(3):1100-10. DOI: 10.1002/hep.23782. View

Ponziani F, Zocco M, Cerrito L, Gasbarrini A, Pompili M . Bacterial translocation in patients with liver cirrhosis: physiology, clinical consequences, and practical implications. Expert Rev Gastroenterol Hepatol. 2018; 12(7):641-656. DOI: 10.1080/17474124.2018.1481747. View

Foldi I, Tornai T, Tornai D, Sipeki N, Vitalis Z, Tornai I . Lectin-complement pathway molecules are decreased in patients with cirrhosis and constitute the risk of bacterial infections. Liver Int. 2017; 37(7):1023-1031. DOI: 10.1111/liv.13368. View

Altorjay I, Vitalis Z, Tornai I, Palatka K, Kacska S, Farkas G . Mannose-binding lectin deficiency confers risk for bacterial infections in a large Hungarian cohort of patients with liver cirrhosis. J Hepatol. 2010; 53(3):484-91. DOI: 10.1016/j.jhep.2010.03.028. View

Bernardi M, Moreau R, Angeli P, Schnabl B, Arroyo V . Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis. J Hepatol. 2015; 63(5):1272-84. DOI: 10.1016/j.jhep.2015.07.004. View

Bellot P, Frances R, Such J . Pathological bacterial translocation in cirrhosis: pathophysiology, diagnosis and clinical implications. Liver Int. 2012; 33(1):31-9. DOI: 10.1111/liv.12021. View

Jalan R, Saliba F, Pavesi M, Amoros A, Moreau R, Gines P . Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure. J Hepatol. 2014; 61(5):1038-47. DOI: 10.1016/j.jhep.2014.06.012. View

Fernandez J, Acevedo J, Wiest R, Gustot T, Amoros A, Deulofeu C . Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis. Gut. 2017; 67(10):1870-1880. DOI: 10.1136/gutjnl-2017-314240. View

Schaapman J, Amoros A, van der Reijden J, Laleman W, Zeuzem S, Banares R . Genetic variants of innate immunity receptors are associated with mortality in cirrhotic patients with bacterial infection. Liver Int. 2020; 40(3):646-653. PMC: 7079071. DOI: 10.1111/liv.14392. View

10.

Berg R, Garlington A . Translocation of certain indigenous bacteria from the gastrointestinal tract to the mesenteric lymph nodes and other organs in a gnotobiotic mouse model. Infect Immun. 1979; 23(2):403-11. PMC: 414179. DOI: 10.1128/iai.23.2.403-411.1979. View

11.

Harputluoglu M, Dertli R, Otlu B, Demirel U, Yener O, Bilgic Y . Nucleotide-Binding Oligomerization Domain-Containing Protein 2 Variants in Patients with Spontaneous Bacterial Peritonitis. Dig Dis Sci. 2016; 61(6):1545-52. DOI: 10.1007/s10620-015-4024-y. View

12.

Janse M, de Rooij B, van Hoek B, van den Berg A, Porte R, Blokzijl H . Recipient's genetic R702W NOD2 variant is associated with an increased risk of bacterial infections after orthotopic liver transplantation. PLoS One. 2013; 8(8):e72617. PMC: 3747080. DOI: 10.1371/journal.pone.0072617. View

13.

Reichert M, Ripoll C, Casper M, Greinert R, Vandieken E, Grunhage F . Common NOD2 Risk Variants as Major Susceptibility Factors for Bacterial Infections in Compensated Cirrhosis. Clin Transl Gastroenterol. 2019; 10(1):e00002. PMC: 6369875. DOI: 10.14309/ctg.0000000000000002. View

14.

Matsushita M, Fujita T . Activation of the classical complement pathway by mannose-binding protein in association with a novel C1s-like serine protease. J Exp Med. 1992; 176(6):1497-502. PMC: 2119445. DOI: 10.1084/jem.176.6.1497. View

15.

Summerfield J, Ryder S, Sumiya M, Thursz M, Gorchein A, Monteil M . Mannose binding protein gene mutations associated with unusual and severe infections in adults. Lancet. 1995; 345(8954):886-9. DOI: 10.1016/s0140-6736(95)90009-8. View

16.

Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, Cordoba J . Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology. 2013; 144(7):1426-37, 1437.e1-9. DOI: 10.1053/j.gastro.2013.02.042. View

17.

Appenrodt B, Grunhage F, Gentemann M, Thyssen L, Sauerbruch T, Lammert F . Nucleotide-binding oligomerization domain containing 2 (NOD2) variants are genetic risk factors for death and spontaneous bacterial peritonitis in liver cirrhosis. Hepatology. 2010; 51(4):1327-33. DOI: 10.1002/hep.23440. View

18.

Endo Y, Matsushita M, Fujita T . The role of ficolins in the lectin pathway of innate immunity. Int J Biochem Cell Biol. 2011; 43(5):705-12. DOI: 10.1016/j.biocel.2011.02.003. View

19.

Dinya T, Tornai T, Vitalis Z, Tornai I, Balogh B, Tornai D . Functional polymorphisms of innate immunity receptors are not risk factors for the non-SBP type bacterial infections in cirrhosis. Liver Int. 2017; 38(7):1242-1252. DOI: 10.1111/liv.13664. View

20.

Koch A, Melbye M, Sorensen P, Homoe P, Madsen H, Molbak K . Acute respiratory tract infections and mannose-binding lectin insufficiency during early childhood. JAMA. 2001; 285(10):1316-21. DOI: 10.1001/jama.285.10.1316. View