Genetic variants of innate immunity receptors are associated with mortality in cirrhotic patients with bacterial infection

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.

Leukocytes, Systemic Inflammation and Immunopathology in Acute-on-Chronic Liver Failure

“…For example, single-nucleotide variants might modulate the release of inflammatory molecules by innate immune cells or might induce changes in the expression of PRRs, such as TLRs. Consistent with this, genetic variants in genes coding for receptors of the innate immune system such as nucleotide-binding oligomerization domain 2 (NOD2) or ligands as mannan-binding lectin (MBL) and MBL-associated serine proteases (MASP) 2 have been shown to associate with increased short-term mortality in AD and ACLF patients [13]. Moreover, single nucleotide polymorphisms within the IL-1 gene cluster have been reported to protect patients with AD cirrhosis from uncontrolled systemic inflammation and to reduce the predisposition of these patients to develop ACLF [14].…”

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

“…Similarly, host genetic factors, for instance, single nucleotide variants might modulate the release of inflammatory mediators by innate immune cells and can change the expression of pattern recognition receptors (PRRs). Genetic variations in genes coding for innate immune receptors including nucleotide-binding oligomerization domain (NOD)-2, mannan-binding lectin (MBL), and MBL-associated serine protease (MASP)-2 are associated with increased short-term mortality in ACLF and patients with acute decompensation ( 39 ). In addition, single nucleotide polymorphism with IL-1 gene clusters plays a protective role in patients with acute decompensated cirrhosis by controlling systemic inflammation and reducing the development of ACLF ( 40 ).…”

Transition to decompensation and acute-on-chronic liver failure: Role of predisposing factors and precipitating events

“…Polymorphisms of pattern recognition receptors, such as nucleotide-binding oligomerisation domain containing 2 (NOD2), Toll-like receptor (TLR) 2 and 4, or nuclear dot protein 52 kDa have been associated with an increased risk of bacterial infections in some studies, but this has not been confirmed by other studies. [79][80][81][82] Sodium dismutase polymorphisms, another critical enzyme in immune defence and cell damage, were associated with decompensation and risk of bacterial infections. 83 In another study, the PNPLA3 G/G genotype was associated with a 2fold increase in the risk of decompensation.…”