KIR2DL2/S2 and KIR2DS5 in alcoholic cirrhotic patients undergoing liver transplantation

Abstract

Introduction: The molecular mechanisms underlying alcoholic liver fibrosis and cirrhosis are not completely understood. Hepatic fibrosis involves the interplay of diverse cells and factors, including hepatic stellate cells (HSCs), Kupffer, NK cells, and T-lymphocyte subsets. Killer-cell immunoglobulin-like receptors (KIR) are membrane receptors involved in mediation between NK and activated HSCs, regulating NK cell function through their interaction with HLA-I molecules. The aim of this study was to analyse the genetic association between KIR genes and the susceptibility to or protection from alcoholic cirrhosis (AC) in a cohort of male AC patients undergoing liver transplantation (LT) with and without concomitant viral infections.

Material and methods: KIR genotyping was performed in nuclear DNA extracted from 281 AC patients and compared with 319 male controls.

Results: Significant differences between total AC patients and healthy controls were only found in the case of KIR2DL2 and KIR2DS5. KIR2DL2 was significantly underrepresented in non-viral AC patients (52.6% vs. 63.3%; p = 0.015), while patients heterozygous for KIR2DL2 were also underrepresented in the non-viral AC group compared with controls (p = 0.034). KIR2DS5 was overrepresented in this group compared with healthy controls (p = 0.002). All these observations were only evident in AC patients older than 54 years old.

Conclusions: Our data suggest a contrary effect of KIR2DL2 and KIR2DS5 in AC patients older than 54 years, in whom the presence of KIR2DL2 appears to be protective against AC, whereas the presence of KIR2DS5 seems to promote the fibrotic process, particularly in patients with no associated viral infection.

Keywords: KIr genes; NK cells; alcohol; cirrhosis; human clinical toxicology.

Figure 1

Analysis of KIR2DL2/S2 and KIR2DL3 zygosity in AC patients and healthy controls. White bars designate healthy control population, grey bars designate non-viral AC patients and solid bars represent viral AC patients. KIR – killer-cell immunoglobulin-like receptors. The p-value was determined by two-sided Fisher’s exact test: ^aOR = 1.474; 95% CI: 1.067–2.037, p = 0.022; ^bOR = 0.683; 95% CI: 0.481–0.969, p = 0.034; ^cOR = 0.648; 95% CI: 0.467–0.899, p = 0.010; ^dOR = 1.557; 95% CI: 1.095–2.215, p = 0.015

Figure 2

Activating KIR gene frequency in AC patients and healthy controls. Telomeric activating KIR genes, KIR2DS1, KIR2DS5, KIR3DS1 and their combinations, were considered. White bars designate healthy control population; grey bars alcoholic cirrhotic liver patients without viral infection and solid bars alcoholic cirrhotic liver patients with viral infection. KIR – killer-cell immunoglobulin like receptors. P-value was determined by two-sided Fisher’s exact test: ^aOR = 1.582; 95% CI: 1.151–2.173, p = 0.006; ^bOR = 2.709; 95% CI: 1.429–5.138, p = 0.002; ^cOR = 1.434, 95% CI: 1.057–1.946; ^dOR = 0.595; 95% CI: 0.432–0.819; ^eOR = 0.350; 95% CI: 0.181–0.674; p = 0.001

Figure 3

KIR genotype profiles in total alcoholic cirrhosis patients and in those with and without viral infection. The ID genotypes refer to the genotype classification according to the allele frequencies website (http://www.allelefrequencies.net). The figure represents the frequency of each genotype and indicates the number of individuals carrying a particular genotype in each group. Genotype groups are defined in Material and methods. Each genotype is classified taking into account the total number of KIR genes as well as inhibitory and activating KIR genes. KIR2DL5 was designated as a centromeric KIR gene. Dark boxes represent the KIR genes present and white boxes represent the absent genes in tested individuals n – number of each genotype, KIR – killer-cell immunoglobulin-like receptors, iKIR – inhibitory killercell immunoglobulin-like receptors, aKIR – activatory killer-cell immunoglobulin-like receptors.