Pattern recognition receptor CD14 gene polymorphisms in alcohol use disorder patients and its Influence on liver disease susceptibility

Abstract

BackgroundAlcohol use disorders (AUDs) leading to liver disease is major concern over other spectrum of disorder. Excessive alcohol consumption resulting in leaky gut syndrome is attributed to alcohol-induced liver injury through portal translocation of bacterial endotoxin. Susceptibility to alcoholic liver disease (ALD) in AUD patients could be dependent upon genes responsible for inflammation and alcohol metabolism. The pattern recognition receptor CD14 gene is a major player in endotoxin-mediated inflammation and susceptibility to ALD. This study investigated the genetic association of CD14 polymorphisms and other mechanisms relevant to altered inflammatory responses leading to ALD.MethodsPatients with alcohol use disorder with ALD (n = 128) and without liver disease (ALC, n = 184) and controls without alcohol use disorder (NALC, n = 152) from North India were enrolled. The CD4 gene polymorphisms in the North Indian population were evaluated by RFLP and sequencing. Secretory CD14 (sCD14), LBP, TLR4, MD2, TNFα, IL1b, IFNγ, IL6, IL10, and IL4 levels in serum were measured by ELISA among groups. The influence of polymorphisms on CD14 gene promoter activity and circulatory bacterial DNA level was determined.ResultsThe CD14 gene promoter and exonic region SNPs were found to be monomorphic, except for SNP rs2569190 for the North Indian population. The genetic association of SNP rs2569190(C/T) with the risk of developing ALD was found significant for TT genotype [ORTT, 95% CI = 2.19, 1.16–4.13 for ALD vs. ALC and OR, 2.09, 1.18–3.72 for ALD vs. NALC]. An increased sCD14 level was observed in AUD patients compared to NALC control. Increased levels of LBP, TLR4, TNFα, IL1β, IFNγ, and IL6 and reduced levels of MD2, IL10, and IL4 were observed among the ALD patients compared to the other two control groups. Elevated levels of pro-inflammatory and reduced levels of anti-inflammatory cytokines were observed in the risk genotype TT groups of ALD patients and the ALC group compared to NALC. Promoter activity was observed in the intronic region flanking SNPs and risk genotype can influence reporter activity, indicating CD14 gene expression.ConclusionEnhanced CD14 expression associated with inflammatory responses increases susceptibility to ALD in the TT genotype of AUD patients.

Biochemical, Hematological, Inflammatory, and Gut Permeability Biomarkers in Patients with Alcohol Withdrawal Syndrome with and without Delirium Tremens

“…Some biomarker changes may be associated with comorbid diseases. The findings of this study on the association of FABP2 and LBP with ALD (Figure 2) are supported by existing data [22,74]. The findings of increased zonulin in patients with concomitant pancreatitis are also consistent with the literature [75].…”

Alcohol use disorder research in India: An update

“…[ 49 ] Another recent study from North India included 128 AUD patients with ALD, 184 AUD patients without ALD, and 152 controls without AUD. [ 50 ] As per the study findings, enhanced CD14 expression increases vulnerability to developing ALD among AUD patients with TT genotype.…”

Steatotic Liver Disease: Metabolic Dysfunction, Alcohol, or Both?

“…Based on a large genome-wide association study, PNPLA3, transmembrane 6 superfamily member 2 (TM6SF2), and membrane-bound O-acyltransferase domain-containing protein 7 (MBOAT7) were determined to be associated with ALD progression presumably via modulating lipid metabolism and/or HCC risk, for which the exact mechanisms have remained unclear [ 57 ]. Further studies have identified an association between susceptibility to ALD and polymorphisms in the pattern recognition receptor CD14 gene, as well as in the nuclear factor erythroid 2-related factor 2 gene, both of which are involved in endotoxin-mediated inflammation and susceptibility to ALD [ 58 , 59 ]. Larger studies are needed to confirm these findings.…”