Genetic variants of TNFα, IL10, IL1β, CTLA4 and TGFβ1 modulate the indices of alcohol-induced liver injury in East Indian population

Abstract

Alcohol induced liver disease or alcoholic liver disease (ALD), a complex trait, encompasses a gamut of pathophysiological alterations in the liver due to continuous exposure to a toxic amount of alcohol (more than 80g per day). Of all chronic heavy drinkers, only 15–20% develops hepatitis or cirrhosis concomitantly or in succession. Several studies revealed that inter-individual as well as inter-ethnic genetic variation is one of the major factors that predispose to ALD. The role of genetic factors in ALD has long been sought for in ethnically distinct population groups. ALD is fast emerging as an important cause of chronic liver disease in India; even in populations such as “Bengalis” who were “culturally immune” earlier. While the genetic involvement in the pathogenesis of ALD is being sought for in different races, the complex pathophysiology of ALD as well as the knowledge of population level diversity of the relevant alcohol metabolizing and inflammatory pathways mandates the need for well designed studies of genetic factors in ethnically distinct population groups. An array of cytokines plays a critical role as mediators of injury, inflammation, fibrosis and cirrhosis in ALD. We, therefore, studied the association of polymorphisms in five relevant cytokine genes with “clinically significant” ALD in an ethnic “Bengali” population in Eastern India. Compared with “alcoholic” controls without liver disease (n=110), TNFα −238AA genotype, IL1β −511CC genotype, TGFβ1 −509CC genotype and IL10 −592AA genotype were significantly overrepresented in ALD patients (n=181; OR=2.4 and 95% CI 1.2–5.5, Pgenotype=0.042, Pallelic=0.008; OR=2.7 and 95% CI 1.2–5.9, Pgenotype=0.018, Pallelic=0.023; OR=4.7 and 95% CI 1.7–13.1, Pgenotype=0.003, Pallelic=0.014; and OR=2.2 and 95% CI 1.1–4.8, Pgenotype=0.04, Pallelic=0.039 respectively). Moreover a cumulative genetic risk analysis revealed a significant trend for developing ALD with an increase in the number of risk alleles on IL10 and TGFβ1 loci among alcoholics. The risk genotype of IL1β and TGFβ1 also influences the total bilirubin, albumin and alanine aminotransferase levels among alcoholic “Bengalis”. The present study is the first case–control study from Eastern India that comprehensively identified polymorphic markers in TNFα, IL10, IL1β and TGFβ1 genes to be associated with ALD in the Bengali population, accentuating the significance of genetic factors in clinical expressions of ALD.