Abstract
Genetic susceptibility is an important modifier of clinical outcome and natural history of progression in Alcoholic liver disease (ALD). While the significance of ethnicity in this evolution is very clear, subtle inter-individual genetic variant(s) might be important and thus we investigated those in an Indian population. Fourteen markers were genotyped within two alcohol metabolism genes [Alcohol dehydrogenase (ADH) gene clusters (ADH1B and ADH1C) and Aldehyde dehydrogenase (ALDH2)], one microsomal ethanol oxidizing enzyme cytochrome p450 (CYP2E1) and three oxidative stress response (OSR) genes (MnSOD, GSTT1 and GSTM1) among 490 Bengali individuals (322 ALD and 168 control) from Eastern and North-Eastern India and validation was performed in a new cohort of 150 Bengali patients including 100 ALD and 50 advanced non-alcoholic steatohepatitis (NASH). Out of 14 genetic variants, carriage of 5 genotypes (rs2066701CC in ADH1B, rs1693425TT in ADH1C, rs4880TT in MnSOD and GSTT1/GSTM1 null, p-value <0.05) were noted significantly higher among ALD patients while inter or intra group gene-gene interaction analysis revealed that addition of risk genotype of any OSR gene enhanced the possibility of ALD synergistically. Multiple logistic regression analysis showed independent association of rs2066701CC, rs4880TT and GSTM1 null genotype with ALD while lower frequencies of those genotypes in advanced NASH patients further confirmed their causal relation to ALD. Thus these findings suggest that the three variants of ADH1C, MnSOD and GSTM1 can be used to identify individuals who are at high risk to develop ALD and may be helpful in proper management of Indian alcoholics.
Highlights
Alcoholic liver disease (ALD) is one of the fast emerging common causes of chronic liver diseases across the globe
This study had explored the role of genetic variations in two primary alcohol metabolizing enzymes alcohol dehydrogenase (ADH) (ADH1B and ADH1C) and aldehyde dehydrogenase (ALDH) (ALDH2); CYP2E1 of microsomal ethanol oxidizing system (MEOS) and three oxidative stress response pathway genes (MnSOD, GSTT1 and Glutathione S- Transferases (GSTM1))
Distribution of only ADH1B genotypes (TT/CT/CC) at rs2066701 loci was found significantly different in ALD from alcoholic control subjects (ALC) (27/48/26 vs. 40/47/13, p-value after B-H correction = 0.004) (S3A Table)
Summary
Alcoholic liver disease (ALD) is one of the fast emerging common causes of chronic liver diseases across the globe. It is the clinical consequences of continuous alcohol over consumption (for e.g., >80gm/day for more than 10 years) [1], which includes reversible fatty liver stage to end-stage cirrhosis through steatohepatitis with or without fibrosis [2]. The biological relevance of genetic variations in two major alcohol metabolizing genes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) ( ALDH2) in risk of development of ALD have been extensively investigated [9,10]. Genetic polymorphisms in ADH gene, which oxidizes alcohol into less toxic acetaldehyde have exhibited significant association in few of the population based case-control studies while others did not [11]. Case-control studies with mitochondrial ALDH, which oxidizes acetaldehyde to acetate revealed incongruous results such as ALDH2Ã2 allele exclusively predispose in Asians [12] and experiences a negative physiological response against alcohol induced tissue damage whereas in another Asian study a significantly increased risk of this genotype was observed among moderate alcohol consumers [13]
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