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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.

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Genetic Association and Gene-Gene Interaction Reveal Genetic Variations in ADH1B, GSTM1 and MnSOD Independently Confer Risk to Alcoholic Liver Diseases in India