title: Genetic Association and Gene-Gene Interaction Reveal Genetic Variations in ADH1B, GSTM1 and MnSOD Independently Confer Risk to Alcoholic Liver Diseases in India.
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.
authors.affiliation: Center for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India.
authors.forename: Neelanjana
authors.initials: N
authors.lastname: Roy
authors.affiliation: Center for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India.
authors.forename: Debanjali
authors.initials: D
authors.lastname: Dasgupta
authors.affiliation: Indian Statistical Institute, Kolkata, India.
authors.forename: Indranil
authors.initials: I
authors.lastname: Mukhopadhyay
authors.affiliation: National Institute of Biomedical Genomics, Kalyani, India.
authors.forename: Ankita
authors.initials: A
authors.lastname: Chatterjee
authors.affiliation: Department of Hepatology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India.
authors.forename: Kausik
authors.initials: K
authors.lastname: Das
authors.affiliation: Agartala Government Medical College, Agartala, Tripura, India.
authors.forename: Pradip
authors.initials: P
authors.lastname: Bhowmik
authors.affiliation: Center for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India.
authors.forename: Soumyajit
authors.initials: S
authors.lastname: Das
authors.affiliation: National Institute of Biomedical Genomics, Kalyani, India.
authors.forename: Priyadarshi
authors.initials: P
authors.lastname: Basu
authors.affiliation: Center for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India.
authors.forename: Amal K
authors.initials: AK
authors.lastname: Santra
authors.affiliation: Center for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India.
authors.forename: Simanti
authors.initials: S
authors.lastname: Datta
authors.affiliation: Department of Gastroenterology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
authors.forename: Gopal Krishna
authors.initials: GK
authors.lastname: Dhali
authors.affiliation: Department of Hepatology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Chowdhury
authors.affiliation: Center for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India.
authors.forename: Soma
authors.initials: S
authors.lastname: Banerjee
mesh_terms: D000426:Alcohol Dehydrogenase / Q000235:genetics*; D000428:Alcohol Drinking / Q000235:genetics / Q000473:pathology; D004843:Epistasis, Genetic; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007194:India; D008108:Liver Diseases, Alcoholic / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013482:Superoxide Dismutase / Q000235:genetics*
chemical_list: D000426:Alcohol Dehydrogenase; D005982:Glutathione Transferase; D013482:Superoxide Dismutase; C489332:ADH1B protein, human