Alcohol Metabolizing Gene Polymorphisms as Genetic Biomarkers of Alcoholic Liver Disease Susceptibility and Severity: A Northeast India Patient Based Study

Background: Excessive alcohol consumption is associated with genetic predisposition to Alcoholic Liver Disease (ALD), but there is very limited data on both molecular and genetic aspects of ALD among the Northeast Indian (NEI) population. Aim and Objectives: Screening the role of genetic alterations in alcohol metabolizing pathway genes in the pathogenesis of ALD which is prevalent in the ethnically NEI population. Material and Methods: Whole blood was collected from ALD patients (n=150) [alcoholic chronic liver disease (CLD, n=110) and alcoholic cirrhosis (Cirr/cirrhosis, n=40)], Alcoholic Without Liver Disease (AWLD, n=93) and healthy controls (HC/controls, n=274) with informed consents along with Fibroscan based liver stiffness measurement (LSM) score and clinical data. Alcohol Dehydrogenase 2 (ADH2) and Aldehyde Dehydrogenase 2 (ALDH2) genotyping was studied by Polymerase Chain Reaction with Confronting Two Pair Primers (PCR-CTPP); and Alcohol Dehydrogenase 3 (ADH3) by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. Results: ADH2*2 genotype was predominant and associated with increased risk of cirrhosis compared to healthy controls, AWLD and CLD cases; and CLD compared to AWLD cases. ADH3*1 genotype was associated with significantly increased risk of cirrhosis compared to healthy controls, AWLD and CLD cases (p<0.001). Variant ALDH2 genotype was rare and analysis of the joint effects of genotypes showed that higher variant genotype resulted increased risk of CLD and cirrhosis compared to AWLD, and cirrhosis compared to CLD; thereby confirming the association of the polymorphisms in key alcohol metabolizing genes in the predisposition to ALD susceptibility and severity. Presence of variant ADH2, ADH3 and ALDH2 genotypes correlated with higher LSM scores in ALD. Conclusion: Alterations in the alcohol metabolizing genes are critically associated with ALD susceptibility and severity.