Polymorphism in cytochrome P450 2E1 and interaction with other genetic risk factors and susceptibility to alcoholic liver cirrhosis.
The association of polymorphism in cytochrome P450 2E1 (CYP2E1), the major microsomal ethanol metabolizing enzyme and its interaction with genes, involved in detoxification of reactive oxygen species, such as glutathione-S-transferases M1 (GSTM1) and alcohol intake, gamma-aminobutyric acid receptor gamma2 (GABRG2) was studied with the risk to alcoholic cirrhosis in a case-control study. A total of 160 alcoholic cirrhotic and 125 non-alcoholic cirrhotic cases, visiting the OPD facility of Gastroenterology Department of Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGI), Lucknow, India and 250 non-alcoholic and 100 alcoholic controls having no evidence of liver disease were included in the study. PCR-based RFLP methodology was followed for genotyping studies. Our data revealed that the variant genotypes of CYP2E1 5B exhibited significant association with the alcoholic liver cirrhosis when compared to non-alcoholic controls (OR: 4.3; 95%CI: 1.5-12.4; p: 0.003) or non-alcoholic cirrhosis patients (OR: 5.4; 95%CI: 1.2-24.5; p: 0.01) or alcoholic controls (OR: 4.3; 95%CI: 0.95-19.62; p: 0.04). Haplotype approach revealed that haplotype T-A-T was found to be associated with more than 5-fold increase in risk for alcoholic cirrhosis. Likewise, combination of variant genotype of CYP2E1 5B with null genotype of GSTM1, a phase II detoxification enzyme, resulted in several fold increase in risk in alcoholic cirrhotic patients when compared with non-alcoholic controls or non-alcoholic cirrhotic patients. Further, the combination of variant genotype of CYP2E1 5B with GABRG2, significantly increased the risk upto 6.5-fold in alcoholic cirrhotic patients when compared with non-alcoholic controls thereby suggesting the role of gene-gene interaction in alcoholic cirrhosis.
Developmental Toxicology Division, Indian Institute of Toxicology Research (formerly ITRC), CSIR, P.O. Box 80, M.G. Marg, Lucknow 226 001, UP, India.
Anwar Jamal
AJ
Khan
Munindra
M
Ruwali
Gourdas
G
Choudhuri
Neeraj
N
Mathur
Qayyum
Q
Husain
Devendra
D
Parmar
D000437:Alcoholism / Q000201:enzymology / Q000235:genetics; D000483:Alleles; D016022:Case-Control Studies; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008103:Liver Cirrhosis / Q000201:enzymology / Q000235:genetics; D008104:Liver Cirrhosis, Alcoholic / Q000201:enzymology* / Q000235:genetics*; D008297:Male; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D011963:Receptors, GABA-A / Q000235:genetics; D012307:Risk Factors
D019392:Cytochrome P-450 CYP2E1; D005982:Glutathione Transferase; D011963:Receptors, GABA-A; C546279:GABRG2 protein, human