CYP2E1 polymorphisms and gene-environment interactions in the risk of upper aerodigestive tract cancers among Indians.

INTRODUCTION: The CYP2E1 enzyme is responsible for the metabolic activation of several procarcinogens into reactive metabolites that result in carcinogenesis. The genetic polymorphisms that modify these enzymatic activities may be associated with upper aerodigestive tract cancer risk. METHODS: This hospital-based study evaluated CYP2E1*1B, CYP2E1*5B and CYP2E1*6 polymorphisms in 408 histopathologically confirmed cases and 220 population-based controls using PCR-RFLP methods. RESULTS: The multivariate logistic regression analyses demonstrated no significant differences between groups for all three polymorphisms when analyzed separately. However, the gene-environment interactions analyses revealed significant interactions among tobacco smokers (11-20 pack years), 20-40 pack years and > 40 pack years), regular tobacco chewers and alcoholics carrying CYP2E1*1B mutant genotypes. Similarly, CYP2E1*6 polymorphisms resulted in significant interactions among tobacco smokers (> 40 pack years) and regular tobacco chewers on the multiplicative scale. CONCLUSION: The significant gene-environment interactions observed for CYP2E1*1B and CYP2E1*6 polymorphic genotypes may confer a substantial risk for upper aerodigestive tract cancers among Indians.

Genetic polymorphisms of glutathione-S-transferase genes (GSTM1, GSTT1 and GSTP1) and upper aerodigestive tract cancer risk among smokers, tobacco chewers and alcoholics in an Indian population.

The glutathione-S-transferase (GST) genes are involved in the detoxification of various carcinogens that increase the risk to upper aerodigestive tract (UADT) cancers. In the present study, 408 unrelated histopathologically confirmed cases and 220 population based controls, matched by age and gender, which belonged to the Tamilian population of south India were genotyped for polymorphisms in GSTM1, GSTT1 and GSTP1 using polymerase chain reaction (PCR) based methods. The multivariate logistic regression analyses demonstrated that GSTT1 null genotype was significantly associated with increased risk for UADT cancers (odds ratio (OR) 2.5; 95% confidence intervals (CIs) 1.3-4.7). The combined effects of GST genes have shown that concurrent lack of GSTM1 and GSTT1 had a significantly increased risk (OR 4.6; 95% CI 1.3-15.6), while GSTT1 null genotype along with GSTP1 polymorphic variants further increased the cancer risk (OR 5.3; 95% CI 2.0-13.6). The most remarkable risk was seen among individuals carrying GSTM1 null, GSTT1 null genotypes and GSTP1 polymorphic variants (OR 7.8; 95% CI 1.0-61.0). Tobacco chewers carrying GSTM1 null genotype had an enhanced risk for UADT cancers. An enhanced risk among tobacco chewers and alcoholics (regular) was noted in individuals with GSTT1 null genotype. Similarly, a significant interaction was observed among smokers (>40 pack-year (PY)) and tobacco chewers carrying GSTP1 mutant genotypes. Although the null genotype of GSTT1 is a strong predisposing risk factor for UADT cancers, we conclude that the significant gene-gene and gene-environment interactions of GST genes may confer a substantial risk to UADT cancers in the Tamilian population of south India.

Common variants of Cholesteryl ester transfer protein gene and their association with lipid parameters in healthy volunteers of Tamilian population.

BACKGROUND: Cholesteryl ester transfer protein (CETP) is involved in a key pathway of reverse cholesterol transport implicated in atherosclerosis and coronary heart disease. CETP gene is known to have many single nucleotide polymorphisms which have been associated with CETP activity and plasma high density lipoprotein cholesterol (HDL-C) concentrations. No data on the prevalence of these polymorphisms and their phenotypic association is available in South Indian population. METHODS: Three CETP polymorphisms: TaqIB, -629C/A and I405V were studied in 171 healthy volunteers from Tamilnadu, a major population of South India. Subjects were clinically examined and lipid profile was estimated. Genotyping was performed by PCR-RFLP and genotype frequencies estimated. RESULTS: The allele frequencies of TaqIB: B1 allele was 0.51; -629C/A: C allele was 0.36; and that of I405V: I allele was 0.47. Study of association between these three polymorphisms and plasma lipid concentrations revealed no significant differences in lipid parameters between genotypes. A gender based subgroup analysis revealed a significant increase in HDL-C in men with B2B2 genotype and decrease in TG in B1B2 genotype. Analysis of the combined effect of multiple mutant genotypes revealed that as the number of mutant genotypes increased, the concentrations of low density lipoprotein-cholesterol (LDL-C), HDL-C and total cholesterol (TC) increased whereas that of triglyceride (TG) decreased in the group of three mutant genotypes significantly. CONCLUSION: The frequency of B2 and A alleles of TaqIB and -629C/A polymorphisms were highest in Tamilian population when compared to other major ethnic groups while that of V allele of I405V polymorphism is between Caucasians and African Americans. Taq1B polymorphism was associated with HDL-C and TG concentrations only in men. Combination of these three polymorphisms was significantly associated with lipid profile than the individual polymorphisms.

Genetic polymorphisms of CYP2E1 and GSTP1 in a South Indian population--comparison with North Indians, Caucasians and Chinese.

CYP2E1 and GSTP1 enzymes belong to phase I and phase II group of drug metabolizing enzymes respectively which are involved in the metabolic activation and detoxification of various potential genotoxic compounds. The functional polymorphism in these genes exhibit inter-individual variations in susceptibility towards various diseases and difference in therapeutic response. The variant sequences of these genes differ considerably between ethnic groups. Therefore, the objective of the study was to assess the prevalence of CYP2E1 & GSTP1 gene variants in healthy volunteers of Tamilnadu, a population of South India. The genotype distribution of CYP2E1*1B A2A2, A2A1 and A1A1 were 61%, 36% and 3% respectively. The distribution of CYP2E1*5B c1c1, c1c2 genotypes were 99.2%and 0.8%. CYP2E1*6 DD, DC and CC genotype frequencies were 72%, 25% and 3% respectively. The allele frequencies of CYP2E1*1B, CYP2E1*5B and CYP2E1*6 were A2- 0.79 A1- 0.21, c1-0.996 c2 - 0.004 and D- 0.84 C- 0.16 respectively. The genotypic distribution of GSTP1 (Ile/Val) were Ile/Ile - 44%, Ile/Val -47% and Val/Val- 9 % whereas, the allelic frequencies were 0.67 for Ile and 0.33 for Val allele. The molecular studies in these enzymes provide basis for further epidemiological investigations in the population where the functional mutations in the genes alter therapeutic response and acts as susceptibility markers for various clinical conditions.