Analyses of frequency profiles of markers on disease or drug-response related genes in diverse populations are important for the dissection of common diseases. We report the results of analyses of data on 405 SNPs from 75 such genes and a 5.2 Mb chromosome, 22 genomic region in 1871 individuals from diverse 55 endogamous Indian populations. These include 32 large (>10 million individuals) and 23 isolated populations, representing a large fraction of the people of India. We observe high levels of genetic divergence between groups of populations that cluster largely on the basis of ethnicity and language. Indian populations not only overlap with the diversity of HapMap populations, but also contain population groups that are genetically distinct. These data and results are useful for addressing stratification and study design issues in complex traits especially for heterogeneous populations.
Attempts were made in the present case-control study to investigate the association of polymorphism in the genes encoding proteins involved in toxication-detoxication and dopaminergic pathways and susceptibility to Parkinson's disease (PD). Seventy patients suffering from PD and one hundred healthy controls belonging to the same geographical location and same ethnicity were included in the study. PCR-RFLP and allele-specific PCR-based methodology were used to identify the genotypes. Multivariate logistic regression analysis revealed that heterozygous genotypes of cytochrome P4502D6*4(CYP2D6*4), CYP2E1*5B (RsaI) polymorphism and homozygous mutant genotypes of CYP2E1*6 (Dra1) were found to be overrepresented in PD cases when compared to the controls. Risk was also found to be increased in patients carrying glutathione S-transferase T1 (GSTT1) null or homozygous variant genotypes of GSTP1. Significant association was observed for monoamine oxidase-B(MAO-B) variant allele G and PD, whereas no difference in genotype and allele frequencies was observed for manganese-superoxide dismutase (MnSOD), dopamine receptor-D2(DRD2), and dopamine transporter (DAT) genes between controls and PD cases. Genotype combinations characterized by the presence of two variant genotypes on their corresponding loci revealed that four combinations of GSTT1 null and MnSOD(-9Val) or GST null and MAOB-G or CYP2E1*5B and MAO-B-AG or CYP2E1*5B and DRD2 (Taq1A-het) genotypes in the patients exhibited severalfold higher and significant association with risk to PD. Our data suggest that polymorphism in the genes involved in detoxification and dopamine regulation may modulate the susceptibility to PD and could be important risk factors in the pathogenesis of PD.
The present case-control study investigates the association of polymorphisms in cytochrome P450 2E1 (CYP2E1), involved in the metabolism of tobacco carcinogens and alcohol, with Head and Neck Squamous Cell Carcinoma (HNSCC). In addition, the interaction of CYP2E1 (CYP2E1*5B and CYP2E1*6) with other genetic factors (null genotype of glutathione-S-Transferase M1, GSTM1, X-Ray Repair Cross Complementing Group I, XRCC1 (Arg194Trp), and environmental risk factors such as alcohol and tobacco in modifying HNSCC risk were investigated. Genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay in a total of 350 male cases of HNSCC and an equal number of healthy male controls. Statistical analysis showed a significant increase in HNSCC risk in cases with variant genotypes of CYP2E1*5B (RsaI) (O.R. 3.44; 95% C.I. 1.45-8.14) and CYP2E1*6 (DraI) (O.R. 1.76; 95% C.I. 1.28-2.41). Haplotype analysis revealed that haplotype T-A was associated with a greater than 10-fold increase in risk for HNSCC. Our data also revealed a several fold increase in HNSCC risk in cases carrying a combination of variant genotypes of CYP2E1 with the null genotype of GSTM1 or XRCC1 variant genotypes. Alcohol or tobacco use (both smoking and chewing) were also found to interact with variant genotypes of CYP2E1 in significantly enhancing HNSCC risk. This increase in risk associated with an interaction of CYP2E1 genotypes with GSTM1 or XRCC1 or with tobacco and alcohol use demonstrates the importance of gene-gene and gene-environment interactions in the development of HNSCC.
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