Badal Dey

Increased risk of antituberculosis drug-induced hepatotoxicity in individuals with glutathione S-transferase M1 'null' mutation

Background: Pathogenesis and genetic factors influencing predisposition to antituberculosis drug (ATD)‐induced hepatotoxicity are not clear. Polymorphism at the genetic locus of a drug and xenobiotic compound metabolizing enzyme, N‐acetyltransferase type 2 (NAT2), is reported to be associated with the excess generation of toxic reactive metabolites. Polymorphisms at the glutathione S‐transferase (GST) loci (GSTM1 and GSTT1) are involved in the detoxification of these toxic metabolites in the human body to a lesser extent. We have examined whether polymorphisms at these loci are associated with the risk of ATD‐induced hepatotoxicity.

Absence of the HIV-1 protective Δccr5 allele in most ethnic populations of India

Recent epidemiological data and projections indicate that HIV infection will spread rapidly in India. An allele Δccr5 of the β-chemokine receptor gene CCR5 has been found to confer protection against HIV-1. We find that this protective allele is absent in most ethnic populations of India, except some populations of the northern and western regions where this allele may have been introduced by Caucasian gene flow. The implications of this finding are discussed in the light of increasing HIV prevalence in India.

Genetic Markers among Meiteis and Brahmins of Manipur, India

Genetic polymorphism of 16 red-cell antigens, enzymes, serum proteins and Hb variants was investigated in 214 male and female individuals belonging to the Meiteis and a Brahmin caste group living in Imphal (Manipur, Northeast India). Ethnohistorical records suggest that the Meiteis are of Mongoloid origin, while the original Brahmin settlers represent the easternmost part of the so-called Caucasoids. The markers studied are: A1A2BO, MNSs, Rh-system, Duffy, Diego; Gm, Km, Gc, Hp, Tf, Cp; Hb; aP, AK, EsD and LDH. The comparison between the two groups on the basis of the markers studied showed that the Meiteis and Brahmins are very close to each other with respect to most of the loci except Gm, EsD and Hb, where significant statistical differences were found.

DNA Sequence Variation and Haplotype Structure of the ICAM1 and TNF Genes in 12 Ethnic Groups of India Reveal Patterns of Importance in Designing Association Studies

We have examined the patterns of DNA sequence variation in and around the genes coding for ICAM1 and TNF, which play functional and correlated roles in inflammatory processes and immune cell responses, in 12 diverse ethnic groups of India. We aimed to (a) quantify the nature and extent of the variation, and (b) analyse the observed patterns of variation in relation to population history and ethnic background. At the ICAM1 and TNF loci, respectively, the total numbers of SNPs that were detected were 28 and 12. Many of these SNPs are not shared across ethnic groups and are unreported in the dbSNP or TSC databases, including two fairly common non‐synonymous SNPs at positions 13487 and 13542 in the ICAM1 gene. Conversely, the TNF‐376A SNP that is reported to be associated with susceptibility to malaria was not found in our study populations, even though some of the populations inhabit malaria endemic areas. Wide between‐population variation in the frequencies of shared SNPs and coefficients of linkage disequilibrium have been observed. These findings have profound implications in case‐control association studies.

Insertion / Deletion DNA Polymorphisms in two South Indian Tribal Populations

Abstract DNA samples from 123 unrelated individuals belonging to 2 endogamous tribal populations, namely, the Koya Doras and Konda Reddis, of East Godavari District, Andhra Pradesh, South India were analysed for 8 human specific polymorphic insertion/deletion loci. Except Alu CD4, all the loci are polymorphic in both the populations. Most of the loci showed high levels of heterozygosity in both the populations. The average heterozygosity is higher in Konda Reddis than in Koya Doras. The results were compared with available Indian data on four other tribal populations, namely, Lodha, Munda, Santal and Tipperah.

A large, systematic molecular-genetic study of G6PD in Indian populations identifies a new non-synonymous variant and supports recent positive selection

Malaria has been endemic in India. G6PD deficiency is known to confer resistance to malaria. Many G6PD deficiency variants, some of which are India-specific, are known to occur in high frequencies in India. This is the first systematic molecular-genetic study in multiple populations from India drawn from diverse ethnic, socio-cultural and geographical backgrounds. Resequencing of the G6PD gene was carried out in 80 males and then the polymorphic variants were genotyped in 400 individuals of both genders, drawn from 10 ethnic groups of India. Our study has identified one new exonic variant (M159I; exon-5), occurring in multiple populations, that is predicted to result in G6PD deficiency. A strong geographical sub-structuring of known G6PD variants has also been established. We have compared all available data from public-domain resources with those generated in this study to identify the nature and extent of natural selection. Our results (a) provide indication of weak negative selection, and (b) reveal signals of recent positive selection for the G6PD Orissa and G6PD Coimbra mutation bearing haplotypes. These inferences have been interpreted in the light of malarial protection to the populations that have been long exposed to plasmodium infection.

Using HapMap data: a cautionary note

The HapMap data are being widely used in human genetic studies. We show by direct resequencing of a ∼6-kb region of chromosome 1 that the HapMap data are unreliable for this region. This region contains a recent mitochondrial (mt) DNA insertion. The HapMap data report the corresponding mtDNA variation and not the nuclear DNA variation. In view of mtDNA insertions of varying lengths throughout the human genome and considerable segmental duplications, it is necessary to use the HapMap data cautiously.

Homozygous Null Genotype at Glutathione S-transferase M1 Locus as a Risk Factor for Oral Squamous Cell Carcinoma in Indian Tobacco Users

Abstract Inter-individual differences in sensitivity to chemical carcinogens may contribute to differences in susceptibility to human cancer subsequent to environmental exposures. It has been reported that polymorphisms in glutathione S-transferase (GST) and cytochrome P-450 oxidase (CYP) genes are associated with increased risk of tobacco-related cancers in different ethnic populations. In this study, we investigated polymorphisms in GSTM1, GSTT1, CYP1A1and CYP2E1genes in 80 oral squamous cell carcinoma (SCC) patients and 67 controls from one Indian population. Prevalence of the GSTM1homozygous null genotype was 39 in 80 patients (49%) compared to 18 in 67 controls (27%) [age and sex adjusted OR=1.8, 95% CI=1.0-3.6]. Analyses of data on polymorphisms in GSTT1, CYP1A1and CYP2E1did not reveal significant differences in distribution of genotypes between patient and control groups. Our results confirm that GSTM1homozygous null genotype adds to the risk of oral cancer development among tobacco users. But low sample size limited the power to estimate tobacco dose-genotype interactions.

High Prevalence of Haemoglobin E in Three Populations of the Malda District, West Bengal, India

High frequencies of haemoglobin (Hb) E were reported earlier from Assam in northeast India. In the present study one of the three populations of the Malda district of West Bengal, called the Deshi, was found to show one of the highest incidences of the Hb E gene (0.61) recorded so far. A founder effect and/or local inbreeding may possibly explain this observation.

Genetic affinities between the migrant and parental populations of fishermen, East coast, India

Genetic affinities between the migrant groups of fishermen from Puri and their parental counterparts in the Southern areas were examined using 11 genetic loci: four blood groups, five red cell enzymes, and two serum proteins. The samples for the parental populations (about 430 subjects) were drawn from 34 villages spread along the 400 km coast in Ganjam district of Orissa and the contiguous Srikakulam, Vishakhapatnam, and East Godavari districts of Andhra Pradesh. Significant departures between the migrant groups and their parental counterparts were observed at some loci, although the configuration of interpopulation distances among the migrants mimicked that of the parental populations. While the observed differences may be due to a founder effect and subsequent random genetic drift in at least two of the three small populations, given high child mortality and the systematic nature of differences observed, the role of selection cannot be totally ruled out.