EPHX1 gene polymorphisms in alcohol dependence and their distribution among the Indian populations.

BACKGROUND: The microsomal epoxide hydrolase is a phase II enzyme of the biotransformation. The human epoxide hydrolase 1 (EPHX1) gene lies in the chromosomal region 1q42.1 and exhibits polymorphism. Two single nucleotide polymorphisms (SNPs) have been described in the coding region of the EPHX1 gene that produces two protein variants. SUBJECTS AND METHODS: A total of 604 samples belonging to 13 Indian populations were included in this study. Based on the DSM-IV criteria, 184 individuals from Kota population were classified into alcoholism cases (100) and controls (84). Genotypes of Tyr113His and His139Arg polymorphisms in the EPHX1 gene were determined using PCR and sequencing. Associations were tested using Pearson's χ(2) test and haplotype analyses. RESULTS: We found significant association between EPHX1 gene Tyr113His polymorphism and alcoholism in the Kota population (T vs. C: OR = .615, 95% CI = .399-.949, p = .027; TT vs. CC + CT: OR = .536, 95% CI = .297-.969, p = .038). The very slow activity haplotype CA (113His-139His) was also found to be associated with alcohol dependence (p = .048). Analysis of additional populations demonstrated that the Tyr113His polymorphism significantly deviated from Hardy-Weinberg equilibrium in four populations but only one population deviated for the His139Arg locus. All populations shared the four possible two-site haplotypes. Linkage disequilibrium between these two loci was not significant in any of the population studied. CONCLUSION: EPHX1 gene polymorphisms and haplotypes are associated with an increased risk for alcoholism in the Kota population. This is the first report from India that will serve as a template for future investigations of the prevalence of EPHX1 alleles in association with various clinical entities.

Multiple alternative splicing of Dmrt1 during gonadogenesis in Indian mugger, a species exhibiting temperature-dependent sex determination.

Dmrt1 is an evolutionarily conserved gene having important role in the sex determination from lower vertebrates to mammals. Recent studies show transcriptional diversity for this important gene during gonadal differentiation in a few vertebrate species having genetic sex determination (GSD). In this study, we show for the first time that the transcriptional diversity of Dmrt1 is also found in the Indian mugger that exhibits temperature-dependent sex determination (TSD). We report here isolation and characterization of eight novel isoforms of Dmrt1 from Crocodylus palustris, along with its genomic locus that is referred as, cpDmrt1. Further, by sequence comparisons of cpDmrt1 and its expressed isoforms, we demonstrate that all the isoforms are generated by alternative splicing, exonization of intronic sequences and alternative polyA sites from the same locus. The eight transcripts range from 494 to 2060 bp and encode six predicted proteins having the characteristic DM domain of Dmrt1. The major heterogeneity in the isoforms and their predicted proteins is seen only in their C-termini and 3'-UTRs, which do not match with any similar sequences reported for other vertebrates. The cpDmrt1 expression was seen mainly in developing GAM (genital ridge-adrenal-mesonephros complex) with significant upregulation only in male embryos from the start of the temperature sensitive period (TSP). More significantly, approximately 70% of this expression was contributed by only one isoform (cpDmrt1e) that also has a unique 15 amino acid domain towards its C-terminal. cpDmrt1 expression was also detected at a lower level in brain and developing kidney. The study thus provides the first account of Dmrt1 locus, its transcriptional diversity and sex-specific expression in Indian mugger, a TSD species.