Genetic contribution of CYP1A1 variant on treatment outcome in epilepsy patients: a functional and interethnic perspective.

CYP1A1 gene is involved in estrogen metabolism, and previously, we have reported association of variant rs2606345 with altered anti-epileptic drugs (AED) response in North Indian women with epilepsy (WWE). The present study aims to replicate the pharmacogenetic association, perform functional characterization and study its distribution within ethnically diverse Indian population. The variant was genotyped in 351 patients to assess the pharmacogenetic association and 552 healthy individuals belonging to 24 different ethnic groups to examine the distribution in Indian population. We observed significant overrepresentation of 'A' allele and 'AA' genotype in poor responders in WWE at Bonferroni-corrected significance levels. The recessive allele was found to lower the promoter activity by ~70-80% which was further substantiated by thermally less stable hairpin formed by it (ΔTm=7 °C). Among all ethnic groups, west Indo-European (IE-W-LP2) subpopulation showed highest genotypic frequency of the variant making women from this community more prone to poor AED response. Our results indicate that rs2606345 influences drug response in WWE by lowering CYP1A1 expression.

Diverse facets of COMT: from a plausible predictive marker to a potential drug target for schizophrenia.

Dopaminergic system in the prefrontal cortex (PFC) is known to regulate the cognitive functions. Catechol-O-methyl transferase (COMT), one of the major modulators of prefrontal dopamine function, has emerged as an important determinant of schizophrenia associated cognitive dysfunction and response to antipsychotics. A common Val->Met polymorphism (rs4680) in the COMT gene, associated with increased prefrontal dopamine catabolism, impairs prefrontal cognition and might increase risk for schizophrenia. Further, the degree of cognitive improvement observed with antipsychotics in schizophrenia patients is influenced by the COMT activity, and Val/Met has been proposed as a potential pharmacogenetic marker. However, studies evaluating the role of COMT have been equivocal. The presence of other functional polymorphisms in the gene, and the observed ethnic variations in the linkage disequilibrium structure at COMT locus, suggest that COMT activity regulation might be complex. Despite these lacunae in our current understanding, the influence of COMT on PFC mediated cognitive tasks is undeniable. COMT thus represents an attractive candidate for novel therapeutic interventions for cognitive dysfunction. The COMT activity inhibiting drugs including tolcapone and entacapone, have shown promising potential as they selectively modulate dopaminergic transmission. This review is an attempt to summarize the rapidly evolving literature exploring the diverse facets of COMT biology, its functional relevance as a predictive marker and a therapeutic target for schizophrenia.

Association of the PIM3 allele of the alpha-1-antitrypsin gene with chronic obstructive pulmonary disease.

OBJECTIVE: The study investigated the association of genetic polymorphism of the alpha1AT gene with COPD. DESIGN AND METHODS: The mutations and polymorphism of alpha1AT gene were investigated by DNA sequence analysis using polymerase chain reaction. RESULTS: The frequency of the PIM3 allele in COPD patients was found to be significantly higher than the controls (P < 0.0001). Five SNPs, including a novel SNP (24_25insA), were observed near the junction of exon-intron I. The occurrence of these SNPs didn't show any association with COPD. However, the PIM3 allele of the alpha1AT gene was found to be associated with COPD. CONCLUSION: The PIM3 allele of the alpha1AT gene is found to have an association with the pathogenesis of COPD in the Indian population.

Agenesis of gallbladder in symptomatic patients.

Three women and one man among 771 patients, who underwent laparotomy with diagnosis of symptomatic gallbladder disease over a period of 5 years, were found to have agenesis of the gallbladder. Preoperative ultrasonography suggested cholelithiasis in all the four patients; three patients with jaundice had choledocholithiasis in addition. The absence of gallbladder was established by meticulous operative exploration and carefully repeated ultrasonography in postoperative period. The patients having choledocholithiasis underwent choledocholithotomy, while the fourth patient had no definitive procedure. One patient expired on 17th postoperative day following biliary leak, septicemia and liver failure. Another two patients were well and symptom free, while the fourth patient remained symptomatic. Awareness of the possibility of agenesis of gallbladder may allow the surgeon to attempt confirmation of diagnosis by non-operative methods and avoid surgical exploration in specific instances.

Responses of the rabbit tracheal epithelium in vitro to H(2)O(2)-induced oxidative stress.

A model of rabbit tracheal epithelial (RTE) cells in primary culture was used to characterize specific and repair responses of airway epithelial cells to oxidative stress. Two well-known reactive oxygen species (ROS) generating systems were used: H(2)O(2) alone or in combination with Fe(2+) to produce the hydroxyl radical. RTE cells exhibited lipid peroxidation when exposed to H(2)O(2) + Fe(2+). Moreover, catalase (CAT) activity decreased after a 1-hour treatment in 3-day-old cultures but increased in 7-day-old cultures which have higher antioxidant enzyme activities. Superoxide dismutase (SOD) activity was never affected. In addition, RTE cells displayed a repair response leading to squamous metaplasia. H(2)O(2) + Fe(2+) treatment resulted in a time-dependent increase in the steady-state level of c-myc mRNA while c-jun and c-fos were not activated. Moreover, a chronic exposure induced the expression of the squamous phenotype characterized by the expression of the cytokeratin 13 confirmed both at the message and protein levels. RTE cells in primary culture react early to H(2)O(2) + Fe(2+) exposure by an increase in c-myc expression and by modifications in CAT activity. Further, a lipid peroxidation occurs and the tracheal epithelium evolves to squamous metaplasia.

Proliferation markers and cell cycle associated expression of prosomes in breast cancers of Parsis and non-Parsis.

The present study has focused attention essentially on the Parsis, an ethnic group with high breast cancer incidence. We have investigated the potential use of prosomes, compared to Ki-67 and PCNA, as an additional cell proliferation marker. We also addressed the question whether or not breast tumors of Parsis differed in their DNA index and in the proportion of the S-phase fraction, compared to that of non-Parsi and European patients. We observed that the benign tumors of Parsis and non-Parsis were hyperdiploids, whereas in case of malignant tumors the Parsis showed essentially diploid characteristics while hyperdiploidy prevailed in the non-Parsis. Tetraploidy was seen as a common feature in the non-Parsis, whereas aneuploidy seemed to be the more common type in the Parsis. The cell cycle analysis also revealed some interesting differences between the cell proliferation compartments of these two populations. A high number of cells in G2+M and S-phases was seen for non-Parsi malignant tumors while only the S-phase had a large cell count in the Parsis malignant tumors. The malignant tumors of Parsis and non-Parsis showed, as would be expected, a high expression of Ki-67 in the proliferation compartment. Surprisingly high Ki-67 expression was also a feature seen in the benign tumors of Parsis only and not any other group. We observed that expression of Ki-67, a proliferation marker directly related to the degree of malignancy, paralleled that of prosomal protein expression. In addition the prosomal monoclonal antibodies appeared to be more sensitive than Ki-67 in detecting a larger quantum of cells in the proliferation compartment.

p53 alterations in breast cancer of the Parsi ethnic group.

Mutations in p53 are the most common genetic abnormality yet found in human cancers. p53 mutations vary among tumor types, ranging from 0-60% in major cancers. The frequency of p53 mutations in breast cancer averages around 25%. The incidence rate and the type of mutations at specific codons seem to be influenced by geographical location as well as racial and ethnic specificities. Women of the Parsi ethnic group living mostly in defined geographical areas around metropolitan Bombay are reported to have a markedly high incidence of breast cancer. In the present work, the p53 gene alterations in the Parsis were investigated using SSCP analysis. The results confirm an earlier observation that over 60% of the Parsi breast tumors harbour p53 alterations. This figure is higher than that observed in other communities. The relevance of the finding in the light of the high breast cancer incidence in the Parsis is discussed.