Pharmacogenetic evaluation of ABCB1, Cyp2C9, Cyp2C19 and methylene tetrahydrofolate reductase polymorphisms in teratogenicity of anti-epileptic drugs in women with epilepsy.

AIM: Pregnancy in women with epilepsy (WWE) who are on anti-epileptic drugs (AEDs) has two- to three-fold increased risk of fetal malformations. AEDs are mostly metabolized by Cyp2C9, Cyp2C19 and Cyp3A4 and transported by ABCB1. Patients on AED therapy can have folate deficiency. We hypothesize that the polymorphisms in ABCB1, Cyp2C9, Cyp2C19 and methylene tetrahydrofolate reductase (MTHFR) might result in differential expression resulting in differential drug transport, drug metabolism and folate metabolism, which in turn may contribute to the teratogenic impact of AEDs. MATERIALS AND METHODS: The ABCB1, Cyp2C9, Cyp2C19 and MTHFR polymorphisms were genotyped for their role in teratogenic potential and the nature of teratogenecity in response to AED treatment in WWE. The allelic, genotypic associations were tested in 266 WWE comprising of 143 WWE who had given birth to babies with WWE-malformation (WWE-M) and 123 WWE who had normal offsprings (WWE-N). RESULTS: In WWE-M, CC genotype of Ex07 + 139C/T was overrepresented (P = 0.0032) whereas the poor metabolizer allele *2 and *2 *2 genotype of CYP2C219 was significantly higher in comparison to WWE-N group (P = 0.007 and P = 0.005, respectively). All these observations were independent of the nature of malformation (cardiac vs. non cardiac malformations). CONCLUSION: Our study indicates the possibility that ABCB1 and Cyp2C19 may play a pivotal role in the AED induced teratogenesis, which is independent of nature of malformation. This is one of the first reports indicating the pharmacogenetic role of Cyp2C19 and ABCB1 in teratogenesis of AED in pregnant WWE.

Antipsychotic drug dosage and therapeutic response in schizophrenia is influenced by ABCB1 genotypes: a study from a south Indian perspective.

AIM: The conventional practice of using trial and error mode to select antipsychotic drugs in treatment of schizophrenia can result in symptom exacerbations, relapse and severe side effects, resulting in higher costs of treatment. P-glycoprotein (ABCB1) is known to regulate the concentration of antipsychotic drugs in the brain. Variable expressivity based on polymorphism in the gene ABCB1 may reflect on the drug response and its relationship to dosage. MATERIALS & METHODS: All antipsychotic dosages administered to patients were converted to common chlorpromazine equivalents. Response to antipsychotics was based on 50% cutoff in Brief Psychiatric Rating Scale ratings after 1-year of follow-up. Using a case-control study design, ABCB1 polymorphisms were screened in 192 individuals grouped into responders and nonresponders. RESULTS: A strong allelic, genotypic and haplotypic association, was observed, which was predictive of good response to antipsychotics. Individuals carrying the favorable homozygous genotypes of rs1045642 and rs2032582 displayed better response with increased dosage while those carrying risk genotype manifested refractoriness on increased dosage. CONCLUSION: The study suggests that a priori knowledge of ABCB1 genotypes can provide a significant input into evaluating the patient's response to medication, and minimizing redundant dosing and refractoriness.

Association of single nucleotide gene polymorphism at interleukin-1beta +3954, -511, and -31 in chronic periodontitis and aggressive periodontitis in Dravidian ethnicity.

BACKGROUND: Interleukin (IL)-1beta gene polymorphisms are considered a potential risk factor for periodontal disease. The aim of this study is to identify the association of IL-1beta gene polymorphisms with chronic periodontitis and aggressive periodontitis in a Malayalam-speaking Dravidian population from South India. METHODS: The case-control study consisted of 43 patients with chronic periodontitis and 54 patients with aggressive periodontitis as cases, and the control group consisted of 101 healthy subjects. All subjects were genotyped for IL-1beta +3954, -511, and -31 loci by polymerase chain reaction amplification followed by restriction enzyme digestion and gel electrophoresis. Genotype, allele, and haplotype analyses were done. RESULTS: Analyses for allele and genotypes showed a high frequency of the C allele and CC genotype for single nucleotide polymorphism IL-1beta +3954 in the group with chronic periodontitis and no difference for patients with aggressive periodontitis compared to controls (P <0.05). Haplotype analysis showed that IL-1beta -31 and -511 were in strong linkage disequilibrium in all groups. The IL-1beta -31 allele T was in linkage with allele T of IL-1beta +3954 in the control group. CONCLUSIONS: In the Malayalam-speaking Dravidian population, allele C of IL-1beta +3954 appeared to be an important risk factor for chronic periodontitis. The IL-1beta -31 allele T was in linkage with allele T of IL-1beta +3954 in the control group. No gene polymorphisms were found in patients with aggressive periodontitis. More studies with a larger sample size involving the entire cluster of the IL-1beta gene are necessary to determine the exact role of IL-1beta gene polymorphisms in periodontal disease.

Evidence of association of serotonin transporter gene polymorphisms with schizophrenia in a South Indian population.

Serotonin (5-hydroxytryptamine (5-HT)) transporter (SLC6A4) is known to influence mood, emotion, cognition and efficacy of antidepressants, particularly that of selective serotonin reuptake inhibitors. Atypical antipsychotics exert their effects partially through serotinergic systems, and hence, variation in 5-HT uptake may affect antipsychotic action mediated through the serotinergic system. Therefore, investigating the role of SLC6A4 as a risk factor for developing schizophrenia and treatment response had been a point of concern for many investigators, but with variable outcome. In this study, we examined the genetic roles of five polymorphisms of SLC6A4, including those of the widely studied 44 base pair variable number of tandem repeat (VNTR) in the promoter region of SLC6A4 (the serotonin transporter gene-linked polymorphic region: 5HTTLPR) and a VNTR polymorphism (STin2) in the second intron, in schizophrenia and its influence on the severity of symptoms in a South Indian population from Kerala, comprising 586 individuals. We detected significant allelic and genotypic associations with rs2066713 (both allelic and genotypic P-value <0.001), 5HTTLPR (allelic P-value=0.008 and genotypic P-value=0.03) and STin2 polymorphisms (allelic P-value=0.001 and genotypic P-value=0.002). A haplotype linking these three risk alleles, 5HTTLPR/S-rs2066713/C-STin2/12-repeat (P-value=0.0059), was also significantly associated with disease in our population. Patients with STin2 12-repeat homozygotes showed a greater severity of blunted effect symptom. These results suggest a strong role of SLC6A4 in schizophrenia, possibly with a specific behavioral endophenotype in a South Indian population.

Analysis of genotype and haplotype effects of ABCB1 (MDR1) polymorphisms in the risk of medically refractory epilepsy in an Indian population.

The transmembrane P-glycoprotein that functions as a drug-efflux transporter coded by ATP-binding cassette, subfamily B, member 1/Multidrug Resistance 1 (ABCB1/MDR1) gene is considered relevant to drug absorption and elimination, with access to the central nervous system. Effects of three ABCB1 single nucleotide polymorphisms (SNPs) in genotypic and haplotypic combination have been evaluated in a south Indian population for risk of pediatric medically refractory epilepsy. The study included age and sex matched medically refractory (N=113) cases and drug responsive epilepsy patients (N=129) as controls, belonging to the same ethnic population recruited from a tertiary referral centre, of Karnataka, Southern India. The genotype frequencies of SNPs c.1236C>T, c.2677G>T/A, and c.3435C>T were determined from genomic DNA of the cases and controls by PCR- RFLP and confirmatory DNA sequencing. 256 normal population samples of the same ethnicity were genotyped for the three loci to check for population stratification. Results indicate that there was no statistically significant difference between allele and genotype frequencies of refractory and drug responsive epilepsy patients. The predicted haplotype frequencies of the three polymorphisms did not show significant difference between cases and controls. The results confirm earlier observations on absence of association of ABCB1 polymorphisms with medically refractory epilepsy.

Universal protocol for generating 100bp size standard for endless usage

Developing countries are facing severe bottlenecks in the technological advancement in biotechnology, due to restrictions imposed by patent protected products and protocols. This calls for designing of simple and cost-effective alternatives for the indispensable products like DNA molecular weight markers. We demonstrate a novel, rapid and cost-effective method of making in-house 100bp ladder for routine use. In our method we use a single forward primer and five reverse primers designed on the backbone sequence of a commonly used vector template. These primers are used at a universal annealing temperature to amplify ten DNA fragments of accurate size ranging from 100bp to 1000bp. Our PCR-based method can provide size standards for an endless usage.

The XVth World Congress of Psychiatric Genetics, October 7-11, 2007: Rapporteur summaries of oral presentations.

The World Congress of Psychiatric Genetics (WCPG) has become an annual event since the early 1990's sponsored by the International Society of Psychiatric Genetics (ISPG). Each year the latest published and unpublished findings are aired for discussion by representatives of the majority of research programs on this topic world-wide. The 2007 congress was held in New York City and attracted over 1000 researchers. The topics emphasized included results from whole genome association studies, the significance of copy number variation and the important contributions of epigenetic events to psychiatric disorders. There were over 20 oral sessions devoted to these and other topics of interest. Young investigator recipients of travel awards served as rapporteurs to summarize sessions and these summaries follow.

Association of dopamine receptor polymorphisms with schizophrenia and antipsychotic response in a South Indian population.

BACKGROUND: Alterations in the dopamine transmission and receptor density are hypothesized in the pathophysiology of schizophrenia but ethnic disparities are reported to exist in disease association and therapeutic response to psychotropic medication. Antipsychotics have higher binding affinity to D2 subtype of dopamine receptor. DRD2 Cys311, TaqIB1 and TaqIA1 variants are considered to have either reduced affinity for dopamine and hypo-dopaminergic activity. METHODS: We examined the role of Taq1B, Taq1D, S311C, H313H and Taq1A polymorphisms of DRD2 gene in schizophrenia and antipsychotic treatment response in 213 patients and 196 controls from a homogenous South Indian population. A more detailed genotype phenotype association analysis was carried out to understand the disease in terms of its socio-cultural factors. RESULTS: H313HTT genotype was found to be associated with schizophrenia (P = 0.004) while TaqIB1B1 genotype was significantly associated with higher psychopathology score. When treatment response was considered H313HCC, TaqIA2A2 and Taq1D1D1 had higher mean improvement scores. TaqID1D1 and H313HTT genotype were found to be significantly higher in responders than in nonresponder group. Distinct shift in the LD patterns of responder and non-responder group was observed. Certain symptoms were characteristic of our patient population. Following medication the scores and presentation of these symptoms tend to vary in the responder and non-responder groups. CONCLUSION: Based on genotype phenotype correlations it can be suggested that certain polymorphisms can be defined for their critical functions in disease and their role in treatment response in South Indian population. The present study suggests that in addition to ethnic bias, socio-cultural factors should also be considered while evaluating genotype phenotype correlations, in association and treatment response to complex disorders like schizophrenia.