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Aim The present study aimed to evaluate association of genetic variants on drug response and therapy optimization parameters in patients treated with first-line antiepileptic drugs ( AEDs). Genetic variants from ion channels, their functionally related genes, and synaptic vesicle cycle ( SVC) genes with a potential role in epilepsy pathophysiology were thus prioritized. Methods A total of 12 genes from ion channels and related gene set and seven genes from SVC comprising 155 SNPs were genotyped and evaluated with drug response, dose levels, and drug levels in 408 patients with epilepsy. Results Both GABRA1 and SCN1A variants showed haplotypic and diplotypic associations in response to phenytoin ( PHT). Diplotype analysis of GABRA1 variants revealed association of rs12658835|rs7735530 ( AG/ AG) ( P-valuecorrected = 0.034, OR = 3.75, 95% CI = 1.36-11.05) and rs12658835|rs7735530|rs7732641|rs2279020 ( AGCA/ AGCA) ( P-valuecorrected = 0.035, OR = 2.48, 95% CI = 0.96-6.41) with recurrent seizures. SCN1A haplotype rs6432860|rs3812718 ( AC: P-valuecorrected = 0.022, OR = 2.72, 95% CI = 1.39-5.35) and diplotype ( AC/ AC: P-valuecorrected = 0.034, OR = 6.42, 95% CI = 1.10-65.76) were further observed to be associated with recurrent seizures. With respect to therapy optimization parameters, we observed significantly lower dose-adjusted drug levels at maximum dose of PHT in patients carrying AC/ AC diplotype ( P-value = 0.021). Conclusion The results further substantiate the role of GABRA1 in PHT mode of action and contribution of SCN1A in response and therapy optimization with PHT monotherapy. [ABSTRACT FROM AUTHOR]

Introduction 'Common epilepsies', merely explored for genetics are the most frequent, nonfamilial, sporadic cases in hospitals. Because of their much debated molecular pathology, there is a need to focus on other neuronal pathways including the existing ion channels. Methods For this study, a total of 214 epilepsy cases of North Indian ethnicity comprising 59.81% generalized, 40.19% focal seizures, and based on epilepsy types, 17.29% idiopathic, 37.38% cryptogenic, and 45.33% symptomatic were enrolled. Additionally, 170 unrelated healthy individuals were also enrolled. Here, we hypothesize the involvement of epilepsy pathophysiology genes, that is, synaptic vesicle cycle, SVC genes (presynapse), ion channels and their functionally related genes (postsynapse). An interactive analysis was initially performed in SVC genes using multifactor dimensionality reduction ( MDR). Further, in order to understand the influence of ion channels and their functionally related genes, their interaction analysis with SVC genes was also performed. Results A significant interactive two-locus model of STX1A_rs4363087| VAMP2_rs2278637 (presynaptic genes) was observed among SVC variants in all epilepsy cases ( P1000-value = 0.054; CVC = 9/10; OR = 2.86, 95% CI = 1.88-4.35). Further, subgroup analysis revealed stronger interaction for the same model in cryptogenic epilepsy patients only ( P1000-value = 0.012; CVC = 10/10; OR = 4.59, 95% CI = 2.57-8.22). However, interactive analysis of presynaptic and postsynaptic genes did not show any significant association. Conclusions Significant synergistic interaction of SVC genes revealed the possible functional relatedness of presynapse with pathophysiology of cryptogenic epilepsy. Further, to establish the clinical utility of the results, replication in a large and similar phenotypic group of patients is warranted. [ABSTRACT FROM AUTHOR]

Neurodevelopmental and neuroimmunological genes critically regulate antipsychotic treatment outcome. We report genetic associations of antipsychotic response in 742 schizophrenia patients from Indian populations of Indo-European and Dravidian ancestry, segregated by disease severity. Meta-analysis comparing the two populations identified CCL2 [rs4795893: OR (95% CI) = 1.79 (1.27-2.52), P = 7.62 × 10−4; rs4586: OR (95% CI) = 1.74 (1.24-2.43), P = 1.13 × 10−3] and GRIA4 [rs2513265: OR (95% CI) = 0.53 (0.36-0.78), P = 1.44 × 10−3] in low severity group; and, ADCY2 [rs1544938: OR (95% CI) = 0.36 (0.19-0.65), P = 7.68 × 10−4] and NRG1 [rs13250975, OR (95% CI) = 0.42 (0.23-0.79), P = 6.81 × 10−3; rs17716295, OR (95% CI) = 1.78 (1.15-2.75), P = 8.71 × 10−3] in high severity group, with incomplete response toward antipsychotics. To our knowledge, this is the first study to identify genetic polymorphisms associated with the efficacy of antipsychotic treatment of schizophrenia patients from two major India populations. [ABSTRACT FROM AUTHOR]

CYP2E1, CYP2A6 and CYP3A5 enzymes belong to phase I group of drug-metabolizing enzymes, which are involved in the metabolism of various compounds and xenobiotics. Presence of polymorphisms in the genes coding for these enzymes results in interindividual variations in drug metabolism, therapeutic response and susceptibility towards various diseases. The frequencies of these variants in genes differ considerably between ethnic groups. This study was carried out to estimate the allele and genotype frequencies of common variants in CYP2E1, CYP2A6 and CYP3A5 in South Indian population. Six hundred and fifty-two unrelated healthy volunteers of South Indian origin (Andhra Pradesh, Karnataka, Kerala and Tamil Nadu) were included in this study. Polymerase chain reaction-restriction fragment length polymorphism, allele-specific PCR, real-time PCR, SNaPshot and gene sequencing methods were used for the identification of gene polymorphisms. The frequencies of CYP2E1* 1B, CYP2E1*5B and CYP2E1*6 alleles in South Indian population were 14.3, 1.3 and 22.4%, respectively. The frequencies of CYP2A6*2, CYP2A6*4A and CYP2A6*5 alleles were found to be 1, 8.9 and 0.7%, respectively. The distribution of CYP3A5*3 allele was 63.5%. There were no variant alleles of CYP3A5*2, CYP3A5*4 and CYP3A5*6 in South Indian population. The frequencies of CYP2E1, CYP2A6 and CYP3A5 in the South Indian population are distinct from Caucasians, Chinese, Japanese, African Americans and other compared populations. This is the first study conducted in the South Indian population with a larger sample size. The findings of our study provide the basic genetic information for further pharmacogenomic investigations in the population. [ABSTRACT FROM AUTHOR]

Variability in the physiological levels of neuroactive estrogens is widely believed to play a role in predisposition to several disorders of the central nervous system. Local biosynthesis of estrogens in the brain as well as their circulating serum levels are known to contribute to this pool of neuroactive steroids. It has been well accepted that estrogens modulate neuronal functions by affecting genesis, differentiation, excitability, and degeneration of nerve cells. These actions of estrogens appear to be more prominent in females with higher concentrations and marked variability of circulating serum levels occurring over a woman's lifetime. However, our knowledge regarding the variability of neuroactive steroid levels is very limited. Furthermore, several studies have recently reported differences in the synchronization of circulating and neuronal levels of estradiol. In the absence of reliable circulating steroid levels, knowledge of genetic variability in estrogen disposition may play a determining factor in predicting altered susceptibility or severity of neuropsychiatric disorders in women. Over the past decade, several genetic variants have been linked to both differential serum estrogen levels and predisposition to diverse types of neuropsychiatric disorders in women. Polymorphisms in genes encoding estrogen-metabolizing enzymes as well as estrogen receptors may account for this phenotypic variability. In this review, we attempt to show the contribution of genetics in determining estrogenicity in females with a particular emphasis on the central nervous system. This knowledge will further provide a driving force for unearthing the novel field of "Estrogen Pharmacogenomics." © 2010 Wiley-Liss, Inc., (Copyright © 2010 Wiley-Liss, Inc.)