Linda V. Koshy

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

BackgroundAlterations 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.MethodsWe 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.ResultsH313HTT 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.ConclusionBased 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.

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.

Risk Factors for Aneurysmal Subarachnoid Hemorrhage in an Indian Population

Background: Aneurysmal subarachnoid hemorrhage (aSAH) has a mortality rate as high as 50%. The prevalence of intracranial aneurysms from various parts of India varies from 0.75 to 10.3%, with higher numbers of cases being diagnosed due to the increasing age of the population and improvements in imaging techniques. However, little is known about the attributable risk factors of aSAH in the Indian population. Methods: Using a case-control study we estimated the risk of factors such as hypertension, cigarette smoking, alcohol consumption, diabetes mellitus and family history of aSAH in a South Indian population. The population-attributable risk (PAR) of smoking, hypertension and alcohol use was estimated for the South Indian as well as for the general Indian population. Results: Our results showed that cigarette smoking (OR, 3.59; p < 0.001) and a history of hypertension (OR, 2.98; p < 0.001) were significant risk factors associated with aSAH. When patients were classified by gender, it was observed that being a smoker and having hypertension increased the risk for aSAH by nearly fourfold in men. Among women, hypertension and older age were significant risk factors. The PAR estimates indicated that smoking (OR, 3.59; 95% CI, 2.13–6.06) and hypertension (OR, 2.98; 95% CI, 1.73–5.12) are significant risk factors. Conclusions: Hypertension and smoking may be causal risk factors which might also modify the effect of genetic factors that could increase susceptibility to aSAH in the Indian population. Since these risk factors are amenable to effective modification, our findings will be useful for a gender-specific management of aSAH.

Pathogenesis of intracranial aneurysm is mediated by proinflammatory cytokine TNFA and IFNG and through stochastic regulation of IL10 and TGFB1 by comorbid factors

BackgroundIntracranial aneurysm (IA) is often asymptomatic until the time of rupture resulting in subarachnoid hemorrhage (SAH).There is no precise biochemical or phenotype marker for diagnosis of aneurysm. Environmental risk factors that associate with IA can result in modifying the effect of inherited genetic factors and thereby increase the susceptibility to SAH. In addition subsequent to aneurismal rupture, the nature and quantum of inflammatory response might be critical for repair. Therefore, genetic liability to inflammatory response caused by polymorphisms in cytokine genes might be the common denominator for gene and environment in the development of aneurysm and complications associated with rupture.MethodsFunctionally relevant polymorphisms in the pro- and anti-inflammatory cytokine genes IL-1 complex (IL1A, IL1B, and IL1RN), TNFA, IFNG, IL3, IL6, IL12B, IL1RN, TGFB1, IL4, and IL10] were screened in radiologically confirmed 220 IA patients and 250 controls from genetically stratified Malayalam-speaking Dravidian ethnic population of south India. Subgroup analyses with genetic and environmental variables were also carried out.ResultsPro-inflammatory cytokines TNFA rs361525, IFNG rs2069718, and anti-inflammatory cytokine IL10 rs1800871 and rs1800872 were found to be significantly associated with IA, independent of epidemiological factors. TGFB1 rs1800469 polymorphism was observed to be associated with IA through co-modifying factors such as hypertension and gender. Functional prediction of all the associated SNPs of TNFA, IL10, and TGFB1 indicates their potential role in transcriptional regulation. Meta-analysis further reiterates that IL1 gene cluster and IL6 were not associated with IA.ConclusionsThe study suggests that chronic exposure to inflammatory response mediated by genetic variants in pro-inflammatory cytokines TNFA and IFNG could be a primary event, while stochastic regulation of IL10 and TGFB1 response mediated by comorbid factors such as hypertension may augment the pathogenesis of IA through vascular matrix degradation. The implication and interaction of these genetic variants under a specific environmental background will help us identify the resultant phenotypic variation in the pathogenesis of intracranial aneurysm. Identifying genetic risk factors for inflammation might also help in understanding and addressing the posttraumatic complications following the aneurismal rupture.

Role of Endothelial Nitric Oxide Synthase Gene Polymorphisms in Predicting Aneurysmal Subarachnoid Hemorrhage in South Indian Patients

Endothelial nitric oxide synthase (eNOS) gene polymorphisms have been implicated as predisposing genetic factors that can predict aneurysmal subarachnoid hemorrhage (aSAH), but with controversial results from different populations. Using a case-control study design, we tested the hypothesis whether variants in eNOS gene can increase risk of aSAH among South Indian patients, either independently, or by interacting with other risk factors of the disease. We enrolled 122 patients, along with 224 ethnically matched controls. We screened the intron-4 27-bp VNTR, the promoter T-786C and the exon-7 G894T SNPs in the eNOS gene. We found marked interethnic differences in the genotype distribution of eNOS variants when comparing the South Indian population with the reported frequencies from Caucasian and Japanese populations. Genotype distributions in control and patient populations were found to be in Hardy-Weinberg equilibrium. In patients, the allele, genotype and estimated haplotype frequencies did not differ significantly from the controls. Multiple logistic regression indicated hypertension and smoking as risk factors for the disease, however the risk alleles did not have any interaction with these risk factors. Although the eNOS polymorphisms were not found to be a likely risk factor for aSAH, the role of factors such as ethnicity, gender, smoking and hypertension should be evaluated cautiously to understand the genotype to phenotype conversion.

Lack of association of Endoglin insertion polymorphism in intracranial aneurysm in South Indian population

Background : Endoglin , is a component of transforming growth factor-β complex. It is involved in vascular development and structural maintenance of the vessel wall. Conflicting reports on the association of a six base insertion polymorphism in intron 7 of the endoglin gene in intracranial aneurysms (IA) have been reported earlier. materials and Methods: A case-control study was designed to compare 102 South Indian patients with intracranial saccular aneurysms and 118 ethnically and geographically matched healthy controls. The frequency of the six base insertion polymorphism was assessed by heteroduplex analysis followed by direct sequencing. Results: Insertion allele count was 39 (19.1%) of 204 alleles in the patient group and 42 (17.8%) of 236 alleles in the control group. The INS allele frequency was similar to the frequency in Caucasian population, but it was significantly lower than the Japanese population ( P =0.01). There was also no relationship of this polymorphism in patients with single aneurysm (33/176 alleles) or those with multiple aneurysms (6/28 alleles). Conclusion: Six base insertion polymorphism in Endoglin gene was not found to be a risk factor for intracranial saccular aneurysms in the South Indian population. Ethnic-related differences were observed. This is the first report on any genetic mutation in intracranial aneurysms in Indian population.

274 – Understanding treatment response and association of genotype phenotype correlates in schizophrenia from a population genetics viewpoint

Background: Schizophrenia is a debilitating psychiatric disorder. Nearly 6–7 million Indians suffer from this disorder. Research over the last three decades has led to a wide variety of loosely collected findings on genetic associations, neurochemical alterations, neuroimaging deficits, cognitive deficits and a host of environmental and social factors. From a therapeutic standpoint also the gains are modest. The main focus of treatment still remains symptomatic control of psychotic symptoms. Thus, the challenge is to provide a model for understanding schizophrenia that allows one to cut across several of the relevant dimensions and to move the therapeutics beyond just the symptomatic control of psychosis. We know that social and cultural traits do impact mental abilities. Various ecological and linguistic barriers further appends to cultural diversity, which can influence differential mental capabilities among different population groups in presenting a disease. Methods: In present study the role of socio-cultural relationship in causing schizophrenia and the genotype phenotype correlations of drug metabolizing enzymes, drug receptor and transporter polymorphisms has been evaluated. Genotype phenotype correlation has also been evaluated in relation to the symptomatic and medication history of the patients using BPRS-E rating scores. Results:We observe distinct shift in the LD patterns in different genes of responder and non-responder groups. 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. Conclusions:Our study suggests that population genetic parameters in relation to socio-cultural factors may help in precise understanding of genotype phenotype correlations in theranostics of schizophrenia.