Synergistic association of STX1A and VAMP2 with cryptogenic epilepsy in North Indian population

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

Gender Specific Association of RAS Gene Polymorphism with Essential Hypertension: A Case-Control Study

Renin-angiotensin system (RAS) polymorphisms have been studied as candidate risk factors for hypertension with inconsistent results, possibly due to heterogeneity among various genetic and environmental factors. A case-control association study was conducted to investigate a possible involvement of polymorphisms of three RAS genes: AGT M235T (rs699), ACE I/D (rs4340) and G2350A (rs4343), and AGTR1 A1166C (rs5186) in essential hypertensive patients. A total of 211 cases and 211 controls were recruited for this study. Genotyping was performed using PCR-RFLP method. The genotype and allele distribution of the M235T variant differed significantly in hypertensives and normotensives (OR-CI = 2.62 (1.24–5.76), P=0.006; OR-CI = 0.699 (0.518–0.943), P=0.018), respectively. When the samples were segregated based on sex, the 235TT genotype and T allele were predominant in the female patients (OR-CI = 5.68 (1.60-25.10), P=0.002; OR-CI = 0.522 (0.330–0.826), P=0.005) as compare to the male patients (OR-CI = 1.54 (1.24–5.76), P=0.34; OR-CI = 0.874 (0.330–0.826), P=0.506), respectively. For ACE DD variant, we found overrepresentation of “I”-allele (homozygous II and heterozygous ID) in unaffected males which suggest its protective role in studied population (OR-CI = 0.401 (0.224–0.718); P=0.0009). The M235T variant of the AGT is significantly associated with female hypertensives and ACE DD variant could be a risk allele for essential hypertension in south India

Genetic Variations of <i>PIP4K2A</i> Confer Vulnerability to Poor Antipsychotic Response in Severely Ill Schizophrenia Patients

<div><p>Literature suggests that disease severity and neurotransmitter signaling pathway genes can accurately identify antipsychotic response in schizophrenia patients. However, putative role of signaling molecules has not been tested in schizophrenia patients based on severity of illness, despite its biological plausibility. In the present study we investigated the possible association of polymorphisms from five candidate genes <i>RGS4</i>, <i>SLC6A3</i>, <i>PIP4K2A</i>, <i>BDNF</i>, <i>PI4KA</i> with response to antipsychotic in variably ill schizophrenia patients. Thus in present study, a total 53 SNPs on the basis of previous reports and functional grounds were examined for their association with antipsychotic response in 423 schizophrenia patients segregated into low and high severity groups. Additionally, haplotype, diplotype, multivariate logistic regression and multifactor-dimensionality reduction (MDR) analyses were performed. Furthermore, observed associations were investigated in atypical monotherapy (n = 355) and risperidone (n = 260) treated subgroups. All associations were estimated as odds ratio (OR) and 95% confidence interval (CI) and test for multiple corrections was applied. Single locus analysis showed significant association of nine variants from <i>SLC6A3</i>, <i>PIP4K2A</i> and <i>BDNF</i> genes with incomplete antipsychotic response in schizophrenia patients with high severity. We identified significant association of six marker diplotype ATTGCT/ATTGCT (rs746203-rs10828317-rs7094131-rs2296624-rs11013052-rs1409396) of <i>PIP4K2A</i> gene in incomplete responders (corrected p-value = 0.001; adjusted-OR = 3.19, 95%-CI = 1.46–6.98) with high severity. These associations were further observed in atypical monotherapy and risperidone sub-groups. MDR approach identified gene-gene interaction among <i>BDNF</i>_rs7103411-<i>BDNF</i>_rs1491851-<i>SLC6A3</i>_rs40184 in severely ill incomplete responders (OR = 7.91, 95%-CI = 4.08–15.36). While <i>RGS4</i>_rs2842026-<i>SLC6A3</i>_rs2975226 interacted synergistically in incomplete responders with low severity (OR = 4.09, 95%-CI = 2.09–8.02). Our findings provide strong evidence that diplotype ATTGCT/ATTGCT of <i>PIP4K2A</i> gene conferred approximately three-times higher incomplete responsiveness towards antipsychotics in severely ill patients. These results are consistent with the known role of phosphatidyl-inositol-signaling elements in antipsychotic action and outcome. Findings have implication for future molecular genetic studies as well as personalized medicine. However more work is warranted to elucidate underlying causal biological pathway.</p></div

Identification of regulatory potential of six marker haplotype using ENCODE data from UCSC genome browser.

<p>Identification of regulatory potential of six marker haplotype using ENCODE data from UCSC genome browser.</p

Demographic and clinical characteristics of schizophrenia cases (n = 482) and healthy controls (n = 230) enrolled in the study.

<p><b>Footnote:</b> SD, Standard deviation.</p>a<p>P-values were calculated by using two-tailed Student’s <i>t</i>-test.</p

Demographic and clinical features of schizophrenia patients who had completed 3-months follow-up (n = 423).

<p><b>Footnote:</b> LSG, Low Severity Group; HSG, High Severity Group; CR, Complete Responders; IR, Incomplete Responders; SD, Standard deviation; OR, Odds ratio; CI, Confidence interval.</p>a<p>Low severity ≤3 CGI-S and High severity ≥4 CGI-S.</p>b<p>early onset <25 yrs; late onset ≥25 yrs,</p>c<p>short duration <4 yrs; long duration ≥4yrs.</p>d<p>P-values were calculated by using Pearson’s χ²-test and^eP-values were calculated by using two-tailed Student’s <i>t</i>-test.</p

Multivariate logistic regression analysis with incomplete antipsychotic response in schizophrenia patients stratified by treatment.

<p>Footnote- OR, Odds ratio; ROC, Receiver operating characteristic; SE, Standard error; CI, Confidence interval.</p>a<p>Taken as continuous variable.</p>b<p>Significant p-value.</p

Interaction dendrogram generated from analysis of 53 polymorphisms by MDR method in patients with (A) low severity and (B) high severity of illness.

<p>A red or orange line indicates synergistic relationship; golden line represents additivity and blue or green shows redundancy. Short length arm of dendrogram indicates strong interaction. Footnote: MDR-Multifactor dimensionality reduction.</p