NOS1AP Gene Variants and Their Role in Metabolic Syndrome: A Study of Patients with Schizophrenia.

Metabolic syndrome (MetS) is common among schizophrenia patients, and one of MetS's causes may be an imbalance in nitric oxide regulation. In this study, we examined associations of three polymorphic variants of the nitric oxide synthase 1 adapter protein (NOS1AP) gene with MetS in schizophrenia. NOS1AP regulates neuronal nitric oxide synthase, which controls intracellular calcium levels and may influence insulin secretion. The aim of the investigation was to study polymorphic variants of the NOS1AP gene as possible markers of MetS in patients with schizophrenia. A total of 489 Caucasian patients with schizophrenia (ICD-10) from Siberia (Russia) were included in the study, and 131 (26.8%) patients had MetS (IDF classification, 2007). The participants were genotyped for three single-nucleotide polymorphisms in NOS1AP (rs12143842, rs10494366, and rs12029454). Logistic regression was used for association analysis. Single-nucleotide polymorphisms, sex, and age served as covariates; the dependent variable was the coded parameter of the presence/absence of MetS. Polymorphisms rs12143842 and rs10494366 showed a stable association even after Bonferroni's correction for multiple comparisons (p = 0.005 and 0.002, respectively), indicating a statistically significant contribution of these polymorphic variants to the pathogenesis of MetS. Our results suggest that in patients with schizophrenia, NOS1AP may be involved in MetS pathophysiology.

The Role of Glutamatergic Gene Polymorphisms in the Clinical Phenotypes of Schizophrenia.

BACKGROUND: Personal variations in genetic risk for schizophrenia relate to its phenotypic heterogeneity-both in disorder development and clinical manifestations. Abnormal glutamatergic neurotransmitter system functioning is integrated in the pathogenesis of schizophrenia. METHODS: A sample of 805 Russian schizophrenia patients from the Siberian Federal region was investigated. We examined the association of 39 single nucleotide polymorphisms in eight genes (GRIN2A, GRIN2B, SLC1A2, SLC1A3, SLC17A7, GRM3, GRM7, and GRM8) involved in the glutamatergic system with the development of clinical heterogeneity of schizophrenia. The MassARRAY Analyzer 4 was used for genotyping. RESULTS: GRIN2A rs11644461, rs8057394 and GRIN2B rs7313149 are associated with the continuous type of schizophrenia. The GRIN2A rs8057394*G allele is a relative risk factor (p = 0.019) for developing the continuous type of schizophrenia. We found a nominally significant association between negative symptoms of schizophrenia and SLC17A7 rs62126236. The SLC17A7 rs62126236*T allele has a protective effect (p = 0.039) against predominant negative symptoms in schizophrenia. The total Positive and Negative Syndrome Scale (PANSS) scores were significantly associated with GRIN2A rs9788936 after adjusting for multiple testing (p = 0.001). CONCLUSIONS: In this study the contribution of the glutamatergic gene polymorphisms to the clinical heterogeneity of schizophrenia has been demonstrated.

Genes of the Glutamatergic System and Tardive Dyskinesia in Patients with Schizophrenia.

BACKGROUND: Tardive dyskinesia (TD) is an extrapyramidal side effect of the long-term use of antipsychotics. In the present study, the role of glutamatergic system genes in the pathogenesis of total TD, as well as two phenotypic forms, orofacial TD and limb-truncal TD, was studied. METHODS: A set of 46 SNPs of the glutamatergic system genes (GRIN2A, GRIN2B, GRIK4, GRM3, GRM7, GRM8, SLC1A2, SLC1A3, SLC17A7) was studied in a population of 704 Caucasian patients with schizophrenia. Genotyping was performed using the MassARRAY Analyzer 4 (Agena Bioscience™). Logistic regression analysis was performed to test for the association of TD with the SNPs while adjusting for confounders. RESULTS: No statistically significant associations between the SNPs and TD were found after adjusting for multiple testing. Since three SNPs of the SLC1A2 gene demonstrated nominally significant associations, we carried out a haplotype analysis for these SNPs. This analysis identified a risk haplotype for TD comprising CAT alleles of the SLC1A2 gene SNPs rs1042113, rs10768121, and rs12361171. Nominally significant associations were identified for SLC1A3 rs2229894 and orofacial TD, as well as for GRIN2A rs7192557 and limb-truncal TD. CONCLUSIONS: Genes encoding for mGlu3, EAAT2, and EAAT1 may be involved in the development of TD in schizophrenia patients.

The Gender-Specific Association of DRD2 Polymorphism with Metabolic Syndrome in Patients with Schizophrenia.

BACKGROUND: Metabolic syndrome is widespread in patients with schizophrenia receiving long-term antipsychotic therapy. Dopamine D2 receptors play an important role in mediating both the therapeutic actions of antipsychotics and their side effects. The present study examined the association of two polymorphisms of the DRD2 gene with metabolic syndrome in patients with schizophrenia. METHODS: We examined 517 patients from several regions of Siberia (Russia) with a clinical diagnosis of schizophrenia. Genotyping of two single nucleotide polymorphisms rs1799732 and rs4436578 of the dopamine D2 receptor gene (DRD2) was performed in a population of 471 patients. The results were analyzed using chi-square tests. RESULTS: Functional polymorphism rs1799732 of the DRD2 gene is associated with drug-induced metabolic syndrome in women with schizophrenia. CONCLUSIONS: Our results show that the DRD2 gene may be involved in the pathogenesis of metabolic disorders in patients with schizophrenia. Further analysis of possible genetic markers will allow for personalized treatment with minimal side effects and optimal efficacy. This which seems relevant in light of the recent focus on improving the quality of life and ensuring a high level of social adaptation of patients with schizophrenia.

Search for Possible Associations of FTO Gene Polymorphic Variants with Metabolic Syndrome, Obesity and Body Mass Index in Schizophrenia Patients.

PURPOSE: Metabolic syndrome (MetS) is characterized by abdominal obesity, hyperglycaemia, dyslipidaemia and hypertension. FTO gene has been implicated in the pathogenesis of obesity, but the available scientific data concerning their relationship to antipsychotic drug-induced obesity and metabolic syndrome is still incomplete and inconsistent, which indicates that continuing the investigation of this gene's role is necessary. PATIENTS AND METHODS: In the present study, 517 patients with schizophrenia underwent antipsychotic drug treatment, and two groups were identified: patients with MetS and without MetS. Genotyping of 6 SNPs in the FTO gene was performed, and the results analyzed using R-programme. RESULTS: We performed a statistical analysis to identify possible associations of the frequencies of genotypes and alleles of the studied polymorphisms with the presence of metabolic syndrome in schizophrenia patients, with the presence of abdominal obesity, and with an increased body mass index. The rs7185735 polymorphism did not meet the Hardy-Weinberg criterion and was excluded. After correcting for differences in age, gender and duration of illnesses, none of the variants was shown to be related to metabolic syndrome or abdominal obesity, but rs9939609, rs1421085, rs3751812 and rs8050136 were associated with body mass index. CONCLUSION: The present study provides additional support for these SNP's roles as a pharmacogenetic biomarker that may become useful in the framework of the personalized medicine approach.

Genetic Polymorphisms of 5-HT Receptors and Antipsychotic-Induced Metabolic Dysfunction in Patients with Schizophrenia.

BACKGROUND: Antipsychotic-induced metabolic syndrome (MetS) is a multifactorial disease with a genetic predisposition. Serotonin and its receptors are involved in antipsychotic-drug-induced metabolic disorders. The present study investigated the association of nine polymorphisms in the four 5-hydroxytryptamine receptor (HTR) genes HTR1A, HTR2A, HTR3A, and HTR2C and the gene encoding for the serotonin transporter SLC6A4 with MetS in patients with schizophrenia. METHODS: A set of nine single-nucleotide polymorphisms of genes of the serotonergic system was investigated in a population of 475 patients from several Siberian regions (Russia) with a clinical diagnosis of schizophrenia. Genotyping was performed and the results were analyzed using chi-square tests. RESULTS: Polymorphic variant rs521018 (HTR2C) was associated with higher body mass index in patients receiving long-term antipsychotic therapy, but not with drug-induced metabolic syndrome. Rs1150226 (HTR3A) was also associated but did not meet Hardy-Weinberg equilibrium. CONCLUSIONS: Our results indicate that allelic variants of HTR2C genes may have consequences on metabolic parameters. MetS may have too complex a mechanistic background to be studied without dissecting the syndrome into its individual (causal) components.

A comprehensive study revealed SNP-SNP interactions and a sex-dependent relationship between polymorphisms of the CYP2J2 gene and hypertension risk.

This study investigated whether common polymorphisms of cytochrome P450 2J2 (CYP2J2), a major enzyme that controls the biosynthesis of vasoactive epoxyeicosatrienoic acids, are collectively involved in the molecular basis of essential hypertension (EH). A total of 2314 unrelated Russian subjects from the Kursk (discovery sample: 913 EH patients and 645 controls) and Belgorod (replication sample: 345 EH patients and 411 controls) regions were recruited for this study. Eight single nucleotide polymorphisms (SNPs), including rs890293, rs11572182, rs10493270, rs1155002, rs2280275, rs7515289, rs11572325, and rs10889162, of CYP2J2 were genotyped using the MassARRAY 4 system and TaqMan-based assays. Significant associations were identified among the SNPs rs890293 (OR = 2.17, 95%CI 1.30-3.65), rs2280275 (OR = 1.59, 95%CI 1.10-2.37) and rs11572325 (OR = 1.89, 95%CI 1.22-2.95) and the risk of EH in females from the Kursk population. Sixteen CYP2J2 genotype combinations only showed significant associations with EH risk only in females. A common haplotype, T-T-G-C-C-C-T-A, increased the risk of EH in females. The bioinformatic analysis enabled identification of the SNPs that possess regulatory potential and/or are located within the binding sites for multiple transcription factors that play roles in the pathways involved in hypertension pathogenesis. Moreover, the polymorphisms rs890293, rs2280275, and rs11572325 were found to be significantly associated with hypertension risk in the Belgorod population. In conclusion, the rs2280275 and rs11572325 SNPs of CYP2J2 may be considered novel genetic markers of hypertension, at least in Russian women. However, sex-specific associations between CYP2J2 gene polymorphisms and hypertension require further investigation to clarify the specific genetic and/or environmental factors that are responsible for the increased disease susceptibility of women compared to that of men.

Frequencies of alleles, genotypes and haplotypes of two polymorphisms in the clusterin gene in the Russian elderly population categorized by cognitive performance.

This article contains data on the frequencies of alleles, genotypes and haplotypes of the single nucleotide polymorphisms (SNPs) rs2279590 and rs1532278 in the CLU gene in a cohort of normal elderly from the Russian population. The SNPs have been reported to be associated with Alzheimer's disease and cognitive functions in genome-wide and candidate genes association studies. Cognitive performance in sample set was estimated by the Montreal Cognitive Assessment (MoCA). The frequencies of alleles, genotypes and haplotypes of two SNPs were calculated in 3 groups: total sample set, sample set with MoCA score less than 21 (the first quartile) and group with MoCA score more than 24 (the fourth quartile).