Effect of 5-HT2C receptor gene polymorphism (HTR2C-759C/T) on metabolic adverse effects in Thai psychiatric patients treated with risperidone.

BACKGROUND: The use of Atypical antipsychotics (AAPs) is related to metabolic disturbances, which put psychiatric patients at risk for cardiovascular morbidity and mortality. Evidence is emerging of genetic risk factors. The HTR2C gene is an essential candidate in pharmacogenetic studies of antipsychotic-induced metabolic effects. Nevertheless, there were inconsistent results among studies. OBJECTIVE: To investigate the relationship between -759C/T, functional polymorphism of the HTR2C gene and metabolic adverse effects in Thai psychiatric patients treated with risperidone monotherapy. METHOD: In this cross-sectional study, 108 psychiatric patients treated with risperidone monotherapy for ≥3 months were recruited. Anthropometric measurements and laboratory tests were obtained upon enrollment and history of treatment was reviewed from medical records. Weight gain was defined as an increase ≥7% of baseline weight. Metabolic syndrome was evaluated according to the 2005 International Diabetes Federation (IDF) Asia criteria. The -759C/T, polymorphism was genotyped. The associations between -759C/T polymorphism and metabolic side effects were analyzed. Multiple logistic regression was used for determining potential confounders. RESULTS: Neither weight gain nor metabolic syndrome was significantly associated with -759C/T allelic and genotype variants of HTR2C. However, T allele of -759C/T polymorphism significantly associated with the hypertension. This association was not affected by possible confounding factors such as gender, risperidone dose, duration of treatment and family history of hypertension. CONCLUSION: Our findings suggest that psychiatric patients with T allele of -759C/T polymorphism may be at higher risk for hypertension. Further study with prospective design with larger patient groups are needed.

Associations of the SREBF2 Gene and INSIG2 Polymorphisms with Obesity and Dyslipidemia in Thai Psychotic Disorder Patients Treated with Risperidone.

BACKGROUND: Patients with psychotic disorders who receive atypical antipsychotic drugs often develop metabolic abnormalities. The sterol regulatory element-binding factor 2 (SREBF2) gene and insulin-induced gene (INSIG) have important roles in lipid metabolism. A previous study indicated that risperidone stimulated both lipogenesis and cholesterogenesis through activation of SREBP2 expression and inhibition of INSIG2. The SREBF2 gene and INSIG2 polymorphisms have been reported to be associated with metabolic abnormalities. OBJECTIVE: To investigate the association of the SREBF2 gene (rs1052717, rs2267439, and rs2267443) and INSIG2 (rs7566605, rs11123469, and rs17587100) polymorphisms and the presence of obesity and dyslipidemia in Thai psychotic disorder patients treated with risperidone. METHODS: All 113 psychiatric patients using risperidone were evaluated for their lipid profile and screened for obesity criteria. We genotyped the SREBF2 gene and INSIG2 polymorphisms using TaqMan real-time polymerase chain reaction. RESULTS: None of the studied SREBF2 gene and INSIG2 SNPs were associated with obesity in Thai psychotic disorder patients receiving risperidone. Nonetheless, the SREBF2 rs2267443 (G/A) A-allele carriers were at a higher risk for hypertriglyceridemia, whereas the INSIG2 rs11123469 (T/C) C-allele carriers had a lower risk for hypertriglyceridemia, after being adjusted for clinical characteristics using multiple logistic regression. CONCLUSIONS: Our findings suggest that the SREBF2 gene rs2267443 (G/A) and the INSIG2 rs11123469 (T/C) polymorphisms are associated with dyslipidemia in Thai psychotic disorder patients treated with risperidone. Further studies with prospective designs and larger patient groups are needed.

Association between polymorphisms of LEP, LEPR, DRD2, HTR2A and HTR2C genes and risperidone- or clozapine-induced hyperglycemia.

OBJECTIVE: To determine whether genetic polymorphisms related to pharmacodynamics with metabolic adverse effects, namely leptin promoter (LEP) rs7799039, leptin receptor rs1137101, dopamine D2 rs4436578, serotonin 5-HT2A rs6313, and serotonin 5-HT2C rs518147 and rs12836771, are associated with hyperglycemia induced by risperidone or clozapine in adult Thai patients with psychosis. METHODS: A total of 180 patients treated with risperidone-based (n=130) or clozapine-based (n=50) regimens were included in this study. Blood samples were analyzed for genotyping of the candidate genes and biochemical testing. Genotyping was performed by conducting a TaqMan real-time polymerase chain reaction-based analysis. RESULTS: The prevalence of hyperglycemia was higher in patients receiving clozapine (64.0%) than in those receiving risperidone (30.8%). Among the candidate genes, only the LEP rs7799039 polymorphism demonstrated a significant association with hyperglycemia (χ2=9.879, P=0.008) in patients treated with risperidone; patients with the AA genotype had the highest risk (41.1%), followed by those with AG (20.8%) and GG (0%) genotypes. Using the recessive genetic model (AA vs AG + GG), the odds ratio and 95% CI were 3.28 and 1.44 -7.50, respectively. None of the genes were associated with hyperglycemia in patients treated with clozapine. A binary logistic regression revealed that the LEP rs7799039 polymorphism demonstrated a significant association with hyperglycemia, independent of body-mass index (BMI) in patients receiving risperidone; the odds ratio (95% CI) was 3.188 (1.399-7.262), P=0.006. By contrast, none of the pharmacodynamic genetic factors, except for BMI, were significantly associated with hyperglycemia in patients receiving clozapine. CONCLUSION: The risk of type 2 diabetes mellitus is associated with the LEP rs7799039 polymorphism in Thai adults receiving risperidone but not in those receiving clozapine. Clarifying underlying mechanisms and risk of hyperglycemia provides an opportunity to prevent impaired glucose metabolism in patients receiving risperidone or clozapine.

Genetic polymorphisms of HTR2C, LEP and LEPR on metabolic syndromes in patients treated with atypical antipsychotic drugs.

OBJECTIVE: Single nucleotide polymorphisms in serotonin 2C receptor (HTR2C), leptin (LEP), and leptin receptor (LEPR) genes are reportedly associated with the presence of metabolic syndrome (MS). We investigated whether HTR2C:rs518147 (-697G/C), rs12836771 (A/G), LEP: rs7799039 (-2548G/A) and LEPR:rs1137101 (668A/G) are related to MS in psychotic disorder patients treated with atypical antipsychotics. METHODS: A cross-sectional study including 200 patients was conducted; genetic polymorphisms in HTR2C (rs518147 and rs12836771), LEP (rs7799039) and LEPR (rs1137101) were genotyped. The presence of MS was evaluated according to the 2005 International Diabetes Federation (IDF) Asia criteria. The associations of genetic factors with the presence of MS are analysed. KEY FINDINGS: Two SNPs in the HTR2C gene but not LEP and LEPR were associated with the presence of MS after adjustment for the combination of atypical antipsychotics. With respect to the effect of gender after treatment with risperidone and clozapine was statistically significant. Moreover, genotype combinations had no effect on MS. CONCLUSIONS: Therefore, HTR2C genetic variants may be involved in the susceptibility to MS in patients treated with atypical antipsychotics. Additionally, there was a gender effect in the presence of MS. No effect of LEP or LEPR polymorphisms or the combination of HTR2C-LEP and HTR2C-LEPR was observed for the presence of MS.