HTR2C Gene Polymorphisms and the Metabolic Syndrome in Patients With Schizophrenia

Abstract

In a previous study, we found an association between 5-hydroxytryptamine (serotonin) receptor 2C (HTR2C) polymorphisms and the occurrence of the metabolic syndrome in patients using antipsychotics. In the current study, we set out to replicate our findings in another sample of patients and to explore in a pooled analysis of both samples the influence of the effect of individual antipsychotics. Data for this cross-sectional study came from 2 different samples, the original sample (n = 112) and the replication sample (n = 164). Primary end point was the prevalence of the metabolic syndrome as classified by a modified version of the National Cholesterol Education Program's Adult Treatment Panel III. Primary determinants were polymorphisms in the promoter region of the HTR2C gene [HTR2C:c.1-142948(GT)n, rs3813929 (-759 C/T), and rs518147 (-697 G/C)] and an intragenic polymorphism (rs1414334:C>G). The variants of HTR2C:c.1-142948(GT)n (odds ratio [OR], 1.69; 95% confidence interval [CI], 0.75-3.81) and rs1414334 (OR, 2.35; 95% CI, 0.96-5.77) were not significantly associated with the metabolic syndrome in the replication sample but did show significance in the pooled analysis (OR, 2.09; 95% CI, 1.12-3.91; and OR, 2.35; 95% CI, 1.19-4.62, respectively). The variant rs1414334 C allele was specifically associated with the metabolic syndrome in patients using clozapine (OR, 9.20; 95% CI, 1.95-43.45) or risperidone (OR, 5.35; 95% CI, 1.26-22.83). This study extends previous findings to a larger sample of patients and implicates specific antipsychotic drugs. The increased risk for the metabolic syndrome is particularly strong in carriers of the rs1414334 C allele using clozapine or risperidone.

Association between HTR2C gene polymorphisms and the metabolic syndrome in patients using antipsychotics: a replication study

“…In our previous two studies, we used a slightly different set of criteria to diagnose the metabolic syndrome. 8,9 In those two studies, the metabolic syndrome was diagnosed when three or more of the following four metabolic criteria were met: waist circumference 4102 cm (male) or 488 cm (female), triglycerides X1.7 mmol l À1 , HDL cholesterol o1.0 mmol l…”

“…However, in western and northern Europeans, allele G appears to be the major allele, which is confirmed in our earlier research. 8,9 In the analysis we therefore considered the C-allele as the variant allele. For the Asians and Africans in our study, the variant rs1414334 allele would actually be the G-allele.…”

“…5 (rs1414334:C4G) and the metabolic syndrome in patients using antipsychotics in two previously reported studies. 8,9 In a cross-sectional study with 112 schizophrenic inpatients using antipsychotic drugs, we found an association between HTR2C polymorphisms and the metabolic syndrome. This association looked particularly strong in patients carrying the variant C-allele of the rs1414334 polymorphism (odds ratio (OR) 4.09; 95% confidence interval (CI) 1.41-11.89).…”

Gene–gene interactions of the INSIG1 and INSIG2 in metabolic syndrome in schizophrenic patients treated with atypical antipsychotics

“…11 They replicated the finding in a recent report and further demonstrated that, the increased risk for MetS, is particularly strong in carriers of the 5-hydroxytryptamine (serotonin) receptor 2C rs1414334 C allele using clozapine or risperidone. 12 Another study investigated association between methylenetetrahydrofolate reductase genetic variants and MetS in schizophrenic patients receiving AAPs and demonstrated that the methylenetetrahydrofolate reductase 677T allele is associated with a 3.6-fold greater risk for developing AAP-associated MetS and the 677TT genotype may place individuals at greater risk for insulin resistance with greater central adiposity. 13 Two insulin-induced gene (INSIG) isoforms, designated INSIG-1 and INSIG-2, are closely related proteins of the endoplasmic reticulum, encoded by individual gene (INSIG1 and INSIG2, respectively).…”

From evidence based medicine to mechanism based medicine. Reviewing the role of pharmacogenetics

“…The gene coding for the 5-HT2c receptor is an example of a drug targeting receptor with a relatively unknown phenotype. One of the suggested clinical phenotypes of the HTR2C gene is a function in regulation of food intake and weight gain but results are conflicting [18][19][20][21][22][23][24][25]. This pharmacodynamic polymorphism is one example of many others.…”