Insig1 Insig2 Gene - Gene Interaction And Clozapine Metabolic Syndrome Related Research

Objectives:Metabolic syndrome (MetS) is an important risk factor for cardiovascular disease. Atypical antipsychopic clozapine can increase the risk of MetS. INSIG1 and INSIG2 are two insulin-induced gene isoforms, which designated encode two proteins that mediate feedback control of lipid metabolism. In this genetic case-control study, we analyze a large sample of patients with schizophrenia treated with atypical antipsychotic clozapine.1. to evaluate and compare the diagnostic criteria of MetS by International Diabetes Federation (IDF) and that by Chinese guidelines on prevention and treatment of dyslipidemia in adults;2. to investigate whether variation in the INSIG1 and INSIG2 is associated with MetS;3. to identify the impact of gene-gene interaction and gene-environment interaction between INSIG1, INSIG2 and treatment of clozapine on the risk of MetS.Methods:1. The study included 372 schizophrenia patients treated with clozapine.2. Four single nucleotide polymorphisms (SNPs) of the INSIG1 gene and eight SNPs of the INSIG2 gene were chosen as tagSNPs. These tagSNPs were genotyped by SNaPshot analysis.3. The gene-gene interaction was analyzed by Multifactor Dimensionality Reduction (MDR) software, and the gene-environment interaction was analyzed by General Multifactor Dimensionality Reduction (GMDR) software.Results:1. The rate of MetS was 42.74%(159/372) by IDF criteria and 37.90%(141/372) by Chinese criteria consecutively.2. In single-marker-based analysis, the INSIG1 rs9769826-GG homozygous genotype carriers had bigger waist circumference (P=0.002,P=0.022 after FDR correction). In addition, rs2161829-T of the INSIG2 gene significantly increased the risk of MetS (P=0.001, P=0.011 after FDR correction). Moreover, the haplotype which combined seven markers (rs1559509-rs10185316-rs2161829-rs889904-rs9308762-rs11123469- rs1352083) was significant, giving a global P=0.003.3. INSIG1 and INSIG2 interactions were found in the significant gene-gene interaction and gene-environment models (P<0.01).Conclusions:The MetS diagnostic criteria of IDF and that of Chinese guidelines on prevention and treatment of dyslipidemia in adults are in good accordance. The IDF-defined MetS was more closely associated with central obesity. The results suggest that the INSIG2 gene may be associated with MetS in patients treated with clozapine independently or in an interactive manner with INSIG1.