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Gene Interactions of the INSIG1 and INSIG2 in Metabolic Syndrome in Schizophrenic Patients Treated with Atypical Antipsychotics

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Gene Interactions of the INSIG1 and INSIG2 in Metabolic Syndrome in Schizophrenic Patients Treated with Atypical Antipsychotics The Pharmacogenomics Journal (2012) 12, 54–61 & 2012 Macmillan Publishers Limited. All rights reserved 1470-269X/12 www.nature.com/tpj ORIGINAL ARTICLE Gene–gene interactions of the INSIG1 and INSIG2 in metabolic syndrome in schizophrenic patients treated with atypical antipsychotics Y-J Liou1,2,3,8, YM Bai1,2,8, The use of atypical antipsychotics (AAPs) is associated with increasing the risk 4,5 6 6 of the metabolic syndrome (MetS), which is an important risk factor for E Lin , J-Y Chen , T-T Chen , cardiovascular disease and diabetes. Two insulin-induced gene (INSIG) 1,2,7 1,2 C-J Hong and S-J Tsai isoforms, designated INSIG-1 and INSIG-2 encode two proteins that mediate feedback control of lipid metabolism. In this genetic case–control study, we 1Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; 2Division of investigated whether the common variants in INSIG1 and INSIG2 genes were Psychiatry, School of Medicine, National Yang- associated with MetS in schizophrenic patients treated with atypical Ming University, Taipei, Taiwan; 3Institute of antipsychctics. The study included 456 schizophrenia patients treated with Clinical Medicine, School of Medicine, National 4 clozapine (n ¼ 171), olanzapine (n ¼ 91) and risperidone (n ¼ 194), for an Yang-Ming University, Taipei, Taiwan; Vita ± Genomics, Taipei, Taiwan; 5Graduate Institute of average of 45.5 27.6 months. The prevalence of MetS among all subjects Clinical Medical Science, China Medical was 22.8% (104/456). Two single-nucleotide polymorphisms (SNPs) of the University, Taichung, Taiwan; 6Department of INSIG1 gene and seven SNPs of the INSIG2 gene were chosen as haplotype- Psychiatry, Yuli Veterans Hospital, Yuli, Hualien, tagging SNPs. In single-marker-based analysis, the INSIG2 rs11123469-C Taiwan and 7Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan homozygous genotype was found to be more frequent in the patients with MetS than those without MetS (P ¼ 0.001). In addition, haplotype analysis Correspondence: showed that the C-C-C haplotype of rs11123469-rs10185316- rs1559509 Dr C-J Hong or Dr S-J Tsai, Department of of the INSIG2 gene significantly increased the risk of MetS (P ¼ 0.0023). Psychiatry, Taipei Veterans General Hospital, No significant associations were found between polymorphisms of INSIG1 No. 201, Shih-Pai Road, Sec. 2, Taipei 11217, Taiwan. gene and MetS, however, INSIG1 and INSIG2 interactions were found in the E-mail: [email protected] or significant 3-locus and 4-locus gene–gene interaction models (P ¼ 0.003 and [email protected] 0.012, respectively). The results suggest that the INSIG2 gene may be associated with MetS in patients treated with AAPs independently or in an interactive manner with INSIG1. The Pharmacogenomics Journal (2012) 12, 54–61; doi:10.1038/tpj.2010.74; published online 28 September 2010 Keywords: gene–gene interaction; insulin-induced gene 1; insulin-induced gene 2; antipsychotic; metabolic syndrome Introduction Metabolic syndrome (MetS) is a combination of risk factors, including weight gain, abdominal or visceral adiposity, dyslipidemia and elevated plasma glucose that increase the risk of developing cardiovascular disease and diabetes. 8 These authors contributed equally to this Individuals with schizophrenia are a high-risk group for MetS due to genetic work. predisposition, medication effects and lifestyle.1,2 Regarding the medication effects, the increased risk to develop MetS under atypical antipsychotic (AAP) Received 7 February 2010; revised 18 August 2010; accepted 26 August 2010; agents, such as clozapine or olanzapine, have been a major concern for the published online 28 September 2010 treatment of schizophrenia.3 In a study of MetS in first-episode patients with INSIGs and metabolic syndrome Y-J Liou et al 55 schizophrenia treated with typical or AAPs, it was found SCAP have a crucial role in feedback regulation of lipid that, at first episode, there was no difference in the metabolism.17 In addition of lipid metabolism, Herbert et prevalence of MetS between the historical and the current al., in a genome-wide association study, demonstrated a cohort.4 However, rates of MetS increased over time in both genetic variant (rs7566605) situated 10-kb upstream of the groups, but patients treated with AAPs had a three times transcription start site of INSIG2 was associated with obesity higher incidence rate of MetS (odds ratio 3.6). In another that was replicated by several replication studies, though study of 3-month follow-up of female patients with schizo- not by all.18 phrenia treated with AAPs, it was found, at baseline, 15% From the above findings, INSIG proteins may be impli- fulfilled criteria for MetS, and, after 3 months of treatment, cated in the pathogenesis of MetS in patients treated 27% fulfilled criteria for MetS.5 Recently, Correll et al. with AAPs. Skelly et al. conducted the first study on the investigated patients with bipolar disorder or schizophrenia association of INSIG2 genetic variation and BMI in 756 patients treated with AAPs.6 They found both bipolar schizophrenia patients before and after 18-month Clinical disorder and schizophrenia patients had comparable and Antipsychotics Trials of Intervention Effectiveness (CATIE) high rates of MetS (43.2 and 45.9%, respectively). The phase 1A trail consisting of four AAPs: olanzapine, risper- pathogenesis underlying AAP-related MetS is still unknown idone, quetiapine and ziprasidone.19 Most of the partici- but some risk factors such as patients older than 50 years, pants in CATIE study were European, African, Spanish, higher body mass index (BMI) at initiation of antipsychotic Hispanic and Latino origins. However, they could not treatment, BMI increase after initiation of antipsychotic observe an association between INSIG2-rs7566605 and the treatment, duration of antipsychotic drug exposure, and baseline BMI or BMI change across all CATIE phase 1A those taking clozapine or multiple antipsychotics have been treatment. A later study consisted of 160 German patients reported.7–9 with clozapine treatment for 12.0±1.2 weeks.20 Although During the past decade, dramatic advances in molecular they also did not observe the association of rs7566605, they biology have led to the modern era of pharmacogenetics, found an association between three SNPs (rs17587100, with variability in drug response, which includes both rs10490624 and rs17047764) localized with or near INSIG2 therapeutic and adverse effect, attributed to genetic factors gene and clozapine-related BMI changes.20 The two studies discovered in different populations. The identification of yielded divergent results. Furthermore there was no report the genetic variants that influence drug-related adverse regarding the association of INSIG1 or INSIG2 genetic effect may help pre-treatment selection and development variations with body weight changes or MetS in patients of drugs that are safe for individual patients on the basis treated with AAP in Oriental population. In the present of their idiosyncratic pharmacogenetic profile.10 Currently, study, we hypothesized that the INSIG1 or INSIG2 genes may there are three reports of pharmacogenetic studies of be associated with MetS in schizophrenic patients treated antipsychotic-related MetS. In 2007, Mulder et al. first with AAPs. Thus we conducted a case–control study in demonstrated that genetic variants in 5-hydroxytryptamine Chinese population to investigate the relationship between (serotonin) receptor 2C is associated with MetS in patients the genetic variants in INSIG1 or INSIG2 and risk of MetS. with schizophrenia.11 They replicated the finding in a recent We also determined whether significant gene–gene inter- report and further demonstrated that, the increased risk for actions exist between these two genes in affecting MetS, MetS, is particularly strong in carriers of the 5-hydroxy- using a novel algorithm called generalized multifactor tryptamine (serotonin) receptor 2C rs1414334 C allele using dimensionality reduction (GMDR) method, an extension clozapine or risperidone.12 Another study investigated of the MDR method.21 association between methylenetetrahydrofolate reductase genetic variants and MetS in schizophrenic patients receiv- ing AAPs and demonstrated that the methylenetetrahydro- Materials and methods folate reductase 677T allele is associated with a 3.6-fold greater risk for developing AAP-associated MetS and the Subjects and measurements 677TT genotype may place individuals at greater risk for This study was approved by the Ethnic Review Committee of insulin resistance with greater central adiposity.13 Yuli Veterans Hospital and was carried out in accordance Two insulin-induced gene (INSIG) isoforms, designated with the principles of the Declaration of Helsinki. Informed INSIG-1 and INSIG-2, are closely related proteins of the consent was obtained from all subjects before commence- endoplasmic reticulum, encoded by individual gene ment. This study was conducted in the largest psychiatric (INSIG1 and INSIG2, respectively).14,15 In the mouse, an hospital in Taiwan, which has approximately 2500 inpati- integrating quantitative trait loci and high-density single- ents. As our previous report,8 patients selected for the study nucleotide polymorphism (SNP) analyses identified INSIG2 had used clozapine, olanzapine or risperidone for at least 3 as a strong susceptibility gene for plasma cholesterol months for treatment of schizophrenia, as diagnosed levels.16 INSIG proteins block the processing
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