477 ISSN 1462-2416 10.2217/PGS.13.220 © 2014 Future Medicine Ltd Pharmacogenomics (2014) 15(4), 477–485 ReseaRch aRticle Association of FTO , LEPR and MTHFR gene polymorphisms with metabolic syndrome in schizophrenia patients receiving antipsychotics Patients who receive long-term treatment with antipsychotics (APs) frequently gain weight, especially so with certain atypical APs [1–3] , and this can lead to development of obesity, glucose intolerance, diabetes and cardiovascular disease (CVD) [4] . There have been an increased num- ber of reports on the association between schizo- phrenia and metabolic syndrome (MS), the lat- ter being an accumulation of risk factors such as increased waist circumference, hypertension, decreased high-density lipoprotein (HDL), and raised triglycerides and glucose levels [5–9] . A study conducted in Malaysia reported that the modified National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII) criteria are more effective in diagnos- ing MS within our population as compared with the International Diabetes Federation criteria. The latter may miss patients that are identified by using the NCEP ATPIII, especially regard- ing lower BMI and lower waist circumference, but with more severe increase in blood pressure and glucose and triglyceride levels [10] . Therefore in our study, the NCEP ATPIII was used to diagnose MS. Second-generation APs, or atypical APs, are favored because of their beneficial effect in reducing extrapyramidal side effects and negative symptoms, this benefit being absent with typical APs such as haloperidol. This difference is hypothesized to be owing to the different binding sites of the two generations, the typical APs mostly targeting the dopa- mine receptor and the atypical APs targeting the serotonin receptor [11] . Although weight gain can occur upon treatment with typical APs such as chlorpromazine [12] , this problem appears to be more pronounced in patients taking atypical APs. However, some patients who have been taking atypical APs do not gain weight and this difference is thought to be due to underlying genetic factors [13] , although the exact mechanism has yet to be determined. Previous literature has reported associations of several SNPs in various genes with AP-induced weight gain [11] , obesity [14] and MS [15] . MS in particular has been studied in schizophrenia patients since 2003, with an increasing number of studies being published since [16] . Among the genes that have been studied are the following: ADIPOQ, ADRA2A, BDNF, FTO, HTR2A, HTR2C, LEP, LEPR, MC4R, MTHFR and PMCH [17] . These genes have been associated with either AP-induced weight gain, obesity or MS in studies that were mainly performed in European and Asian populations [17] . Although Aim: The occurrence of metabolic syndrome (MS) in schizophrenia patients receiving long-term antipsychotics (APs) contributes to their high mortality rate. We aimed to determine whether genetic polymorphisms of identified candidate genes are associated with MS in our study population. Materials & methods: We recruited 206 schizophrenia patients receiving AP treatment for at least a year. Cross- sectional measurements of weight, height, blood pressure, waist and hip circumference, and other lipid profiles were recorded. Patient DNA was genotyped for 16 candidate gene polymorphisms. Results: Of these patients, 59.7% were found to have MS while 40.3% did not. All metabolic parameters were significantly different between the two groups. Only three of the 16 polymorphisms studied showed significant association with MS; rs9939609 of the FTO gene confers risk for MS (odds ratio [OR]: 1.73, 95% CI: 1.07–2.78, p = 0.026), while rs1137101 of the LEPR gene (OR: 0.47, 95% CI: 0.28–0.80, p = 0.005) and rs1801133 of the MTHFR gene (OR: 0.59, 95% CI: 0.35–0.99, p = 0.049) are protective against MS. Conclusion: Polymorphisms of the FTO, LEPR and MTHFR genes may play a role in MS in Malaysian schizophrenia patients receiving long-term treatment with APs. Original submitted 29 July 2013; Revision submitted 28 October 2013 KEYWORDS: antipsychotics n FTO rs9939609 n LEPR rs1137101 n metabolic syndrome n MTHFR rs1801133 n schizophrenia Sit Norsyuhada Rofeei* 1 , Zahurin Mohamed 1 , Gavin P Reynolds 2 , Mas Ayu Said 3 , Ahmad Hatm 4 , Elsa Hanifah Mejia Mohamed 1 , Syarinaz Ahmad Aida 4 & Nor Zuraida Zainal 4 1 Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia 2 Biomedical Research Centre, Shefeld Hallam University, Shefeld, UK 3 Department of Social & Preventve Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia 4 Department of Psychological Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia *Author for correspondence: Tel.: +60 17 6191086 Fax: +60 3 79674791 rofeeirahim@gmail.com part of