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Association of FTO, LEPR and MTHFR gene polymorphisms with metabolic syndrome in schizophrenia patients receiving antipsychotics 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. Crosssectional 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
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 number of reports on the association between schizophrenia and metabolic syndrome (MS), the latter 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 diagnosing 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 regarding 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 dopamine 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
10.2217/PGS.13.220 © 2014 Future Medicine Ltd
Pharmacogenomics (2014) 15(4), 477–485
Siti Norsyuhada Roffeei*1, Zahurin Mohamed1, Gavin P Reynolds2, Mas Ayu Said3, Ahmad Hatim4, Elsa Haniffah Mejia Mohamed1, Syarinaz Ahmad Aida4 & Nor Zuraida Zainal4 Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia 2 Biomedical Research Centre, Sheffield Hallam University, Sheffield, UK 3 Department of Social & Preventive 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 [email protected] 1
part of
ISSN 1462-2416
477
Research Article
Roffeei, Mohamed, Reynolds et al.
the T allele of HTR2C rs3813929 was found to be associated with protection against weight gain in Asians [18] and Caucasians [19], the A allele of LEP rs7799309 was associated with weight gain in Asians [20,21] and the G allele was associated with weight gain in Caucasians [19,22], suggesting that racial variations may underlie the difference. Hence, in this study, we aimed to identify which of the candidate SNPs are associated with the occurrence of MS within our multiethnic Asian population.
Materials & methods Patient recruitment A total of 206 schizophrenia patients aged between 18 and 65 years were recruited, each of whom fulfilled the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision [23], for the diagnosis of schizophrenia. The determination of MS was made on the basis of NCEP ATPIII criteria modified for Asian subjects [24]. MS is said to be present in an individual when at least three of the following criteria are met: abdominal obesity (waist circumference ≥90 cm in men and ≥80 cm in women); raised triglyceride levels (≥1.7 mmol/l); reduced HDL cholesterol level (
Association of FTO, LEPR and MTHFR gene polymorphisms with metabolic syndrome in schizophrenia patients receiving antipsychotics 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. Crosssectional 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
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 number of reports on the association between schizophrenia and metabolic syndrome (MS), the latter 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 diagnosing 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 regarding 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 dopamine 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
10.2217/PGS.13.220 © 2014 Future Medicine Ltd
Pharmacogenomics (2014) 15(4), 477–485
Siti Norsyuhada Roffeei*1, Zahurin Mohamed1, Gavin P Reynolds2, Mas Ayu Said3, Ahmad Hatim4, Elsa Haniffah Mejia Mohamed1, Syarinaz Ahmad Aida4 & Nor Zuraida Zainal4 Pharmacogenomics Laboratory, Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia 2 Biomedical Research Centre, Sheffield Hallam University, Sheffield, UK 3 Department of Social & Preventive 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 [email protected] 1
part of
ISSN 1462-2416
477
Research Article
Roffeei, Mohamed, Reynolds et al.
the T allele of HTR2C rs3813929 was found to be associated with protection against weight gain in Asians [18] and Caucasians [19], the A allele of LEP rs7799309 was associated with weight gain in Asians [20,21] and the G allele was associated with weight gain in Caucasians [19,22], suggesting that racial variations may underlie the difference. Hence, in this study, we aimed to identify which of the candidate SNPs are associated with the occurrence of MS within our multiethnic Asian population.
Materials & methods Patient recruitment A total of 206 schizophrenia patients aged between 18 and 65 years were recruited, each of whom fulfilled the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision [23], for the diagnosis of schizophrenia. The determination of MS was made on the basis of NCEP ATPIII criteria modified for Asian subjects [24]. MS is said to be present in an individual when at least three of the following criteria are met: abdominal obesity (waist circumference ≥90 cm in men and ≥80 cm in women); raised triglyceride levels (≥1.7 mmol/l); reduced HDL cholesterol level (
