Kao A C C, Rojnic Kuzman M, Tiwari A K, Zivkovic M V, Chowdhury N I, Medved V, Kekin I, Zai C C, Lieberman J A, Meltzer H Y, Bozina T, Bozina N, Kennedy J L, Sertic J, Müller D J
Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Biological Sciences, University of Toronto, Scarborough, ON, Canada.
Department of Psychiatry, University Hospital Centre Zagreb, Zagreb School of Medicine, Croatia.
J Psychiatr Res. 2014 Jul;54:36-42. doi: 10.1016/j.jpsychires.2014.03.012. Epub 2014 Mar 21.
Weight gain and metabolic disturbances represent serious side-effects in antipsychotic (AP) treatment, particularly with clozapine and olanzapine. The methylenetetrahydrofolate reductase (MTHFR) gene is a key determinant in the folate metabolism and previous studies reported a significant effect on AP-induced weight gain and related metabolic abnormalities. Thus, we investigated MTHFR gene variants and changes in several important metabolic parameters in AP-treated patients. In this study, two functional MTHFR polymorphisms, rs1801133 (C677T) and rs1801131 (A1298C), were investigated for changes in weight and metabolic parameters. Genotypic associations were evaluated in a large population (n = 347 including 66 first episode psychosis, FEP patients) treated mostly with clozapine and olanzapine. We did not detect any genotypic association with weight changes (p > 0.05) in our total sample and in the sample refined for ancestry and medication. In our allelic analyses, we observed a trend for the 677-C allele to be associated with weight gain in the total sample (p = 0.03). This effect appeared to be driven by the FEP patients where those carrying the C-allele gained, on average, twice as much weight. Exploratory analyses revealed a significant association between the C677T and the A1298C polymorphism with HDL cholesterol serum levels in patients (p = 0.031). Overall we did not detect a major effect of two functional MTHFR gene variants and AP-induced weight gain. However, our findings suggest an effect of the C677T polymorphism in FEP patients and changes in weight and cholesterol levels. Further investigations in a larger sample are required.
体重增加和代谢紊乱是抗精神病药物（AP）治疗中严重的副作用，尤其是使用氯氮平和奥氮平治疗时。亚甲基四氢叶酸还原酶（MTHFR）基因是叶酸代谢的关键决定因素，先前的研究报道其对AP引起的体重增加及相关代谢异常有显著影响。因此，我们研究了接受AP治疗患者的MTHFR基因变异以及几个重要代谢参数的变化。在本研究中，我们调查了两种功能性MTHFR多态性，即rs1801133（C677T）和rs1801131（A1298C）在体重和代谢参数方面的变化。在一个主要使用氯氮平和奥氮平治疗的大样本群体（n = 347，包括66例首发精神病患者，即FEP患者）中评估了基因型关联。在我们的总样本以及根据血统和用药情况细化的样本中，未检测到与体重变化的任何基因型关联（p > 0.05）。在我们的等位基因分析中，我们观察到在总样本中677-C等位基因与体重增加相关的趋势（p = 0.03）。这种效应似乎是由FEP患者驱动的，携带C等位基因的患者平均体重增加了两倍。探索性分析显示，患者中C677T和A1298C多态性与高密度脂蛋白胆固醇血清水平之间存在显著关联（p = 0.031）。总体而言，我们未检测到两种功能性MTHFR基因变异对AP诱导的体重增加有主要影响。然而，我们的研究结果表明C677T多态性对FEP患者的体重和胆固醇水平有影响。需要在更大样本中进行进一步研究。
