载脂蛋白E基因多态性与利培酮所致体质量降低的关联研究
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摘要
目的:探讨载脂蛋白E(apolipoprotein E,APOE)基因多态性与精神分裂症(schizophrenia,SZ)患者抗精神病药物治疗所致体质量变化的关联。方法:调查并随访1 516例首发SZ患者使用利培酮、阿立哌唑、喹硫平、氯氮平、奥氮平、奋乃静治疗2至7周后的体质量变化。使用TaqMan基因分型技术检测APOE基因多态性,应用Cox比例风险模型分析APOE基因变异与SZ患者药物治疗所致体质量变化之间的关系。结果:研究结果显示,在使用利培酮药物治疗患者中,rs7412位点相加模型增加体质量降低风险,HR(95%CI)为1.78(1.01-3.14),P=0.045。在使用利培酮药物治疗患者中,rs405509位点AC/CC基因型携带者相比AA基因携带者体质量降低的风险升高,HR(95%CI)为1.75(1.02-2.98),P=0.04。在除利培酮以外的其他药物治疗患者中,未发现rs769450,rs7412和rs405509不同基因型(相加模型、显性模型和隐性模型)与体质量增加、体质量降低的发生风险存在统计学关联,P值均>0.05。分层分析结果显示,在基线体质量正常组以及基线体质量超重或肥胖中,rs7412和rs405509不同基因型(相加模型、显性模型和隐性模型)与体质量降低的发生风险无异质性,P值均>0.05。结论:APOE基因rs7412和rs405509位点变异增加了SZ患者服用利培酮所致体质量降低的风险;临床应关注基线体质量正常患者APOE基因rs7412 C>T、rs405509A>C变异与利培酮所致体质量降低。
AIM: To explore the association between apolipoprotein E(APOE) gene polymorphisms and weight change in schizophrenia(SZ) patients induced by antipsychotic treatment. METHODS: 1 516 first-episode SZ patients treated with risperidone, aripiprazole, quetiapine, clozapine, olanzapine and perphenazine for 2 to 7 weeks were followed up. TaqMan genotyping technique was used to detect APOE gene polymorphisms. Cox regression was used to analysis the association between APOE gene variation and risk of weight change induced by drug treatment in SZ patients. RESULTS:The results showed that rs7412 increased the risk of weight loss in patients treated with risperidone, HR(95% CI) was 1.78(1.01-3.14) with P=0.045. In patients treated with risperidone, the risk of weight loss was higher in carriers of AG/GG genotype of rs405509 than in carriers of AA genotype, HR(95% CI) was 1.75(1.02-2.98), P value was 0.04. In SZ patients treated with other antipsychotic drugs, the associations between rs769450, rs7412 and rs405509 genotypes(additive model, dominant model and recessive model) with weight change were not found. There was no statistical association; all the P values were more than 0.05. Stratified analysis showed that there was no heterogeneity between rs7412 and rs405509 genotypes(additive model, dominant model and recessive model) and the risk of weight loss in baseline normal weight group and baseline overweight or obesity group(P>0.05). CONCLUSION: rs7412 and rs405509 of APOE increase the risk of weight loss in SZ patients treated by risperidone. Clinician should pay more attention to association between APOE gene rs7412 C>T, rs405509 A>C variations and risperidone-induced weight loss in normal body weight patients.
AIM: To explore the association between apolipoprotein E(APOE) gene polymorphisms and weight change in schizophrenia(SZ) patients induced by antipsychotic treatment. METHODS: 1 516 first-episode SZ patients treated with risperidone, aripiprazole, quetiapine, clozapine, olanzapine and perphenazine for 2 to 7 weeks were followed up. TaqMan genotyping technique was used to detect APOE gene polymorphisms. Cox regression was used to analysis the association between APOE gene variation and risk of weight change induced by drug treatment in SZ patients. RESULTS:The results showed that rs7412 increased the risk of weight loss in patients treated with risperidone, HR(95% CI) was 1.78(1.01-3.14) with P=0.045. In patients treated with risperidone, the risk of weight loss was higher in carriers of AG/GG genotype of rs405509 than in carriers of AA genotype, HR(95% CI) was 1.75(1.02-2.98), P value was 0.04. In SZ patients treated with other antipsychotic drugs, the associations between rs769450, rs7412 and rs405509 genotypes(additive model, dominant model and recessive model) with weight change were not found. There was no statistical association; all the P values were more than 0.05. Stratified analysis showed that there was no heterogeneity between rs7412 and rs405509 genotypes(additive model, dominant model and recessive model) and the risk of weight loss in baseline normal weight group and baseline overweight or obesity group(P>0.05). CONCLUSION: rs7412 and rs405509 of APOE increase the risk of weight loss in SZ patients treated by risperidone. Clinician should pay more attention to association between APOE gene rs7412 C>T, rs405509 A>C variations and risperidone-induced weight loss in normal body weight patients.
引文
[1]许梦蓓,单纯烁,郑国庆.精神疾病治疗进展(一):精神分裂症[J].医药导报,2017,36(10):1133-1137.
[2]李申.抗精神病药引发体重和糖脂代谢改变的动态观察及相关基因关联性分析[D].天津:天津医科大学,2016.
[3]Alexander ST,Kattula D,Mannam P,et al.Risperidone induced benign intracranial hypertension leading to visual loss[J].Indian J Psychol Med,2016,38(3):249-251.
[4]Chen CH,Shyue SK,Hsu CP,et al.Atypical antipsychotic drug olanzapine deregulates hepatic lipid metabolism and aortic inflammation and aggravates atherosclerosis[J].Cell Physiol Biochem,2018,50(4):1216-1229.
[5]刘小蕾,王志仁,周晨辉,等.奥氮平引起体质量增加的药理学机制研究进展[J].国际精神病学杂志,2015,42(5):65-68.
[6]Daray FM,Rodante D,Carosella LG,et al.-759C>Tpolymorphism of the HTR2C gene is associated with second generation antipsychotic-induced weight gain in female patients with schizophrenia[J].Pharmacopsychiatry,2017,50(1):14-18.
[7]Schrder C,Czerwensky F,Leucht S,et al.Fat mass and obesity-related gene variants rs9939609 and rs7185735 are associated with second-generation antipsychotic-induced weight gain[J].Pharmacopsychiatry,2019,52(1):16-23.
[8]Hatziri A,Kalogeropoulou C,Xepapadaki E,et al.Site-specific effects of apolipoprotein E expression on diet-induced obesity and white adipose tissue metabolic activation[J].Biochim Biophys Acta Mol Basis Dis,2018,1864(2):471-480.
[9]陶世武,杨诚,陈强,等.4种非典型抗精神病药物对精神分裂症患者血糖及血脂代谢的影响[J].广西医学,2009,31(9):1238-1241.
[10]王海燕.抗精神病药物对精神病患者血糖和血脂代谢的影响[J].临床医学研究与实践,2016,1(16):117.
[11]Poirier J.Apolipoprotein E in animal models of CNSinjury and in Alzheimer's disease[J].Trends Neurosci,1994,17(12):525-530.
[12]Schürhoff F,Krebs MO,Szake A,et al.Apolipoprotein E in schizophrenia:a French association study and meta-analysis[J].Am J Med Genet B Neuropsychiatr Genet,2003,119B(1):18-23.
[13]Gao J,Katagiri H,Ishigaki Y,et al.Involvement of apolipoprotein E in excess fat accumulation and insulin resistance[J].Diabetes,2007,56(1):24-33.
[14]国际生命科学学会中国办事处中国肥胖问题工作组联合数据汇总分析协作组.中国成人体质指数分类的推荐意见简介[J].中华预防医学杂志,2001,35(5):62-63.
[15]杨闯.氯氮平体内代谢机制的研究进展[J].国外医学.精神病学分册,2001,28(1):35-38.
[16]Tzouvelekis A,Pneumatikos I,Bouros D.Serum biomarkers in acute respiratory distress syndrome an ailing prognosticator[J].Respir Res,2005,6:62.
[17]Mc Evoy JP,Lieberman JA,Perkins DO,et al.Efficacy and tolerability of olanzapine,quetiapine,and risperidone in the treatment of early psychosis:a randomized,double-blind 52-week comparison[J].Am J Psychiatry,2007,164(7):1050-1060.
[18]伍海姗,赵丽萍,赵靖平,等.抗精神病药引起体质量增加的药物基因组学研究进展[J].中国新药与临床杂志,2013,32(7):507-512.
[19]王雪诗.BDNF基因多态性与抗精神病药导致体质量增加的关联研究[D].天津:天津医科大学,2017.
[20]张婷,张旭,汪昕,等.RABEP1基因与精神分裂症患者药物治疗所致体质量变化的关联分析[J].临床精神医学杂志,2017,27(6):377-381.
[21]李华芳.新型抗精神病药:利培酮[J].上海精神医学,1997,9(1):47-50.
[22]顾牛范,姚芳传.利培酮的国内临床应用概况[J].中华精神科杂志,2001,34(4):61-63.
[2]李申.抗精神病药引发体重和糖脂代谢改变的动态观察及相关基因关联性分析[D].天津:天津医科大学,2016.
[3]Alexander ST,Kattula D,Mannam P,et al.Risperidone induced benign intracranial hypertension leading to visual loss[J].Indian J Psychol Med,2016,38(3):249-251.
[4]Chen CH,Shyue SK,Hsu CP,et al.Atypical antipsychotic drug olanzapine deregulates hepatic lipid metabolism and aortic inflammation and aggravates atherosclerosis[J].Cell Physiol Biochem,2018,50(4):1216-1229.
[5]刘小蕾,王志仁,周晨辉,等.奥氮平引起体质量增加的药理学机制研究进展[J].国际精神病学杂志,2015,42(5):65-68.
[6]Daray FM,Rodante D,Carosella LG,et al.-759C>Tpolymorphism of the HTR2C gene is associated with second generation antipsychotic-induced weight gain in female patients with schizophrenia[J].Pharmacopsychiatry,2017,50(1):14-18.
[7]Schrder C,Czerwensky F,Leucht S,et al.Fat mass and obesity-related gene variants rs9939609 and rs7185735 are associated with second-generation antipsychotic-induced weight gain[J].Pharmacopsychiatry,2019,52(1):16-23.
[8]Hatziri A,Kalogeropoulou C,Xepapadaki E,et al.Site-specific effects of apolipoprotein E expression on diet-induced obesity and white adipose tissue metabolic activation[J].Biochim Biophys Acta Mol Basis Dis,2018,1864(2):471-480.
[9]陶世武,杨诚,陈强,等.4种非典型抗精神病药物对精神分裂症患者血糖及血脂代谢的影响[J].广西医学,2009,31(9):1238-1241.
[10]王海燕.抗精神病药物对精神病患者血糖和血脂代谢的影响[J].临床医学研究与实践,2016,1(16):117.
[11]Poirier J.Apolipoprotein E in animal models of CNSinjury and in Alzheimer's disease[J].Trends Neurosci,1994,17(12):525-530.
[12]Schürhoff F,Krebs MO,Szake A,et al.Apolipoprotein E in schizophrenia:a French association study and meta-analysis[J].Am J Med Genet B Neuropsychiatr Genet,2003,119B(1):18-23.
[13]Gao J,Katagiri H,Ishigaki Y,et al.Involvement of apolipoprotein E in excess fat accumulation and insulin resistance[J].Diabetes,2007,56(1):24-33.
[14]国际生命科学学会中国办事处中国肥胖问题工作组联合数据汇总分析协作组.中国成人体质指数分类的推荐意见简介[J].中华预防医学杂志,2001,35(5):62-63.
[15]杨闯.氯氮平体内代谢机制的研究进展[J].国外医学.精神病学分册,2001,28(1):35-38.
[16]Tzouvelekis A,Pneumatikos I,Bouros D.Serum biomarkers in acute respiratory distress syndrome an ailing prognosticator[J].Respir Res,2005,6:62.
[17]Mc Evoy JP,Lieberman JA,Perkins DO,et al.Efficacy and tolerability of olanzapine,quetiapine,and risperidone in the treatment of early psychosis:a randomized,double-blind 52-week comparison[J].Am J Psychiatry,2007,164(7):1050-1060.
[18]伍海姗,赵丽萍,赵靖平,等.抗精神病药引起体质量增加的药物基因组学研究进展[J].中国新药与临床杂志,2013,32(7):507-512.
[19]王雪诗.BDNF基因多态性与抗精神病药导致体质量增加的关联研究[D].天津:天津医科大学,2017.
[20]张婷,张旭,汪昕,等.RABEP1基因与精神分裂症患者药物治疗所致体质量变化的关联分析[J].临床精神医学杂志,2017,27(6):377-381.
[21]李华芳.新型抗精神病药:利培酮[J].上海精神医学,1997,9(1):47-50.
[22]顾牛范,姚芳传.利培酮的国内临床应用概况[J].中华精神科杂志,2001,34(4):61-63.