【作者】 曹海燕；

【导师】 李洁；

【作者基本信息】 天津医科大学 ， 临床医学（专业学位）， 2021， 博士

【摘要】 目的:近年来,抗精神病药物导致的QTc间期延长(Antipsychotic-induced QTc interval prolongation,AIQTIP)得到了越来越多的关注。目前关于抗精神病药物导致QTc间期延长发生率、影响因素及相关基因的研究大多是关于白种人群的,关于亚洲人群的研究很少,关于中国人群的研究则更少。我们分别以首次系统治疗的精神分裂症患者和住院治疗的慢性精神分裂症患者为研究对象研究精神分裂患者QTc间期延长的发生率以及相关影响因素,并研究了中国精神分裂症患者QTc间期延长的相关基因。方法:(1)本研究以首次系统治疗的精神分裂症患者和慢性精神分裂症患者为研究对象,首次系统治疗的精神分裂症患者均采用单一非典型抗精神病药物(Atypical antipsychotic drugs,AAPD)治疗4周。共入组首次系统治疗的精神分裂症患者203例,并收集性别和年龄匹配的健康对照组505例。共入组住院治疗的慢性精神分裂症患者436例,并收集性别和年龄匹配的健康对照组291例。收集所有患者的人口学资料、临床信息、血液学指标,并进行相关量表评分。(2)入组首次系统治疗精神分裂症患者203例,均接受单一AAPD治疗4周,比较治疗前基线心电图数据和健康对照组心电图数据,研究首次系统治疗精神分裂症患者基线QTc间期延长发生率,并探讨基线QTc间期与人口学资料、临床特征、代谢指标的关系,分析基线QTc间期延长的可能影响因素。经过单一AAPD治疗4周后,比较治疗前后QTc间期的变化,计算治疗4周后QTc间期延长的发生率。(3)入组的203例首次系统治疗精神分裂症患者中,共有153例患者完成了4周单一AAPD治疗并复查了4周心电图,153例患者中有112例患者完成了基因分型。我们在8个与代谢密切相关的候选基因中筛选出10个SNP位点,分别为:rs1137101(LEPR),rs7732687(EPB41L4A),rs7799039(LEP),rs6265(BDNF),rs7141420(NRXN3),rs9939609(FTO),rs1558902(FTO),rs6567160(MC4R),rs489693(MC4R)和rs4680(COMT)。研究首次系统治疗的精神分裂症患者AIQTIP与代谢相关基因位点的关系。(4)入组住院治疗慢性精神分裂症患者436例,并收集性别和年龄匹配的健康对照组291例,分析慢性精神分裂症患者QTc间期延长的发生率,并探讨QTc间期延长与人口学资料、临床特征、代谢指标和抗精神病药物治疗的关系,分析慢性精神分裂症患者QTc间期延长的可能影响因素。精神分裂症患者和健康对照组QTc间期比较采用两个独立样本t检验,QTc间期延长发生率比较采用χ~2检验。精神分裂症患者治疗前后QTc间期比较采用配对样本t检验。采用Pearson和Spearman相关分析进行相关分析,并采用二元Logisitic回归分析和多元线性回归分析慢性精神分裂症患者QTc间期延长的可能危险因素。候选基因关联分析采用PLINK统计软件进行统计分析,使用线性回归模型分析所选SNPs和表型之间的关联,以治疗4周后QTc间期的变化作为表型。对全部患者、男性患者、女性患者分别使用PLINK进行基因-基因交互作用分析。结果:1、与性别和年龄匹配的健康对照组比较,首次系统治疗的精神分裂症患者基线心率较健康对照组快(P=0.000),基线QTc间期较对照组长(P=0.018)。2、首次系统治疗的精神分裂症患者基线心电图QTc间期延长发生率为5.91%,健康对照组QTc间期延长发生率为2.38%,精神分裂症患者基线心电图QTc间期延长发生率较健康对照组高(P=0.019)。3、Pearson和Spearman相关分析表明,首次系统治疗精神分裂症患者基线QTc间期与以下变量之间存在相关:性别(P=0.021)、年龄(P=0.001)、BMI(P=0.039)、FPG(P=0.017)、CHOL(P=0.009)、首发年龄(P=0.036)、LDL(P=0.006)。多元线性回归分析显示FPG(β=0.163,t=2.261,P=0.025)仍与QTc间期相关,FPG可能是首次系统治疗的精神分裂症患者基线QTc间期延长的可能危险因素。4、首次系统治疗的精神分裂症患者经过单一AAPD治疗4周后QTc间期较基线延长(P=0.018),男性患者治疗前后QTc间期比较,差异无统计学意义(P=0.278),女性患者治疗4周后QTc间期延长(P=0.047)。5、候选基因关联分析结果显示,在所有患者中EPB41L4A基因的SNP rs7732687和AIQTIP之间存在显著关联(P=0.042)。在男性患者中,EPB41L4A基因的SNP rs7732687和AIQTIP之间存在显著关联(P=0.034)。在女性患者中,LEP基因的SNP rs7799039与AIQTIP之间存在显著关联(P=0.004)。QTc间期变化(ΔQTc)基因×基因交互作用定量分析显示,在全部患者中,NRXN3基因和FTO基因、FTO基因和COMT基因等基因位点之间存在交互作用,与AIQTIP相关;在男性患者中,LEP基因和NRXN3基因、FTO基因和NRXN3基因等基因位点之间存在交互作用,与AIQTIP相关;在女性患者中,NRXN3基因和COMT基因、FTO基因和COMT基因等基因位点之间存在交互作用,与AIQTIP相关。6、慢性精神分裂症患者与年龄和性别匹配的健康对照组比较,精神分裂症患者心率快(P=0.000),QTc间期长(P=0.000)。慢性精神分裂症患者QTc间期延长的发生率为8.26%,其中女性患者QTc间期延长的发生率为12.24%,男性患者QTc间期延长的发生率为6.23%,女性患者QTc间期延长的发生率较男性高(P=0.031)。男女患者QTc间期比较,女性患者QTc间期长(P=0.004)。7、将慢性精神分裂症患者按照QTc间期是否延长分为QTc间期延长组和QTc间期不延长组。QTc间期延长在有精神疾病家族史的患者中更为常见(P=0.031)。两组患者比较,QTc间期延长组患者的认知损害因子评分高(P=0.019),LDL水平低(P=0.007),TP水平低(P=0.035)。二元Logistic回归分析结果显示:住院次数(Waldχ~2=6.267,OR=1.042,P=0.012),认知损害因子评分(Waldχ~2=5.500,OR=1.130,P=0.019)和LDL(Waldχ~2=4.179,OR=0.549,P=0.041)与QTc延长相关。在控制年龄混杂因素的影响后,住院次数(Waldχ~2=6.356,OR=1.042,P=0.012),认知损害因子评分(Waldχ~2=5.002,OR=1.126,P=0.025)和LDL(Waldχ~2=4.323,OR=0.542,P=0.038)仍与QTc间期延长相关。8、Pearson和Spearman相关分析表明,慢性精神分裂症患者QTc间期与以下变量之间存在相关:性别(P=0.004)、年龄(P=0.000)、病程(P=0.001)、住院次数(P=0.011)、PANSS总分(P=0.001)、认知损害因子评分(P=0.002)、兴奋敌对因子评分(P=0.006)、抑郁焦虑因子评分(P=0.024)、FPG(P=0.022)。多元线性回归分析显示年龄(β=0.238,t=2.687,P=0.008)、多种抗精神病药物联合治疗(β=0.118,t=2.005,P=0.046)、PANSS总分(β=0.128,t=2.325,P=0.021)和LDL(β=-0.112,t=-2.036,P=0.043)仍与QTc间期相关,其中LDL与QTc间期呈负相关。结论:1、首次系统治疗的精神分裂症患者基线QTc间期较性别和年龄匹配的健康对照组长,心率较健康对照组快。首次系统治疗的精神分裂症患者基线心电图QTc间期延长发生率高于健康对照组。2、首次系统治疗的精神分裂症患者接受单一AAPD治疗4周后心电图QTc间期较基线延长。3、空腹血糖可能是首次系统治疗的精神分裂症患者基线QTc间期延长的危险因素。4、EPB41L4A基因和LEP基因与抗精神病药物导致的QTc间期延长存在显著相关。在男性患者中,EPB41L4A基因SNP rs7732687和AIQTIP之间存在显著关联。在女性患者中,LEP基因的SNP rs7799039与AIQTIP之间存在显著关联。5、住院治疗的慢性精神分裂症患者心率较性别和年龄匹配的健康对照组快,QTc间期较健康对照组长。住院治疗的慢性精神分裂症患者QTc间期延长的发生率为8.26%,男性患者的QTc间期延长发生率为6.23%,女性患者的QTc间期延长发生率为12.24%,女性慢性精神分裂症患者AIQTIP的发生率较男性患者高。6、一些人口统计学特征和临床特征可能是慢性精神分裂症患者发生QTc间期延长的危险因素,其中包括高龄、住院次数较多、LDL水平较低、PANSS认知损害因子评分较高、PANSS总分较高以及使用多种抗精神病药物联合治疗。7、LDL可能是慢性精神分裂症患者发生AIQTIP的一个保护性因素。更多还原

【Abstract】 Objective:In recent years,antipsychotic-induced QTc interval prolongation(AIQTIP)has attracted more and more attention.At present,most of the studies on the prevalence,risk factors and related genes of AIQTIP are of Caucasians,and there are few studies on Asian population,even less on Chinese population.We analyzed the prevalence and related factors of AIQTIP in Chinese patients with schizophrenia,and explored the related genes of AIQTIP in Chinese patients with schizophrenia.Method:(1)Patients with schizophrenia treated systematically for the first time and patients with chronic schizophrenia were enrolled in this study.A total of 203 patients with schizophrenia treated systematically for the first time were enrolled and 505 healthy controls matched by sex and age were collected.A total of 436 hospitalized patients with chronic schizophrenia were enrolled and 291 healthy controls matched by gender and age were collected.The demographic data,clinical information and hematological indexes of all the patients were collected.(2)203 patients with schizophrenia treated systematically for the first time were enrolled,all of whom received single atypical antipsychotic drugs(AAPD)treatment for 4 weeks.The baseline ECG data was compared with that of healthy control group,and the prevalence of QTc interval prolongation was calculated.The relationship between baseline QTc interval and demographic data,clinical features and metabolic indicators was also analyzed,and the possible risk factors of baseline QTc interval prolongation were analyzed.After 4 weeks of single AAPD treatment,the changes of QTc interval was analyzed,the prevalence of QTc interval prolongation after 4 weeks of treatment was calculated.(3)Of the 203 patients with schizophrenia,153 patients completed 4-week electrocardiogram,among which 112 patients completed genotyping.10 SNP loci were screened out from 8 candidate genes closely related to metabolism,which were rs1137101(LEPR),rs7732687(EPB41L4A),rs7799039(LEP),rs6265(BDNF),rs7141420(NRXN3),rs9939609(FTO),rs1558902(FTO),rs6567160(MC4R),rs489693(MC4R)和rs4680(COMT).(4)436 hospitalized patients with chronic schizophrenia were enrolled,and 291healthy controls matched by sex and age were collected.The prevalence of QTc interval prolongation in patients with chronic schizophrenia was calculated,and the relationship between QTc interval prolongation and demographic data,clinical characteristics,metabolic indicators and antipsychotic treatment was analyzed.And the possible risk factors of QTc interval prolongation in Chinese patients with chronic schizophrenia were analyzed.The QTc interval between patients with schizophrenia and healthy controls was compared by two independent samples t test,and the prevalence of QTc interval prolongation was compared byχ~2test.The QTc interval of schizophrenia patients before and after treatment was compared by paired sample t test.Pearson and Spearman correlation analysis were used for correlation analysis,and Logisitic regression analysis and multiple linear regression were used to analyze the possible risk factors of QTc interval prolongation in patients with schizophrenia.The association between the selected SNPs and several phenotypes was analyzed by using linear regression model in PLINK,where the changes of QTc were used as phenotypes for the quantitative trait locus analysis.We used PLINK to perform pairwise gene-gene interaction analysis(epistasis)among selected gene SNPs in all patients,male patients and female patients.Results:1.Compared with the healthy control group,the baseline electrocardiogram of patients with schizophrenia treated systematically for the first time showed that the heart rate of patients with schizophrenia was faster(P=0.000)and the QTc interval was longer(P=0.018).2.The prevalence of QTc interval prolongation in baseline electrocardiogram of patients with schizophrenia treated systematically for the first time was 5.91%,while that of healthy control group was 2.38%,and the prevalence of QTc interval prolongation in baseline electrocardiogram of patients with schizophrenia was higher than that of healthy control group(P=0.019).3.Pearson and Spearman correlation analysis showed that there was a correlation between the baseline QTc interval and the following variables:gender(P=0.021),age(P=0.001),BMI(P=0.039),FPG(P=0.017),CHOL(P=0.009).Multiple linear regression analysis showed that FPG(β=0.163,t=2.261,P=0.025)was still associated with QTc interval,and FPG may be a possible risk factor for the baseline QTc interval prolongation of patients with schizophrenia who were treated systematically for the first time.4.After 4 weeks of single AAPD treatment,the QTc interval of patients with schizophrenia treated systematically for the first time was longer than that of baseline(P=0.018),and QTc interval was also prolonged in female patients after 4 weeks of treatment(P=0.047),while there was no significant difference between the QTc interval of male patients before and after treatment(P=0.278).5.In our study,SNP in EPB41L4A yielded significant association for AIQTIP.After grouping according to gender,SNP in EPB41L4A yielded significant association for AIQTIP in male patients,and SNP in LEP yielded significant association for AIQTIP in female patients.The results of quantitative gene-gene interaction analysis of AIQTIP(ΔQTc)showed significant epistasis between NRXN3 and FTO and FTO and COMT gene SNPs for AIQTIP(ΔQTc)in all patients.We found significant epistasis between LEP and NRXN3,and FTO and NRXN3 gene SNPs for AIQTIP(ΔQTc)in male patients.We also found significant epistasis between NRXN3 and COMT,and FTO and COMT gene SNPs for AIQTIP(ΔQTc)in female patients.6.Compared with healthy control group,patients with chronic schizophrenia have faster heart rate(P=0.000)and longer QTc interval(P=0.000).The prevalence of QTc interval prolongation in patients with schizophrenia was 8.26%,and the prevalence of QTc interval prolongation in female patients was 12.24%,that in male patients was6.23%.The prevalence of QTc interval prolongation in female patients was higher than that of male patients(P=0.031).The QTc interval of female patients was longer than that of male patients(P=0.004).7.Patients with chronic schizophrenia were divided into QTc interval prolonged group and QTc interval not prolonged group according to whether QTc interval prolonged or not.The prolongation of QTc interval is more common in patients with a family history of mental illness(P=0.031).The patients with prolonged QTc interval had higher scores of Concrete/Disorganized subscore(P=0.019),lower LDL levels(P=0.007)and lower TP levels(P=0.035).Furthermore,binary Logistic regression analysis showed that the number of hospitalizations(Waldχ~2=6.267,OR=1.042,P=0.012),concrete/disorganized subscore(Waldχ~2=5.500,OR=1.130,P=0.019)and LDL cholesterol(Waldχ~2=4.179,OR=0.549,P=0.041)were associated with QTc interval prolongation.After controlling for the confounding factors,the number of hospitalizations(Waldχ~2=6.356,OR=1.042,P=0.012),concrete/disorganized subscore(Waldχ~2=5.002,OR=1.126,P=0.025)and LDL cholesterol(Waldχ~2=4.323,OR=0.542,P=0.038)were still associated with QTc interval prolongation.Within them,LDL seemed to be a protective factor for QTc interval prolongation.8.Pearson and Spearman correlation analysis showed that there was a correlation between QTc interval and the following variables:gender(P=0.004),age(P=0.000),duration of illness(P=0.001),the number of hospitalizations(P=0.011),PANSS total score(P=0.001)and FPG(P=0.022).Furthermore,a multiple regression analysis showed that age(beta=0.238,t=2.687,P=0.008),antipsychotic polytherapy(beta=0.118,t=2.005,P=0.046),PANSS total score(beta=0.128,t=2.325,P=0.021),and LDL(beta=-0.112,t=-2.036,P=0.043)were still associated with QTc interval.Among them,LDL was negatively correlated with QTc interval.Conclusion:1.The baseline QTc interval of patients with schizophrenia treated systematically for the first time was longer than that of healthy control group.The prevalence of baseline QTc interval prolongation was higher than that of healthy control group.After receiving single AAPD treatment for 4 weeks,the QTc interval of patients with schizophrenia was longer than that of baseline.2.FPG may be a risk factor for the prolongation of baseline QTc interval of patients with schizophrenia treated systematacially for the first time.3.EPB41L4A gene and LEP gene are significantly associated with AIQTIP.After grouping according to gender,SNP in EPB41L4A yielded significant association for AIQTIP in male patients,and SNP in LEP yielded significant association for AIQTIP in female patients.4.The QTc interval of chronic schizophrenia patients was longer than that of normal control group.The prevalence of QTc interval prolongation of chronic schizophrenia patients was 8.26%,and the prevalence of AIQTIP in male patients is 6.23%,in female patients is 12.24%.And the prevalence of AIQTIP in female patients was higher than that of male patients.5.Some demographic and clinical characteristics were found to be risk factors for AIQTIP in patients with choronic schizophrenia,including older age,higher number of hospitalizations,higher concrete/disorganized subscore,higher PANSS total score,or treatment with antipsychotic polytherapy.6.LDL may be a protective factor for AIQTIP in patients with chronic schizophrenia.更多还原