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

发布时间：2019-06-22 19:55

【摘要】：目的:抗精神病药导致体重增加(Antipsychotic-induced weight gain,AIWG)及其代谢改变是精神障碍治疗面临的一个严峻问题。AIWG的发生与遗传因素密切相关,但是其与单纯肥胖的区别,以及其代谢谱的变化特点尚不明确。本研究通过动态临床跟踪研究,观察单一非典型抗精神病药(Atypical antipsychotic drug,AAPD)干预后患者的体重及27个糖脂代谢相关因子的动态变化,并比较首发患者(Firstepisode patients,FEP)和非首发患者(Non-firstepisode patients,NFEP),以及不同AAPD干预后各指标变化之间的差异。精神障碍患者在接受抗精神病药干预前,可能就存在一些代谢异常。本研究通过对比FEP和健康对照的糖脂代谢的差异,来进一步厘清精神障碍和抗精神病药对精神障碍代谢影响的关系;同时筛选检测与糖脂代谢及肥胖相关的生物标记物。AIWG存在明显的个体差异,这可能与不同的遗传背景有关。另一方面,AIWG与单纯肥胖的遗传学基础有何异同尚不明确。我们对候选基因的多态性位点与AIWG人群的体重、糖脂代谢指标及其变化趋势等160项指标进行数量性状的关联分析,以期找到与AIWG相关的基因。方法:共纳入符合入组标准的患者339例,其中包含FEP 86人;另外,入组年龄和性别与FEP匹配的正常健康对照88人。根据临床治疗需要所有患者接受单一AAPD干预,其中接受奥氮平(Olanzapine,OLA)治疗有131人,服用利培酮(Risperidone,RIS)的患者有133人。治疗观察12周,所有患者于治疗前和治疗后第2、4、6、8、12周末测量体重、腰围、腹围和臀围,同时计算出体质指数(BMI)和腰臀比(WHR);治疗前和治疗后第4、8、12周末测量患者的甘油三脂(TG)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、总胆固醇(CHOL)、总蛋白(TP)、白蛋白(ALB)、空腹血糖(FPG)、血肌酐(CRE)、尿素氮(UREA)、肌酐/尿素(Ur/Cr)、血清C反应蛋白(CRP)、催乳素(PRL)、T3、T4和促甲状腺激素(TSH)。此外,通过酶联免疫吸附法(ELISA)测定FEP基线时期的空腹胰岛素(FINS)、血浆同型半胱氨酸(HCY)、脂联素(ADP)、脑源性神经营养因子(BDNF)和瘦素(LEP)。同时,所有正常对照均做体重及代谢相关检测。采用重复测量资料方差分析观察患者接受AAPD治疗后各指标的动态变化差异;采用独立样本t检验比较FEP和健康对照各指标,FEP和NFEP以及OLA和RIS干预后各指标变化之间的差异。服药后体重变化的影响因素采用Spearman相关分析和多元回归分析。选取本项目组成员以往在欧美人群全基因组关联分析(GWAS)中得到的与AIWG存在显著关联的基因位点,以及单纯肥胖-AIWG差异的基因位点,以基质辅助激光解吸电离飞行时间质谱(MALDI-TOF-MS)进行候选基因多态性位点基因分型。分别在所有患者中、首发患者组、OLA治疗组和RIS治疗组,对体重变化、糖脂代谢和血生化指标及其在不同时间点的变化值,应用PLINK软件进行数量性状的基因关联分析和基因-基因交互作用分析。结果:1.与健康对照相比,FEP组在基线时期的TG、TP和ALB显著下降(P值均0.001),SBP和DBP显著上升(P值均0.001);FEP的FINS和HOMA-IR显著较高(P值分别为0.001和0.000),QUICKI、HOMA-ISI和G/I显著降低(P值均小于0.001);FEP组血浆ADP显著降低(P=0.023)。2.AAPD对精神障碍患者的体重、BMI和WHR有显著影响,在接受治疗后第2周末就已显著上升,之后持续增加。首发患者和服用OLA的患者比非首发患者和服用RIS的患者体重、BMI和WHR增加更为显著。在基线时期,FEP和NFEP之间体重就有显著差异(P0.01),而在其它指标并未发现两组之间存在显著差异。3.经AAPD治疗后,精神障碍患者的TP、ALB和CRE在不同检测时间之间有显著差异(P值均0.05);在第4周末,精神障碍患者会出现显著的脂代谢变化,TG和LDL显著上升,而HDL、TP和ALB显著下降。与非首发患者比较,首发患者在第12周末LDL显著升高(P=0.045);与RIS干预相比,服用OLA后,LDL在第4周末就显著增加(P0.001)。在服药初期,服用OLA的患者CHOL增加更为显著(P=0.003)。所有患者在接受AAPD治疗后,FPG都显著下降,8周之后开始上升。4.首发和抗精神病药物种类可能与服药后体重增加密切相关,而年龄、性别和基线BMI水平可能与AIWG无关;基线时期的T4和WHR水平与患者服用AAPD后体重变化呈负相关,相关系数分别为-0.154和-0.199,经多元回归分析后仍显著相关。5.候选基因的关联分析发现,与WHR变化显著相关的位点有BDNF基因的SNP rs6265(P=0.002)、BDAF基因的SNP rs11030104(P=0.001)、ADIPOQ基因的SNP rs822396(P=0.003)和rs1501299(P=0.040)。同时,在OLA组中也得到了一致的结果。TOX基因的SNPrs11777927(P=0.009)和ADIPOQ基因的SNP rs182052(P=0.019)与AIWG存在显著关联,CDKN2A/B基因的SNP rs3731245(P=0.04)和rs2811708(P=0.039)与AIWG相关,以上结果经年龄调整后均存在显著关联。经进一步分组分析,发现在FEP组和RIS组内CDKN2A/B基因与AIWG均存在显著相关。6.PKHD1基因rs9395706位点与抗精神病药物引起的脂代谢变化存在相关,且与LDL、HDL和CHOL的变化均存在关联,经年龄调整后仍然显著关联。CDKN2A/B基因SNP rs3731245与OLA干预后FPG变化有关(P=0.009)。7.与携带rs3731245 C等位基因的患者相比,rs3731245 TT型的患者在接受抗精神病药物治疗后BMI显著增加(P0.05);与携带rs2811708 G等位基因的患者相比,rs2811708 TT型的患者在接受抗精神病药物治疗后BMI显著增加(P0.05)。8.基因×基因交互作用分析得出,在全部患者中,MTHFR基因和PCAF基因、EPB41L4A基因分别与LEPR基因和TMEM18基因、ADIPOQ基因分别与和CDKN2A/B基因和NRXN3基因、TOX基因分别与PKHD1基因和RPTOR基因、MC4R基因和COMT基因等基因位点之间存在交互作用,与AIWG相关。结论:1.精神障碍患者在治疗前已有代谢的相关改变,TG、TP和ALB显著下降,SBP和DBP显著上升,胰岛素敏感性下降,胰岛素抵抗水平增加,脂联素水平显著低于健康对照。2.AIWG及相关糖脂代谢变化不同于单纯性肥胖,其糖脂代谢有其自身的特点,在治疗干预第2周末,体型指标出现显著增加,至第4周末,血脂指标(LDL,HDL,TG等)才显著变化。其中,FGP呈现先下降后上升的趋势。在首发患者和接受奥氮平治疗的患者中这些变化更为显著。AAPD可能会对患者的体重有长期的影响。3.未服药基线时期的T4和WHR水平与患者服用AAPD后体重变化呈负相关,可以作为AAPD干预后患者体重变化的预测因子。4.AIWG的遗传因素存在与单纯肥胖不同的特点:一些与肥胖显著关联的基因(如FTO,MC4R等)并未发现与AIWG显著相关,而基因ADIPOQ、TOX和CDKN2A/B基因多态性的与AIWG存在显著关联;ADIPOQ基因、BDNF和BDAF基因与抗精神病药导致的WHR变化存在显著关联;PKHD1基因与抗精神病药物引起的脂代谢变化存在显著关联。
[Abstract]:Objective: Antipsychotic-induced weight gain (AIWG) and its metabolic changes are a serious problem in the treatment of mental disorders. The occurrence of AIWG is closely related to the genetic factors, but the difference between the AIWG and the simple obesity is not clear. A dynamic clinical follow-up study was conducted to observe the dynamic changes of the body weight and 27 glycolipid metabolism-related factors in patients after the intervention of the single atypical antipsychotic (AAPD), and to compare the first-time patients (FEP) and non-first-time patients (NEP). And the difference between the change of each index after different apd intervention. Patients with mental disorders may have some metabolic abnormalities prior to the intervention of antipsychotics. In this study, the effects of mental disorders and antipsychotics on the metabolic effects of mental disorders were further clarified by comparing the differences in glycolipid metabolism between the FEP and the healthy control; and screening for biomarkers associated with glycolipid metabolism and obesity. The AIWG has a distinct individual difference, which may be related to a different genetic background. On the other hand, the similarities and differences between AIWG and the genetic basis of simple obesity are not clear. The association between the polymorphism site of the candidate gene and the weight of the AWG population, the metabolic index of the glycolipid and the change tendency of the AWG population was analyzed, with a view to finding the gene related to the AIWG. Methods:339 patients were included in the criteria for inclusion, including 86 of the FEP; in addition, the enrolled age and gender were 88 normal healthy controls matched with the FEP. According to clinical treatment, all patients received a single APD intervention in which 131 were treated with olanzapine (OLA) and 133 for risperidone (RIS). Body weight, waist circumference, abdominal circumference, and hip circumference were measured at weeks 2,4,6,8 and 12 before and after treatment, and the body mass index (BMI) and waist-to-hip ratio (WHR) were calculated at the same time, and the patient's triglyceride (TG) was measured at the 4,8, and 12 weekends before and after treatment. high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (CHOL), total protein (TP), albumin (ALB), fasting blood glucose (FPG), blood myoglobin (CRE), urea nitrogen (UREA), myoglobin/ urea (Ur/ Cr), serum C-reactive protein (CRP), Prolactin (PRL), T3, T4 and thyroid stimulating hormone (TSH). In addition, fasting insulin (FINS), plasma homocysteine (HCY), adiponectin (ADP), brain-derived neurotrophic factor (BDNF) and leptin (LEP) were determined by enzyme-linked immunosorbent assay (ELISA). At the same time, all normal controls were tested for body weight and metabolism. The difference of the dynamic changes of each index after the treatment of AAPD was observed with the analysis of variance of repeated measurement data. The difference between the changes of the index, FEP and NEP and the changes of the indexes after the intervention of the OLA and the RIS was compared by the independent sample t test. The influencing factors of body weight change after taking medicine were Spearman correlation analysis and multiple regression analysis. in that past, the group memb of the project has the gene site which is significantly associated with the AIWG in the whole genome association analysis (GWAS) of the European and American group, and the gene site of the simple obesity-AIWG difference, Using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), the genetic typing of candidate genes was carried out. In all patients, the changes of body weight, lipid metabolism and blood biochemical indexes and their change in different time points were analyzed in the first group, the OLA treatment group and the RIS treatment group, and the genetic association analysis and the gene-gene interaction analysis of quantitative traits were carried out using the PLINK software. Results:1. Compared with the healthy controls, the TG, TP and ALB in the FEP group decreased significantly (P <0.001), and the SBP and DBP increased significantly (P <0.001); the FINS and HOMA-IR of the FEP were significantly higher (P values were 0.001 and 0.000, respectively), and the QUICKI, HOMA-ISI and G/ I were significantly lower (P <0.001); The plasma ADP of the FEP group was significantly lower (P = 0.023).2. The body weight, BMI and WHR of the patients with mental disorders were significantly affected by the APD. The second weekend after the treatment had increased significantly and then continued to increase. The weight, BMI, and WHR of patients with first-time and patients taking OLA increased more significantly than in non-starting patients and in patients taking RIS. There was a significant difference in body weight between FEP and NEP during the baseline period (P0.01), while there was no significant difference between the two groups in other indicators. After the treatment of AAPD, the TP, ALB and CRE of the patients with mental disorders had a significant difference between the detection time (P <0.05); in the fourth week, the patients with mental disorders had significant changes in lipid metabolism, and the TG and LDL significantly increased, while HDL, TP and ALB decreased significantly. The first patient had a significant increase in LDL at the end of the 12th week (P = 0.045) compared with the non-starter, and the LDL increased significantly at the 4th weekend compared to the RIS intervention (P0.001). In the early stage of the administration, the number of patients with OLA increased significantly (P = 0.003). All patients had a significant decrease in FPG after treatment with AAPD and started to rise after 8 weeks. The type of first and anti-psychotic drugs may be closely related to the weight gain after administration, while the age, sex, and baseline BMI may not be related to AIWG; the level of T4 and WHR in the baseline period is negatively correlated with the change in body weight after taking AAPD, and the correlation coefficient is-0.154 and-0.199, respectively. After multiple regression analysis, the correlation was still significant. The association analysis of the candidate genes found that the SNP rs6265 (P = 0.002), the SNP rs11030104 of the BDAF gene (P = 0.001), the SNP rs82396 (P = 0.003) and the rs1501299 (P = 0.040) of the ADIPOQ gene were found to be significantly related to the changes in the WHR. In the same time, a consistent result was obtained in the OLA group. The SNP rs182052 (P = 0.009) of the TOX gene and the SNP rs182052 (P = 0.019) of the ADIPOQ gene were significantly associated with the AIWG, and the SNP rs3731245 (P = 0.04) and rs2811708 (P = 0.039) of the CDKN2A/ B gene were associated with the AIWG, and the above results were significantly associated after the age adjustment. It was found that the CDKN2A/ B gene in the FEP group and the RIS group had a significant correlation with the AIWG. The SNP rs3731245 of CDKN2A/ B was related to the change of FPG after OLA intervention (P = 0.009). Compared with the patients with rs3731245 C allele, the BMI of rs3731245 TT was significantly increased after the treatment with antipsychotics (P0.05); compared with those with the rs281178G allele, the BMI of rs2811708 TT was significantly increased after the treatment with antipsychotics (P0.05). in all of that patient, the MTHFR gene and the PCAF gene, the EPB41L4A gene are respectively associated with the LEPR gene and the TMEM18 gene, the ADIPOQ gene and the CDKN2A/ B gene and the NRXN3 gene, and the TOX gene is respectively associated with the PKHD1 gene and the RPTOR gene, The interaction between the MC4R gene and the COMT gene is related to the AIWG. Conclusion:1. In the patients with mental disorders, the related changes of metabolism before treatment, the significant decrease of TG, TP and ALB, the significant increase of SBP and DBP, the decrease of insulin sensitivity, the increase of insulin resistance, and the level of adiponectin were significantly lower than that of healthy controls. Its glycolipid metabolism has its own characteristics. In the second end of the treatment, the body size index has increased significantly, and the blood lipid index (LDL, HDL, TG, etc.) has changed significantly to the fourth weekend. In which the fgp exhibits a tendency to rise after a first drop. These changes were more pronounced in the first and the patients treated with olanzapine. APD may have a long-term effect on the patient's body weight. The T4 and WHR levels in the non-drug baseline period were negatively correlated with the change in body weight following the administration of AAPD, which could be used as a predictor of the change in body weight after APD intervention.4. The genetic factors of AIWG were different from that of pure obesity: some genes associated with obesity (such as FTO, No significant association with AIWG was found in the gene ADIPOQ, TOX and CDKN2A/ B, while the ADIPOQ gene, the BDNF and BDAF genes were significantly associated with the WHR changes due to antipsychotics, and the PKHD1 gene was significantly associated with changes in lipid metabolism due to antipsychotics.
【学位授予单位】：天津医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R749

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