社会环境与遗传交互作用对不同程度心理应激影响的研究

发布时间：2018-05-29 07:37

本文选题：心理应激 + 社会环境　；参考：《新疆医科大学》2012年博士论文

【摘要】：目的：研究不同程度的应激对心理健康的影响。系统的阐述心理应激过程，影响心理应激的社会（环境）因素以及遗传因素，结合结构方程模型（SEM）以及遗传流行病学的统计方法（多因子降维法）综合分析心理应激的影响因素以及与候选基因多态性的关联，包括社会（环境）因素与基因的交互作用以及基因与基因的交互作用，全面揭示心理应激的作用机制。方法：1）以新疆野外作业石油工人为例，利用症状自评量表、社会支持量表、人格特征量表、职业倦怠问卷、职业紧张问卷结合结构方程模型探讨影响轻度心理应激的社会（环境）因素，以及各因素间的相互作用；2）以交通事故导致创伤人群为例探讨中度心理应激及过程，利用PCL-C量表及临床表现筛查创伤后应激障碍阳性症状患者，基于结构方程模型分析影响中度心理应激反应的社会（环境）因素与遗传易感性的交互作用；3）基于病例对照研究利用问卷调查和实验室方法结合Logistic回归、MDR分析影响重度心理应激的社会（环境）因素与基因交互作用以及基因－基因交互作用。结果：1）野外石油工人SCL-90量表得分与全国常模比较，敌对因子和偏执因子得分与全国常模比较差异无统计学意义，除人际敏感外，其他各因子得分均高于全国常模，且P＜0.05。与新疆地区部分汉族职业人群SCL-90常模比较石油工人抑郁因子得分（1.63±0.54）、精神病性因子得分（1.48±0.44）均高于职业人群常模得分，分别为：（1.57±0.61）、（1.41±0.50），P均＜0.05；2）多因素Logistic回归分析发现影响轻度心理应激的因素为：心理紧张反应（PSY）、自我保健（SC）、神经质（N）、精神质（P）、支持利用度以及情感耗竭；3）利用SEM建立影响轻度心理应激的多因素模型，结果表明模型拟和符合理论，拟和优度指数较好（RMSEA＝0.048，NFI＝0.949，GFI＝0.906）。各个观测指标和潜变量之间的因子载荷较高，且具有统计学意义；4）以PCL-C得分分值38分为临界值，PTSD阳性筛查率为15%（25人发生）；25例创伤后应激障碍患者分数在38～52分之间，20例集中在38～46之间；5）创伤初期精神健康状况（SCL-90）与创伤后应激障碍的总分以及各症状得分均存在着显著正相关，提示创伤初期心理健康水平可以预测后期PTSD的发生；人格特征因素神经质（N）和精神质（P）与创伤后应激障碍总得分、各症状得分具有正相关，社会支持总分与PTSD总分呈负相关；6）影响中度心理应激的多元线性回归分析，结果表明强迫症状、精神质（P）、主观支持、人际关系敏感、内外向（E）等因素进入回归方程，5个变量解释PTSD阳性发生程度变异的65.0%，估计值的标准误为4.758；7）利用SNP-SHOT方法共检测了4个基因：糖皮质激素受体（GCCR）基因、多巴胺D2受体（DRD2）基因、五羟色胺转运体（SLC6A4）基因、CRHR1（促肾上腺皮质释放激素受体-1）基因的10个tag SNPs位点的多态性，其中GCCR基因的rs6189位点没有突变，故未将其列入后期数据分析。其他9个SNPs位点经X2检验，基因型及等位基因频率均分布符合Hardy-Weinberg平衡定律，各P值均大于0.05，表明其基因频率已达到遗传平衡有群体代表性；8）影响中度心理应激反应遗传易感因素分析：①GCCR基因：rs258747突变纯合子GG基因型在闯入/重复体验症状得分高于杂合子AG型和野生纯合子AA型。rs10482605位点，血浆皮质醇水平突变杂合子AG型高于野生纯合子AA型；rs41423247位点血浆皮质醇水平突变纯合子GG型高于突变杂合子GC型和野生纯合子CC型。rs258747可能是一个具有重要生物学功能的SNP位点，应进一步结合临床病例证实G等位基因的个体在受到创伤性事件后发展成PTSD的危险性相对较高，对PTSD可能是一个易感因子，可作为PTSD相关疾病易感性的一个重要指标。②DRD2基因：rs1800497位点突变纯合子AA型在闯入/重复体验症状上的得分高于杂合子GA型和野生纯合子GG型得分。DRD2受体浓度的测定发现rs1800497突变纯合子的浓度高于杂合子和野生纯合子的浓度。rs6275位点携带突变纯合子AA基因型的创伤患者在支持利用度方面得分低于杂合子GA基因型和野生纯合子GG型。rs1076560位点携带杂合子AC基因型在主观支持上的得分低于野生纯合子CC基因型。rs1800497位点携带突变纯合子AA基因型支持利用度低于野生纯合子GG基因型。③SLC6A4基因：rs1042173位点突变纯合子AA基因型在警觉因子上的得分高于杂合子AC型和野生纯合子CC基因型。rs242948位点突变纯合子GG基因型的创伤患者血浆多巴胺D2受体浓度高于杂合子GT基因型个体和野生纯合子TT基因型个体；9）利用结构方程模型对基因与社会（环境）相互作用对PTSD阳性症状影响进行模型拟和，通过对模型拟和发现，在增加了遗传易感因素后整体模型拟和更好（与第一部分图1-1比较，RMSEA＝0.041，NFI＝0.951，GFI＝0.914）大多数指标的因子荷载提高；10）LES总分比较显示，应激障碍组得分高于对照组，应激障碍组的负性生活事件高于对照组，差异有统计学意义，P＜0.05，OR＝9.650；社会支持总分、主观支持、支持利用度在应激障碍组和对照组间具有差异，P＜0.05，OR分别＝0.035，0.027，0.025；消极应对方式在应激障碍组和对照组之间得分有差别，差别具有统计学意义，OR＝1.014；应激精神障碍组和对照组人格特征进行T检验发现，两组在P（精神质）量表的得分差异显著，应激障碍组得分高于对照组，进一步进行趋势卡方检验发现随着P量表得分增加，OR值显著增加，P的T分大于60分，OR＝8.741；11）影响应激精神障碍的遗传因素分析：①GCCR基因上的rs10482605位点和rs258747与应激精神障碍有关联（P＜0.05）。rs10482605位点携带有G突变型等位基因是应激精神障碍的危险因素（OR＝1.431，，95%CI＝1.186～1.999）；rs258747位点携带有G突变型等位基因是应激精神障碍的危险因素（OR＝1.781，95%CI＝1.567～2.0782）；由3个位点组成的2个单倍体型（AGC和AGG）与应激精神障碍的发生有关联（P＜0.05）。OR分别＝1.468，1.419。②DRD2基因：应激障碍组rs1800497位点突变纯合子AA基因型和杂合子GA基因型基因频率高于对照组，OR＝1.434，1.766，并且携带有A突变型等位基因是应激精神障碍的危险因素（OR＝1.211，95%CI＝0.890～1.647）；由3个位点组成的1个单倍体型（GAA）与应激精神障碍的发生有关联（P＜0.05）。OR分别＝1.233。③SLC6A4基因2个位点、CRHR1基因1个位点，其基因频率和等位基因频率在应激障碍组和对照组间无差异（P＞0.05）；12）通过MDR软件分析后，选择了由5个位点组成的交互模型作为最佳基因-基因交互模型来说明基因交互作用对应激精神障碍的影响。该5个位点组成的交互模型其具有最大的检测准确度（67.48）和最大的交叉验证一致性（CV＝10/10），此最佳的基因-基因交互模型由rs10482605，rs258747，rs242948，rs1800497和rs4142324五个多态性位点组成；13）应激精神障碍的基因环境交互作用显示：显示GCCR基因的rs258747位点与N（神经质）有交互作用，OR＝3.304；rs41423247与主观支持有交互作用OR＝0.269；DRD2基因的rs1076560位点与消极应对方式有交互作用，OR＝2.320；rs1800497位点与主观支持有交互作用，OR＝0.397。结论：1）影响轻度心理应激的社会环境因素有心理紧张反应（PSY），自我保健（SC），神经质（N）精神质（P）、支持利用度。预测总符合率为62.70%；2）轻度心理应激模型拟和较好，SEM量化了社会环境因素对心理应激的影响，职业任务、个体紧张反应、社会支持、人格特征对心理应激的影响分别为：0.165、0.139、0.077、0.189；3）创伤初期的精神健康状况（SCL-90）与PTSD症状严重程度成正相关，具有神经质和精神质人格特征的人群更易患PTSD，社会支持是其保护性因素；4）影响中度心理应激的社会环境因素有强迫症状、精神质（P）、主观支持、人际关系敏感、内外向，预测总符合率为65.0%；5）GCCR基因rs258747位点以及DRD2基因rs1800497位点是2个具有重要生物学功能的SNP位点，可作为PTSD相关疾病易感性的重要TagSnp；6）SEM构建的社会环境与遗传交互作用模型拟和较好，大多数指标的因子荷载提高。血浆皮质醇和多巴胺D2受体浓度与精神状况（SCL-90）和PTSD的发生以及症状严重程度具有相关性，路径系数分别为0.09和0.21，且对PTSD的预测能力较大；7）过强的负性生活事件刺激可使患应激精神障碍的风险增大9倍；社会支持总分、主观支持、支持利用度使患应激精神障碍的风险分别降低73%，75%，65%具有精神质倾向的人格可以增加应激精神障碍的患病风险；8）病例对照研究GCCR基因上的rs10482605和rs258747位点以及DRD2基因rs1800497位点与应激精神障碍有关联；9）最佳的基因-基因互模型由rs10482605，rs258747，rs242948，rs1800497和rs4142324多态性位点组成。
[Abstract]:Objective: To study the influence of different degrees of stress on mental health. The systematic exposition of psychological stress process, social (environmental) factors and genetic factors affecting psychological stress, combined with structural equation model (SEM) and the statistical method of genetic epidemiology (multi factor reduction method) to analyze the influencing factors of psychological stress and their candidates. The association of genetic polymorphisms, including the interaction of social (environmental) factors and genes, and the interaction of genes and genes, comprehensively reveals the mechanism of psychological stress. Method: 1) taking the field working oil workers in Xinjiang as an example, using the symptom checklist, social support scale, personality scale, job burnout questionnaire, occupational stress. The questionnaire combined with the structural equation model to explore the social (environmental) factors affecting mild psychological stress and the interaction among the factors. 2) to explore the moderate psychological stress and process by the traffic accident caused by the trauma crowd, and to screen the patients with positive symptoms of post traumatic stress disorder using the PCL-C scale and clinical manifestation, based on the structural equation model. Analysis of the interaction between social (environmental) factors and genetic susceptibility to moderate psychological stress; 3) a case-control study, based on a combination of questionnaires and laboratory methods, combined with Logistic regression, and MDR analysis of social (environmental) factors and gene interaction and gene gene interaction in severe psychological stress. Results: 1 Compared with the national norm, the scores of the SCL-90 scale of the field oil workers and the national norm were not statistically significant compared with the national norm. Except for interpersonal sensitivity, the scores of all the other factors were higher than the national norm, and the scores of P < 0.05. and the SCL-90 norm of the Han ethnic group in Xinjiang were compared with the depression factor scores of the oil workers. (1.63 + 0.54), the scores of psychosis factors (1.48 + 0.44) were higher than those of the occupational group, respectively: (1.57 + 0.61), (1.41 + 0.50), P < 0.05; 2.) multiple factor Logistic regression analysis found that the factors affecting mild psychological stress were psychological stress reaction (PSY), self health care (SC), neuroticism (P), support utilization, and support utilization. Emotional exhaustion; 3) using SEM to establish a multi factor model that affects mild psychological stress. The results show that the model is fit for the theory, and the pseudo sum index is better (RMSEA = 0.048, NFI = 0.949, GFI = 0.906). The factor load between the observed and the latent variables is higher and has statistical significance; 4) is divided into the critical value of the PCL-C score score of 38 as the critical point. The positive screening rate of PTSD was 15% (25 people), 25 patients with posttraumatic stress disorder were between 38~52, 20 and 38~46; 5) there were significant positive correlations between the mental health status (SCL-90) and the total score of posttraumatic stress disorder and the scores of all the symptoms, suggesting that the mental health level in the early stage of trauma could be found. The occurrence of PTSD in the later period was predicted; the personality factors neuroticism (N) and mental quality (P) were positively correlated with the total score of posttraumatic stress disorder, the score of each symptom, the total score of social support and the total score of PTSD were negatively correlated; 6) multiple linear regression analysis of moderate psychological stress showed that the symptoms of compulsion, mental quality (P), subjective support and interpersonal relationship were the result. Sensitive, internal and external (E) and other factors entered the regression equation, 5 variables explained 65% of the PTSD positive occurrence variation, the estimated value was 4.758; 7) 4 genes were detected by the SNP-SHOT method: the glucocorticoid receptor (GCCR) gene, the dopamine D2 receptor (DRD2) gene, the five serotonin transporter (SLC6A4) gene, and the CRHR1 (suprarenal). The polymorphism of the 10 tag SNPs loci of the adenocorticocorticosteroid receptor -1 gene, in which the rs6189 site of the GCCR gene is not mutated, is not included in the late data analysis. The other 9 SNPs loci are tested by X2, and the distribution of genotype and alleles conforms to the law of Hardy-Weinberg balance, and the P values are more than 0.05, indicating the frequency of their genes. Genetic balance has a population representation; 8) analysis of genetic susceptibility factors affecting moderate psychological stress: (1) GCCR gene: rs258747 mutant homozygous GG genotypes are higher than heterozygote AG and wild homozygote AA.Rs10482605 locus, and plasma cortisol level mutation heterozygote AG type is higher than wild Homozygous AA type; rs41423247 site plasma cortisol level mutation homozygous GG higher than mutant heterozygote GC and Nobu Juriko CC.Rs258747 may be an important biological function of SNP locus, which should be further combined with the risk of developing PTSD after a traumatic event in individuals with a clinically proven G allele. Relatively high, it may be a susceptible factor to PTSD, and can be an important indicator of susceptibility to PTSD related diseases. (2) DRD2 gene: the score of rs1800497 site mutant homozygous AA in intruding / repeated experience symptoms is higher than that of heterozygote GA and the determination of.DRD2 receptor concentration in the wild homozygote GG type score of.DRD2, and the discovery of rs1800497 mutation homozygosity The concentration of the child was higher than the heterozygote and the Nobu Juriko concentration.Rs6275 site carrying the mutant homozygote AA genotype. The score of the trauma patients in the support utilization was lower than the heterozygote GA genotype and the wild homozygote GG type.Rs1076560 locus carrying the heterozygote AC genotypes in subjective support lower than the wild homozygote CC genotype.Rs18. The 00497 loci carrying mutant homozygote AA genotype was lower than the wild homozygote GG genotype. (3) SLC6A4 gene: rs1042173 locus mutation homozygous AA genotypes were higher than heterozygote AC and wild homozygous CC genotype.Rs242948 site mutated homozygous GG genotyping of dopamine D2 The receptor concentration is higher than the heterozygote GT genotype individual and the wild homozygote TT genotype individual; 9) using the structural equation model to model the effect of the gene and social (environment) interaction on the PTSD positive symptoms, the whole model of the genetic predisposing factor is proposed and better (with the first part of figure 1-1). Comparison, RMSEA = 0.041, NFI = 0.951, GFI = 0.914) the factor load of most indexes increased; 10) LES total score comparison showed that the score of stress disorder group was higher than that of the control group, the negative life events in the stress disorder group were higher than the control group, the difference was statistically significant, P < 0.05, OR = 9.650; social support total score, subjective support, support utilization in should There was a difference between the irritable and the control groups, P < 0.05, OR = 0.035,0.027,0.025, and the scores of the negative coping styles between the stress disorder group and the control group were different, the difference was statistically significant, OR = 1.014; the personality characteristics of the stress mental disorder group and the control group were detected by T, and the difference between the two groups in the P (psychotic) scale was different. Significantly, the score of the stress disorder group was higher than that of the control group. Further trend chi square test found that with the increase of the P scale, the OR value increased significantly, the T score of P was greater than 60, OR = 8.741; 11) the genetic factors affecting stress mental disorders were analyzed: (1) the rs10482605 sites and rs258747 on GCCR gene were associated with stress mental disorders (P < 0.05).R. The s10482605 locus with G mutational allele was a risk factor for stress disorder (OR = 1.431,95%CI = 1.186 ~ 1.999); the rs258747 locus with G mutational allele was a risk factor for stress disorder (OR = 1.781,95%CI = 1.567 ~ 2.0782), and 2 haplotypes (AGC and AGG) and stress sperm consisting of 3 loci. The occurrence of deity disorders was associated with (P < 0.05).OR = 1.468,1.419. 2 DRD2 gene: the frequencies of the homozygous AA genotypes and heterozygote GA genotypes in the rs1800497 site of the stress disorder group were higher than those of the control group, OR = 1.434,1.766, and the A mutant allele was a risk factor for stress disorder (OR = 1.211,95%CI = 0.890) To 1.647), 1 haplotypes (GAA) composed of 3 loci were associated with the occurrence of stress mental disorders (P < 0.05).OR = 2 loci of 1.233. (SLC6A4) gene and 1 loci of the CRHR1 gene, and the frequency and allele frequency of the allele were no difference between the stress disorder group and the control group (P > 0.05); 12) selected by MDR software analysis. The interaction model composed of 5 loci was used as the best gene gene interaction model to illustrate the effect of gene interaction on psychotic disorders. The interactive model of the 5 loci has the maximum detection accuracy (67.48) and the largest cross validation conformance (CV = 10/10), and the best gene gene interaction model is rs10482605 Five polymorphic loci of rs258747, rs242948, rs1800497 and rs4142324; 13) the genetic environmental interaction of stress disorder showed that the rs258747 locus of the GCCR gene had interaction with N (neuroticism), OR = 3.304; rs41423247 and the subjective support were interacting with OR = 0.269, rs1076560 sites and negative responses of DRD2 genes. Interaction, OR = 2.320; rs1800497 locus and subjective support interaction, OR = 0.397. conclusion: 1) social environmental factors affecting mild psychological stress (PSY), self health care (SC), neuroticism (P), support utilization, predictive total coincidence rate of 62.70%; 2) mild psychological stress model and Better, SEM quantified the influence of social environmental factors on psychological stress. Occupational tasks, individual stress reactions, social support, and personality characteristics were respectively the effects of 0.165,0.139,0.077,0.189; 3) mental health status (SCL-90) in the early stage of trauma was positively related to the severity of PTSD symptoms, with neuroticism and psychotic personality traits. The social support is a protective factor for PTSD, and social support is a protective factor. 4) social environmental factors affecting moderate psychological stress include compulsive symptoms, mental quality (P), subjective support, interpersonal sensitivity, internal and external, and the total coincidence rate is 65%; 5) the rs258747 locus of GCCR gene and the rs1800497 locus of DRD2 gene are of important biological merits. The SNP locus can be used as an important TagSnp for susceptibility to PTSD related diseases; 6) the social environment and genetic interaction model constructed by SEM is well planned and better, and the factor load of most indicators is improved. The concentration of plasma cortisol and dopamine D2 receptor is related to the occurrence of SCL-90 and PTSD and the severity of the symptoms, and the path is related. The coefficients were 0.09 and 0.21 respectively, and the predictive ability of PTSD was greater; 7) too strong negative life event stimulation could increase the risk of stress mental disorder by 9 times; social support total score, subjective support, support utilization to reduce the risk of stress mental disorder by 73%, 75%, 65% with psychotic personality can increase stress essence. The risk of deity disorders; 8) the rs10482605 and rs258747 loci in the case-control study GCCR gene and the rs1800497 locus of the DRD2 gene were associated with stress mental disorders; 9) the best gene gene cross model was composed of rs10482605, rs258747, rs242948, rs1800497 and rs4142324 polymorphisms.
【学位授予单位】：新疆医科大学
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R395

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