雌激素受体α和微小RNA-137基因多态性与精神分裂症的关联研究

发布时间：2018-06-15 02:54

本文选题：精神分裂症 + 雌激素受体α　；参考：《新乡医学院》2013年硕士论文

【摘要】：背景精神分裂症是一种重性精神疾病,症状复杂、异质性强,其病因和发病机制至今未明。遗传因素在精神分裂症的病理机制中起到重要作用。雌激素假说认为雌激素在精神分裂症中起保护作用,雌激素受体(Estrogen receptor, ESR)的遗传变异可能影响雌激素这一生物学作用,其基因多态性可能与精神分裂症的易感性有关。而基于候选基因策略的另一基因微小RNA-137(MicroRNA137, miR-137)是能影响神经发育的小RNA分子,其遗传变异也可能与精神分裂症有关。目的 1.检测中国豫北地区汉族人群中精神分裂症患者和健康对照ESRa和miR-137基因4个多态性位点基因型,分析其基因多态性与精神分裂症的遗传关联； 2.分析ESRa和miR-137基因多态性与精神分裂症首发年龄、临床症状和药物疗效之间的关系,进一步探讨其与精神分裂症易感性的关系。方法 1.筛选适合入组的中国豫北地区汉族人群精神分裂症患者322例作为病例组,在治疗前和治疗6周后进行阳性和阴性症状量表(Positive and negative syndrome scale, PANSS)评定；同时纳入300例性别和年龄均与病例组匹配的健康志愿者作为对照组； 2.收集受试者的一般资料,抽取外周静脉血5ml。从全血中提取基因组DNA,使用聚合酶链反应扩增ESRa和miR-137基因片段,并采用限制性片段长度多态性技术和直接测序法分别对ESRa和miR-137基因多态性进行基因型分析； 3.采用Haploview V4.1软件进行哈迪-温伯格平衡分析；使用SPSS18.0软件对ESRα和miR-137基因型在病例和对照组中的分布差异及其与精神分裂症首发年龄、临床症状和药物疗效等临床表型的关系进行分析；使用SHEsis在线软件测量连锁不平衡系数；采用SNPStats在线软件进行单体型分布差异分析； 4.采用Review Manager5.1软件进行ESRα基因多态性与精神分裂症关联的metα分析。结果 1. ESRα基因多态性位点rs2234693(T/C)、rs9340799(A/G)基因型和等位基因频率在病例组和对照组中分布的差异均无统计学意义；meta分析结果显示rs2234693、rs9340799基因型和等位基因频率在病例组和对照组的分布差异也无统计学意义；单体型C-A、C-G和T-G的频率在病例组和对照组之间的差异具有统计学意义(P均0.05),按性别分层后,三者在女性中的差异仍具有统计学意义(P值分别为0.0002、0.012和0.0035),在男性中仅C-A的分布差异具有统计学意义(P=0.0036)； 2.首发年龄在rs2234693位点共显性模型中比较差异具有统计学意义(P=0.02),按性别分层后在女性中仍有意义(P=0.004)；rs2234693不同基因型之间的冲动控制障碍症状分(P=0.015)及其减分(P=0.003)的比较差异具有统计学意义,按性别分层后,在男性中rs2234693不同基因型之间PANSS一般精神病理评分比较差异具有统计学意义(P=0.048),在女性中仅rs2234693不同基因型之间PANSS一般精神病理评分减分率比较差异具有统计学意义(P=0.045)；药物分层后,在阿立哌唑组rs2234693不同基因型之间紧张症状减分比较差异具有统计学意义(P=0.015),而在利培酮组冲动控制障碍症状减分比较差异具有统计学意义(P=0.006)。 3.MiR-137基因多态性位点rs66642155(存在串联重复序列为MU,无则为WT)和rs1625579(A/C)基因型频率在病例组和对照组中的分布差异均无统计学意义；rs66642155位点多态性WT基因型携带者的首发年龄晚于MU基因型携带者,差异具有统计学意义(P=0.045)；rs66642155不同基因型携带者之间基线PANSS阳性症状、五因子中阳性因子、妄想症状和意志障碍症状分的差异均具有统计学意义(P均0.05)；按性别分层后,在男性中rs66642155不同基因型携带者之间PANSS阳性症：状、五因子中阳性因子、妄想症状分的差异仍具有统计学意义(P值分别为0.003、0.001和0.002),而在女性中只有妄想症状分的差异具有统计学意义(P=0.03)。结论 1.在中国汉族人群中,ESRα基因单个多态性位点rs2234693和rs9340799与SZ不存在关联,但它们组成的单体型与SZ易感性有关,一定程度上支持ESRα基因为SZ候选基因；而miR-137基因多态性位点rs66642155和rs1625579与SZ不存在关联性,不支持其为SZ候选基因； 2. ESRα和miR-137基因均与SZ首发年龄相关；ESRα基因CC(rs2234693)基因型携带者的一般精神病理症状更突出,ESRα基因与SZ一般精神病理症状相关；miR-137基因WT(rs66642155)基因型携带者阳性症状更严重,miR-137基因与SZ阳性症状相关； 3. ESRα基因与SZ一般精神病理症状的药物疗效相关,阿立哌唑对CC(rs2234693)基因型携带者紧张症状的疗效更显著,而利培酮对其冲动控制障碍症状的疗效更明显。
[Abstract]:background
Schizophrenia is a kind of heavy mental disease with complex symptoms and strong heterogeneity, its etiology and pathogenesis are still unknown. Hereditary factors play an important role in the pathological mechanism of schizophrenia. The estrogen hypothesis suggests that estrogen plays a protective role in schizophrenia, and the genetic variation of Estrogen receptor receptor (ESR) can be found. It can affect the biological effect of estrogen, and its genetic polymorphism may be related to the susceptibility of schizophrenia, while the other gene RNA-137 (MicroRNA137, miR-137) based on the candidate gene strategy is a small RNA molecule that can affect the nerve development, and its genetic variation may also be associated with schizophrenia.
objective
1. the genotypes of 4 polymorphic loci (ESRa and miR-137) in the Han population of the Han population in the north of Henan Province were detected and the genetic association between the polymorphism of the gene and schizophrenia was analyzed.
2. the relationship between the ESRa and miR-137 gene polymorphisms and the first age of schizophrenia, the relationship between clinical symptoms and drug efficacy, and the relationship with the susceptibility of schizophrenia were further explored.
Method
1. selected 322 cases of schizophrenic patients in the Han population of Northern Henan Province as a case group, before and after 6 weeks of treatment, the positive and negative symptom scale (Positive and negative syndrome scale, PANSS) was evaluated. At the same time, 300 healthy volunteers with the matching of sex and age were matched with the case group as the control group. ;
2. the general data of the subjects were collected, the genomic DNA extracted from the peripheral venous blood 5ml. was extracted from the whole blood, the ESRa and miR-137 gene fragments were amplified by polymerase chain reaction, and the gene polymorphism of ESRa and miR-137 genes was analyzed by restriction fragment length polymorphism and direct sequencing, respectively.
3. the Hardy Weinberg balance analysis was carried out by Haploview V4.1 software; the distribution difference between the ESR alpha and miR-137 genotypes in the case and the control group and the relationship between the clinical phenotypes of the first age of schizophrenia, the clinical symptoms and the drug effect were analyzed by SPSS18.0 software, and the linkage disequilibrium was measured by the SHEsis online software. Coefficient; SNPStats online software for haplotype distribution difference analysis.
4. Review Manager5.1 software was used to analyze the met alpha analysis of the association between ESR alpha polymorphism and schizophrenia.
Result
1. ESR alpha gene polymorphism site rs2234693 (T/C), rs9340799 (A/G) genotype and allele frequency in the case group and the control group were not statistically significant differences; Meta analysis showed that the distribution of rs2234693, rs9340799 genotype and allele frequency in the case group and the group was also not statistically significant; monosomatotype C- The differences in the frequency of A, C-G and T-G between the case group and the control group were statistically significant (P 0.05). The differences in the three in women were still statistically significant (P was 0.0002,0.012 and 0.0035 respectively), and the distribution of C-A in males was statistically significant (P=0.0036).
The difference of the 2. first age in the rs2234693 locus co dominant model was statistically significant (P=0.02), and it was still significant in women (P=0.004) after sex stratification, and the difference in the symptom score of impulse control disorder (P=0.015) and its subtraction (P=0.003) among the different genotypes of rs2234693 was statistically significant. The difference of general psychopathological scores of PANSS among different genotypes of rs2234693 was statistically significant (P=0.048), and there was significant difference in the reduction rate of PANSS general psychopathological score among different genotypes of rs2234693 in women (P=0.045), and in the aripiprazole group, there were different genotypes in the aripiprazole group after the drug substratification. There was a statistically significant difference in the difference in the reduction of the symptoms of the symptoms (P=0.015), but in the risperidone group, the difference in the reduction of the symptoms of the impulsive control disorder was statistically significant (P=0.006).
There was no significant difference in the distribution of 3.MiR-137 gene polymorphic loci rs66642155 (there were series repeats MU, no WT) and rs1625579 (A/C) genotype frequency in case group and control group, and the initial age of rs66642155 polymorphic WT genotype carriers was later than that of MU genotype carriers, and the difference was statistically significant (P=0). .045); the baseline PANSS positive symptoms among the different genotype carriers of rs66642155, the positive factors in the five factor, the paranoid symptoms and the volitional disorders were all statistically significant (P 0.05). After the sex stratification, the PANSS positive syndrome among the men with different genotype of rs66642155 in the male, the positive factor of the five factor, the positive factor of the five factor, delusional The difference in symptom scores was still statistically significant (P values were 0.003,0.001 and 0.002), but only paranoid symptoms in women were statistically significant (P=0.03).
conclusion
1. in Chinese Han population, the single polymorphic loci of ESR a gene and rs9340799 are not associated with SZ, but their haplotype is related to the susceptibility to SZ. To some extent, the ESR alpha gene is a candidate gene for SZ, but rs66642155 and rs1625579 are not associated with miR-137 gene polymorphisms and do not support it as a SZ syndrome. Selection of genes;
2. ESR alpha and miR-137 genes were associated with the initial age of SZ; the general psychopathological symptoms of ESR alpha gene CC (rs2234693) genotype carriers were more prominent, and the ESR a gene was associated with the general psychopathological symptoms of SZ; the positive symptoms of the miR-137 gene WT (rs66642155) genotype carriers were stricter, and the miR-137 genes were associated with the positive symptoms.
3. ESR alpha gene is associated with the efficacy of SZ in general psychopathological symptoms. Aripiprazole has a more significant effect on the symptoms of CC (rs2234693) genotype carriers, while risperidone is more effective for its impulsive control disorders.
【学位授予单位】：新乡医学院
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R749.3

【参考文献】