本文選題：精神分裂癥 + 雌激素受體α��； 參考：《新鄉(xiāng)醫(yī)學(xué)院》2013年碩士論文

【摘要】：背景 精神分裂癥是一種重性精神疾病,癥狀復(fù)雜、異質(zhì)性強(qiáng),其病因和發(fā)病機(jī)制至今未明。遺傳因素在精神分裂癥的病理機(jī)制中起到重要作用。雌激素假說認(rèn)為雌激素在精神分裂癥中起保護(hù)作用,雌激素受體(Estrogen receptor, ESR)的遺傳變異可能影響雌激素這一生物學(xué)作用,其基因多態(tài)性可能與精神分裂癥的易感性有關(guān)。而基于候選基因策略的另一基因微小RNA-137(MicroRNA137, miR-137)是能影響神經(jīng)發(fā)育的小RNA分子,其遺傳變異也可能與精神分裂癥有關(guān)。 目的 1.檢測(cè)中國(guó)豫北地區(qū)漢族人群中精神分裂癥患者和健康對(duì)照ESRa和miR-137基因4個(gè)多態(tài)性位點(diǎn)基因型,分析其基因多態(tài)性與精神分裂癥的遺傳關(guān)聯(lián)； 2.分析ESRa和miR-137基因多態(tài)性與精神分裂癥首發(fā)年齡、臨床癥狀和藥物療效之間的關(guān)系,進(jìn)一步探討其與精神分裂癥易感性的關(guān)系。 方法 1.篩選適合入組的中國(guó)豫北地區(qū)漢族人群精神分裂癥患者322例作為病例組,在治療前和治療6周后進(jìn)行陽性和陰性癥狀量表(Positive and negative syndrome scale, PANSS)評(píng)定；同時(shí)納入300例性別和年齡均與病例組匹配的健康志愿者作為對(duì)照組； 2.收集受試者的一般資料,抽取外周靜脈血5ml。從全血中提取基因組DNA,使用聚合酶鏈反應(yīng)擴(kuò)增ESRa和miR-137基因片段,并采用限制性片段長(zhǎng)度多態(tài)性技術(shù)和直接測(cè)序法分別對(duì)ESRa和miR-137基因多態(tài)性進(jìn)行基因型分析； 3.采用Haploview V4.1軟件進(jìn)行哈迪-溫伯格平衡分析；使用SPSS18.0軟件對(duì)ESRα和miR-137基因型在病例和對(duì)照組中的分布差異及其與精神分裂癥首發(fā)年齡、臨床癥狀和藥物療效等臨床表型的關(guān)系進(jìn)行分析；使用SHEsis在線軟件測(cè)量連鎖不平衡系數(shù)；采用SNPStats在線軟件進(jìn)行單體型分布差異分析； 4.采用Review Manager5.1軟件進(jìn)行ESRα基因多態(tài)性與精神分裂癥關(guān)聯(lián)的metα分析。 結(jié)果 1. ESRα基因多態(tài)性位點(diǎn)rs2234693(T/C)、rs9340799(A/G)基因型和等位基因頻率在病例組和對(duì)照組中分布的差異均無統(tǒng)計(jì)學(xué)意義；meta分析結(jié)果顯示rs2234693、rs9340799基因型和等位基因頻率在病例組和對(duì)照組的分布差異也無統(tǒng)計(jì)學(xué)意義；單體型C-A、C-G和T-G的頻率在病例組和對(duì)照組之間的差異具有統(tǒng)計(jì)學(xué)意義(P均0.05),按性別分層后,三者在女性中的差異仍具有統(tǒng)計(jì)學(xué)意義(P值分別為0.0002、0.012和0.0035),在男性中僅C-A的分布差異具有統(tǒng)計(jì)學(xué)意義(P=0.0036)； 2.首發(fā)年齡在rs2234693位點(diǎn)共顯性模型中比較差異具有統(tǒng)計(jì)學(xué)意義(P=0.02),按性別分層后在女性中仍有意義(P=0.004)；rs2234693不同基因型之間的沖動(dòng)控制障礙癥狀分(P=0.015)及其減分(P=0.003)的比較差異具有統(tǒng)計(jì)學(xué)意義,按性別分層后,在男性中rs2234693不同基因型之間PANSS一般精神病理評(píng)分比較差異具有統(tǒng)計(jì)學(xué)意義(P=0.048),在女性中僅rs2234693不同基因型之間PANSS一般精神病理評(píng)分減分率比較差異具有統(tǒng)計(jì)學(xué)意義(P=0.045)；藥物分層后,在阿立哌唑組rs2234693不同基因型之間緊張癥狀減分比較差異具有統(tǒng)計(jì)學(xué)意義(P=0.015),而在利培酮組沖動(dòng)控制障礙癥狀減分比較差異具有統(tǒng)計(jì)學(xué)意義(P=0.006)。 3.MiR-137基因多態(tài)性位點(diǎn)rs66642155(存在串聯(lián)重復(fù)序列為MU,無則為WT)和rs1625579(A/C)基因型頻率在病例組和對(duì)照組中的分布差異均無統(tǒng)計(jì)學(xué)意義；rs66642155位點(diǎn)多態(tài)性WT基因型攜帶者的首發(fā)年齡晚于MU基因型攜帶者,差異具有統(tǒng)計(jì)學(xué)意義(P=0.045)；rs66642155不同基因型攜帶者之間基線PANSS陽性癥狀、五因子中陽性因子、妄想癥狀和意志障礙癥狀分的差異均具有統(tǒng)計(jì)學(xué)意義(P均0.05)；按性別分層后,在男性中rs66642155不同基因型攜帶者之間PANSS陽性癥：狀、五因子中陽性因子、妄想癥狀分的差異仍具有統(tǒng)計(jì)學(xué)意義(P值分別為0.003、0.001和0.002),而在女性中只有妄想癥狀分的差異具有統(tǒng)計(jì)學(xué)意義(P=0.03)。 結(jié)論 1.在中國(guó)漢族人群中,ESRα基因單個(gè)多態(tài)性位點(diǎn)rs2234693和rs9340799與SZ不存在關(guān)聯(lián),但它們組成的單體型與SZ易感性有關(guān),一定程度上支持ESRα基因?yàn)镾Z候選基因；而miR-137基因多態(tài)性位點(diǎn)rs66642155和rs1625579與SZ不存在關(guān)聯(lián)性,不支持其為SZ候選基因； 2. ESRα和miR-137基因均與SZ首發(fā)年齡相關(guān)；ESRα基因CC(rs2234693)基因型攜帶者的一般精神病理癥狀更突出,ESRα基因與SZ一般精神病理癥狀相關(guān)；miR-137基因WT(rs66642155)基因型攜帶者陽性癥狀更嚴(yán)重,miR-137基因與SZ陽性癥狀相關(guān)； 3. ESRα基因與SZ一般精神病理癥狀的藥物療效相關(guān),阿立哌唑?qū)C(rs2234693)基因型攜帶者緊張癥狀的療效更顯著,而利培酮對(duì)其沖動(dòng)控制障礙癥狀的療效更明顯。
[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.
【學(xué)位授予單位】：新鄉(xiāng)醫(yī)學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2013
【分類號(hào)】：R749.3

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本文編號(hào)：2020279