本文選題：孤獨(dú)癥譜系障礙 + SHANK3��； 參考：《吉林大學(xué)》2017年碩士論文

【摘要】：孤獨(dú)癥譜系障礙(ASD)起病于嬰幼兒期,多在12~18個(gè)月齡癥狀逐漸出現(xiàn),是以持續(xù)性缺乏社會(huì)交流和社會(huì)互動(dòng)以及局限的、重復(fù)的行為、興趣或活動(dòng)為特征的一類嚴(yán)重影響兒童健康的神經(jīng)發(fā)育障礙性疾病。國內(nèi)外ASD的患病率均呈現(xiàn)逐年上升趨勢(shì),據(jù)WHO2013年估計(jì),全球每160個(gè)人中有1人患有ASD,男性患病率約為女性的4倍。目前無ASD的特效治療方法和藥物,ASD的預(yù)后差,可造成終生殘疾,多需終生照顧,給社會(huì)和家庭帶來巨大的經(jīng)濟(jì)和精神負(fù)擔(dān)。ASD的病因及發(fā)病機(jī)制尚不明確,研究表明腦內(nèi)突觸功能障礙可能會(huì)引發(fā)ASD,而編碼突觸多結(jié)構(gòu)域骨架蛋白的SHANK3基因,在棘突的形態(tài)構(gòu)建過程中和突觸的可塑性中發(fā)揮重要作用,可能是ASD的風(fēng)險(xiǎn)基因,但關(guān)于SHANK3基因多態(tài)性與ASD的關(guān)聯(lián)研究結(jié)果不一致,有待進(jìn)一步研究和探討。目的:探討SHANK3基因多態(tài)性與ASD易感性的關(guān)聯(lián)。方法:本研究基于病例-對(duì)照設(shè)計(jì)的方法,共納入470例研究對(duì)象,其中病例229例,對(duì)照241例。病例一部分來源于吉林大學(xué)白求恩第一醫(yī)院二部?jī)嚎凭驮\的ASD患者,另一部分來源于春光康復(fù)醫(yī)院體檢的ASD患者;對(duì)照來源于吉林大學(xué)白求恩第一醫(yī)院二部?jī)嚎茻o神經(jīng)精神疾患的正常兒童。應(yīng)用多重高溫連接酶檢測(cè)反應(yīng)技術(shù)(improved multiple ligase detection reaction,i MLDR)檢測(cè)SHANK3基因5個(gè)SNP位點(diǎn)(rs756638、rs4824116、rs76268556、rs9616915、rs75767639)的基因型。采用擬合優(yōu)度的χ2檢驗(yàn),判斷所選研究對(duì)象的基因型分布是否符合哈迪-溫伯格平衡定律(Hardy-Weinberg equilibrium,HWE)。通過χ2檢驗(yàn)來比較本文兩組研究對(duì)象在基因型和等位基因頻率分布上是否存在差異。運(yùn)用Haploview4.2軟件和在線SNPStats分析程序,計(jì)算各位點(diǎn)間的連鎖不平衡(LD)程度。采用在線SNPStats分析程序,分析在5種不同遺傳模型下各位點(diǎn)多態(tài)性與ASD是否存在關(guān)聯(lián)。采用SNPStats在線分析程序進(jìn)行單體型分析。結(jié)果:(1)本研究共納入470例研究對(duì)象,其中病例229例(男性191例,女性38例),對(duì)照241例(男性195例,女性46例),平均年齡均為4.00(3.00,5.00)歲,兩組研究對(duì)象性別、年齡分布差異均無統(tǒng)計(jì)學(xué)意義(P0.05)。(2)5個(gè)多態(tài)性位點(diǎn)的基因型分布均符合Hardy-Weinberg平衡定律(P0.05)。(3)rs756638、rs4824116、rs76268556、rs9616915和rs75767639位點(diǎn)的突變純合子在病例組中的頻率分別為5.7%、0.4%、0.0%、1.3%、0.4%,在對(duì)照組中分別為2.9%、1.2%、1.2%、1.2%、1.2%,突變等位基因在病例組中的頻率分別為19.2%、9.4%、9.0%、10.3%、8.8%,對(duì)照組中分別為16.7%、8.9%、7.5%、9.5%、8.9%,5個(gè)位點(diǎn)基因型和等位基因頻率在ASD組和對(duì)照組分布差異沒有統(tǒng)計(jì)學(xué)意義(P0.05)。(4)遺傳模型分析中,rs756638、rs4824116、rs76268556和rs75767639位點(diǎn)的最優(yōu)模型分別為,隱性模型(ORGG vs CC/GC=2.04,95%CI 0.80-5.20,P=0.13,AIC=652.0)、隱性模型(ORTTvs CT/CC=0.34,95%CI 0.04-3.34,P=0.32,AIC=657.5)、共顯性模型(ORTC vs CC=1.52,95%CI 0.91-2.54,P=0.038,AIC=654.0)和隱性模型(ORGG vs CC/GC=0.35,95%CI 0.04-3.36,P=0.33,AIC=656.1),而rs9616915多態(tài)性位點(diǎn),顯性模型(ORCT/CCvs TT=1.09,95%CI0.68-1.74,P=0.71,AIC=658.4)、超顯性模型(ORCTvs CC/TT=1.09,95%CI0.68-1.77,P=0.71,AIC=658.4)和相加模型(OR=1.08,95%CI 0.71-1.64,P=0.74,AIC=658.4)均為該位點(diǎn)的最優(yōu)遺傳模型。(5)單體型分析中,SHANK3基因5個(gè)多態(tài)性位點(diǎn)中任意2個(gè)、3個(gè)、4個(gè)和5個(gè)位點(diǎn)組成的單體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(P0.05)。結(jié)論:(1)未發(fā)現(xiàn)SHANK3基因rs756638、rs4824116、rs76268556、rs9616915、rs75767639位點(diǎn)的多態(tài)性與中國北方漢族ASD易感性存在關(guān)聯(lián)。(2)未發(fā)現(xiàn)SHANK3基因rs756638、rs4824116、rs76268556、rs9616915、rs75767639位點(diǎn)組成的各種單體型與中國北方漢族ASD易感性存在關(guān)聯(lián)。(3)SHANK3基因可能不是中國北方漢族ASD的易感基因。
[Abstract]:Autism spectrum disorder (ASD) onset in infantile period, more and more at 12~18 months of age, is a kind of neurodevelopmental disorder that seriously affects children's health, which is characterized by persistent lack of social communication and social interaction as well as limited, repetitive behavior, interest or activity. The prevalence rate of ASD at home and abroad is present year by year. The trend, according to WHO2013, is estimated that 1 out of 160 people in the world suffer from ASD and that the prevalence of men is about 4 times that of women. There are no ASD special treatment methods and drugs, and the poor prognosis of ASD can cause lifelong disability, more life-long care, and the cause and pathogenesis of great economic and mental burden.ASD to society and family are not clear, The study shows that the synaptic dysfunction in the brain may cause ASD, and the SHANK3 gene encoding the synaptic multiple domain skeleton protein plays an important role in the formation of the spinous process and the plasticity of the synapse. It may be the risk gene of ASD, but the correlation of the association between the SHANK3 gene polymorphism and ASD needs to be further studied. Objective: To explore the association of SHANK3 gene polymorphisms with ASD susceptibility. Methods: a total of 470 cases were included in this study based on case control design, including 229 cases of cases and 241 cases of control. A part of the case was derived from the ASD patients in two Department of pediatrics at Bethune First Hospital of Jilin University and the other part from spring light. The ASD patients in the physical examination of the rehabilitation hospital were derived from the normal children of two pediatric neuropsychiatric disorders in Bethune First Hospital of Jilin University. The improved multiple ligase detection reaction, I MLDR (I MLDR) was used to detect the 5 SNP loci of the SHANK3 gene. 75767639) genotype. Using the chi square test of goodness of fit, determine whether the genotype distribution of the selected research subjects conforms to the Hardy Weinberg equilibrium law (Hardy-Weinberg equilibrium, HWE). By the x 2 test, the difference between the genotype and allele frequency distribution of the two subjects in this paper is compared. The application of Haploview4.2 soft to the frequency distribution of the genotypes and alleles. An online SNPStats analysis program was used to calculate the degree of linkage disequilibrium (LD) between the points. Online SNPStats analysis program was used to analyze the association of polymorphisms with ASD under 5 different genetic models. The SNPStats online analysis program was used for haplotype analysis. (1) 470 subjects were included in this study. 229 cases (male 191 cases, female 38 cases), control 241 cases (male 195 cases, female 46 cases), average age is 4 (3.00,5.00) years old, two groups of subjects sex, age distribution difference is not statistically significant (P0.05). (2) 5 polymorphic loci distribution in line with the Hardy-Weinberg equilibrium law (P0.05). (3) rs756638, rs4824116, rs76268 556, the frequencies of mutant homozygotes in the rs9616915 and rs75767639 loci were 5.7%, 0.4%, 0%, 1.3%, 0.4% respectively. The frequencies of alleles in the control group were 2.9%, 1.2%, 1.2%, 1.2%, 1.2%, respectively. There was no significant difference in the distribution of genotype and allele frequencies between the ASD group and the control group (P0.05). (4) in the analysis of the genetic model, the optimal models of rs756638, rs4824116, rs76268556 and rs75767639 were the recessive models (ORGG vs CC/GC=2.04,95%CI 0.80-5.20, P= 0.13, AIC=652.0), and the recessive model 0.32, AIC=657.5), the co dominant model (ORTC vs CC=1.52,95%CI 0.91-2.54, P=0.038, AIC=654.0) and the recessive model (ORGG vs CC/GC=0.35,95%CI 0.04-3.36, P=0.33), and the dominant model. AIC=658.4) and the additive model (OR=1.08,95%CI 0.71-1.64, P=0.74, AIC=658.4) were the best genetic models for this loci. (5) in haplotype analysis, there was no significant difference in the distribution of haplotype frequencies of 5 polymorphic loci of SHANK3 gene in 2, 3, 4 and 5 loci (P0.05). Conclusion: (1) The polymorphism of the SHANK3 gene rs756638, rs4824116, rs76268556, rs9616915, rs75767639 loci was associated with the susceptibility to ASD in the Han nationality in northern China. (2) no SHANK3 gene rs756638, rs4824116, rs76268556, rs9616915, and all kinds of haplotypes were associated with the susceptibility to the Han nationality in northern China. (3) It may not be the susceptible gene of ASD in Han nationality in northern China.

【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R749.94

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