SHANK3基因多态性与孤独症谱系障碍易感性的关联性研究

发布时间：2018-05-11 08:27

本文选题：孤独症谱系障碍 + SHANK3　；参考：《吉林大学》2017年硕士论文

【摘要】：孤独症谱系障碍(ASD)起病于婴幼儿期,多在12~18个月龄症状逐渐出现,是以持续性缺乏社会交流和社会互动以及局限的、重复的行为、兴趣或活动为特征的一类严重影响儿童健康的神经发育障碍性疾病。国内外ASD的患病率均呈现逐年上升趋势,据WHO2013年估计,全球每160个人中有1人患有ASD,男性患病率约为女性的4倍。目前无ASD的特效治疗方法和药物,ASD的预后差,可造成终生残疾,多需终生照顾,给社会和家庭带来巨大的经济和精神负担。ASD的病因及发病机制尚不明确,研究表明脑内突触功能障碍可能会引发ASD,而编码突触多结构域骨架蛋白的SHANK3基因,在棘突的形态构建过程中和突触的可塑性中发挥重要作用,可能是ASD的风险基因,但关于SHANK3基因多态性与ASD的关联研究结果不一致,有待进一步研究和探讨。目的:探讨SHANK3基因多态性与ASD易感性的关联。方法:本研究基于病例-对照设计的方法,共纳入470例研究对象,其中病例229例,对照241例。病例一部分来源于吉林大学白求恩第一医院二部儿科就诊的ASD患者,另一部分来源于春光康复医院体检的ASD患者;对照来源于吉林大学白求恩第一医院二部儿科无神经精神疾患的正常儿童。应用多重高温连接酶检测反应技术(improved multiple ligase detection reaction,i MLDR)检测SHANK3基因5个SNP位点(rs756638、rs4824116、rs76268556、rs9616915、rs75767639)的基因型。采用拟合优度的χ2检验,判断所选研究对象的基因型分布是否符合哈迪-温伯格平衡定律(Hardy-Weinberg equilibrium,HWE)。通过χ2检验来比较本文两组研究对象在基因型和等位基因频率分布上是否存在差异。运用Haploview4.2软件和在线SNPStats分析程序,计算各位点间的连锁不平衡(LD)程度。采用在线SNPStats分析程序,分析在5种不同遗传模型下各位点多态性与ASD是否存在关联。采用SNPStats在线分析程序进行单体型分析。结果:(1)本研究共纳入470例研究对象,其中病例229例(男性191例,女性38例),对照241例(男性195例,女性46例),平均年龄均为4.00(3.00,5.00)岁,两组研究对象性别、年龄分布差异均无统计学意义(P0.05)。(2)5个多态性位点的基因型分布均符合Hardy-Weinberg平衡定律(P0.05)。(3)rs756638、rs4824116、rs76268556、rs9616915和rs75767639位点的突变纯合子在病例组中的频率分别为5.7%、0.4%、0.0%、1.3%、0.4%,在对照组中分别为2.9%、1.2%、1.2%、1.2%、1.2%,突变等位基因在病例组中的频率分别为19.2%、9.4%、9.0%、10.3%、8.8%,对照组中分别为16.7%、8.9%、7.5%、9.5%、8.9%,5个位点基因型和等位基因频率在ASD组和对照组分布差异没有统计学意义(P0.05)。(4)遗传模型分析中,rs756638、rs4824116、rs76268556和rs75767639位点的最优模型分别为,隐性模型(ORGG vs CC/GC=2.04,95%CI 0.80-5.20,P=0.13,AIC=652.0)、隐性模型(ORTTvs CT/CC=0.34,95%CI 0.04-3.34,P=0.32,AIC=657.5)、共显性模型(ORTC vs CC=1.52,95%CI 0.91-2.54,P=0.038,AIC=654.0)和隐性模型(ORGG vs CC/GC=0.35,95%CI 0.04-3.36,P=0.33,AIC=656.1),而rs9616915多态性位点,显性模型(ORCT/CCvs TT=1.09,95%CI0.68-1.74,P=0.71,AIC=658.4)、超显性模型(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)均为该位点的最优遗传模型。(5)单体型分析中,SHANK3基因5个多态性位点中任意2个、3个、4个和5个位点组成的单体型频率在病例组和对照组中的分布差异均无统计学意义(P0.05)。结论:(1)未发现SHANK3基因rs756638、rs4824116、rs76268556、rs9616915、rs75767639位点的多态性与中国北方汉族ASD易感性存在关联。(2)未发现SHANK3基因rs756638、rs4824116、rs76268556、rs9616915、rs75767639位点组成的各种单体型与中国北方汉族ASD易感性存在关联。(3)SHANK3基因可能不是中国北方汉族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.

【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R749.94

【参考文献】