【作者】 纪育斌；

【导师】 韩东一； 王秋菊；

【作者基本信息】 中国人民解放军军医进修学院 ， 耳鼻咽喉头颈外科， 2010， 博士

【摘要】 听力障碍是人类最为常见感觉障碍之一,遗传因素在听力障碍致病因素中所占比例高达50%以上。耳聋基因的流行病学研究,不仅有利于揭示耳聋基因在人群中突变的流行病学特征,为耳聋疾病的早期诊断、早期干预、早期治疗和遗传咨询提供理论和数据支持,而且关系到我国人口整体素质的提高和国民经济的顺利发展。纵观近10年来对耳聋基因的流行病学研究发现,国内外在这类研究中都普遍存在的一个问题——不同研究数据结果差异性较大甚至相互矛盾。因此,为了准确反映我国耳聋基因的流行病学特征,找出导致研究数据之间差异性的影响因素,本课题通过文献回顾分析了目前我国耳聋基因流行学研究中存在的一些问题,并对我国大样本非综合征型感音神经性耳聋(nonsyndromic sensorineural hearing loss, NSHL)人群进行分组对比研究,对不同分组样本的常见核染色体耳聋基因GJB2和SLC26A4,以及线粒体DNA 12SrRNA A1555G (mitochondrial DNA 12SrRNA A1555G, mtDNAA1555G)的流行病学特征进行研究,不仅取得了不同来源和特征耳聋人群三种常见耳聋基因的流行病学数据资料,而且揭示了导致耳聋基因流行病学数据之间出现差异性的影响因素。本研究共分两个部分：第一部分耳聋基因突变流行病学研究现状分析本研究首先回顾了近10年来有关mtDNAA1555G、GJB2基因和SLC26A4基因突变的流行病学文献,提出了目前这类研究中存在的主要问题——数据之间存在较大的差异性甚至矛盾。为了进一步探讨导致这些差异性的原因,在第一部分第一章中我们检索了1996年～2008年3月间报道的我国各地区mtDNAA1555G突变流行病学文献资料,对每篇文献中样本量的选择、样本特征、地域分布、突变频率特征及该突变与氨基糖甙类抗生素(aminoglycoside antibiotics, AmAn)应用情况相互关系等多个因素进行分析。发现在国内mtDNAA1555G突变频率的流行病学调查中存在样本选择量不足、地区数据差异较大、缺少种族和年龄划分等较多问题。其中样本量差异可能是影响耳聋基因流行病学数据差异性的重要因素之一。因此在第二章中,采用严格的样本量估计公式,选择山东省NSHL耳聋人群进行mtDNA A1555G、GJB2和SLC26A4三种常见耳聋基因研究。在山东省485例患者中,mtDNAA1555G突变频率为5.57%；GJB2致病突变频率为24.12%,突变携带率为34.34%,高于多数的国内报道；SLC26A4基因致病突变频率为7.42%,突变携带率为13.61%。485名患者中有37.11%是由这三种基因突变导致的耳聋；推断山东省约有2.45万NSHL患者是由这三种基因突变所导致。第二部分ntDNAA1555G,GJB2和SLC26A4基因流行病学数据影响因素研究在本课题第二部分研究中,着重根据患者的来源和特征进行分组对比研究,对不同来源和特征的NSHL患者三种耳聋基因突变频率进行比较,找出可能影响耳聋基因突变频率的重要因素。在第一章研究中,发现mtDNAA1555G基因突变频率会受到研究样本中家系患者与散发患者数量比例,药物性耳聋(aminoglucoside antibiotics induced deafness, AAID)患者与非AAID患者数量比例的影响。对于散发样本来讲,聋校与门诊来源的患者数量比例变化也会影响到该基因突变频率。在第二章研究中,发现GJB2基因突变频率受到样本中语前聋与语后聋患者数量比例的影响；对于散发样本,聋校与门诊来源的患者数量比例变化同样也会影响到GJB2基因突变频率。在第三章研究中,发现SLC26A4突变频率相对于mtDNAA1555G和GJB2基因来讲,受到更多因素的影响,研究样本中家系患者与散发患者,语前聋患者与语后聋患者,门诊患者与聋校患者,EVAS (enlarged vestibular aqueduct syndrome,EVAS)患者与非EVAS患者的样本比例变化均是影响其数据结果的主要因素。通过两个部分的研究,本研究认为在耳聋致病基因的流行病学研究中,研究样本的样本量,样本来源和特征等诸多因素影响着流行病学数据资料的准确性。对不同基因来讲,这些影响因素的作用效应也是不同的。因此,为了准确反映耳聋基因的流行病学特征,必须进行大样本研究,根据不同的基因特征制定正确的符合流行病学要求的样本纳入标准,确保样本具有相同的来源和特征。只有这样,才能有效避免研究数据之间出现差异性,保证研究结果的准确性和稳定性,为防聋治聋措施和策略的制定提供准确的数据支持。更多还原

【Abstract】 Hearing loss is the most common sensory impairment. Genetic factors are attributed to over 50% of all etiological factors. Conducting genetic epidemiological studies of deafness genes will be valuable to revealing epidemiological characteristics of deafness genes, and providing important data for prophylaxis, counseling, early diagnosis, early intervention and treatment. But reviewing epidemiological literatures about deafness genes in the past 10 years, we found that there were large differences and some inconsistencies data from many studies. In order to reveal the epidemiological characteristics of deafness genes in Chinese populations and find some factors leading differences, we used group studies and comparative studies to reveal the mutation characteristics of mtDNA A1555G, GJB2 and SLC26A4, and reveal some impact factors of mutation frequencies in the three genes. Based on these impact factors, we suggested it was very necessary to regulate the sample inclusion criteria according to individual characteristics of every gene in order to make these criteria fit the standard of epidemiological study. This study is divided into two parts:Part one:The Situation Analysis of Epidemiological Studies of mitochondrial DNA 12SrRNAA1555G, GJB2 and SLC26A4 Mutations.In part one, we firstly reviewed some epidemiological data of the three common deafness genes in past ten years, and indicated the large differences and contradictions existing between these data were one of main problems in present epidemiological studies. In the first chapter of Part one, we collected all published epidemiological literatures about Chinese mtDNA A1555G mutation from 1996 to March,2008. By literature review and statistical analysis, we believed some deficiencies, such as insufficiency of samples, age bias and area bias, existed in epidemiological researches about mtDNA A1555G mutation in China. We believed that the number of samples was a very important factor that influenced the accuracy of epidemiological data in the past studies. So in the second chapter, we determined the number of samples by using the formula for sample size estimates, enrolled 485 patients with NSHL in Shandong Province and screened mutations of the three common deafness genes in these patient. Of 485 patients, 180 patients (37.11%) had two mutated alleles (homozygote and compound heterozygote) of GJB2 (24.12%) and SLC26A4 (7.42%) and mtDNA A1555G (5.57%). We supposed that about 24.5 thousand deaf-mute patients who were caused by the three sensitive deafness genes mutation in Shandong province.Part two:Group and Comparative studies of Epidemiological data of mtDNA A1555G, GJB2 and SLC26A4 mutationsIn the Part two study, we divided research samples into different subgroups according to their sources and characteristics, and then we compared the mutation frequencies of the three deafness genes between different subgroups in order to find some factors that influenced the accuracy of epidemiological data of the three deafness genes mutation frequencies. In Chapter one, we found mtDNA A1555G mutation frequency was influenced by the proportionalities of familial and sporadic patients, AAID and non-AAID patients in research samples. The proportionality of SES patients and outpatients in sporadic samples was also important impact factor. In Chapter two, we found GJB2 mutation frequency was influenced by the proportionality of prelingual and postlingual patients among samples. The proportionality of SES patients and outpatient in sporadic samples was also impact factor. In Chapter three, compared with GJB2 and mtDNA A1555G, the mutation frequency of SLC26A4 were influenced by more factors. The proportionality of familial and sporadic patients, prelingual and postlingual patients, SES and outpatients, EVAS and non-EVAS patients all influenced the accuracy of SLC26A4 mutation frequency.We suggested that Ethnic background, samples’sources and characteristics including familial or sporadic patients, hospital or SES patients, prelingual or postlingual patients, EVAS and non-EVAS patients, AAID or non-AAID patients were all important impact factors in epidemiological studies. But the effects of these factors were different or converse for different gene. So we must regulate the correct and reasonable sample inclusion criteria according to different genes’ characteristics in order to effectively avoid significant differences among data of the epidemiological studies and ensure the accuracy and stability of research results.更多还原