聋病遗传与环境相关高危因素的流行病学研究

发布时间：2018-06-08 11:18

本文选题：耳聋 + 高危因素　；参考：《中国人民解放军医学院》2014年博士论文

【摘要】：据WHO2005年估计全球耳聋残疾人达2.78亿，占世界总人口4.6%，已成为世界性的公共卫生问题，给家庭和社会带来沉重负担。作为世界人口大国，我国因聋致哑的问题尤为突出。耳聋的早期诊断、早期干预和早期干预已成为防聋控聋工作的重点，而作为相应策略和措施的制订的依据，准确反映我国聋病流行病学特征及环境与遗传高危因素与聋病的相关性数据尤为重要。本研究以在全国范围内推广实施新生儿听力与基因联合筛查为基础，分别在作为普通人群的新生儿、作为高危人群的NICU新生儿开展大规模聋病遗传和环境高危因素流行病学研究；并对具有特殊表型的听神经病在不同人群中进行了发病情况调查及高危因素分析；同时在王秋菊教授1999-2002博士论文《遗传性耳聋家系的收集收集、保存及基因定位研究》成果和保存的聋病资源基础之上，建立了中国聋病基因库，为进一步聋病基因研究及遗传和环境的复杂互做与患病危险的相关研究奠定基础。本研究共分四个部分：第一部分新生儿听力与基因联合筛查的耳聋高危因素与流行病学特点分析选取2006年12月-2014年3月实施新生儿听力及基因联合筛查的118106例新生儿作为筛查对象，分析全国总体及各地区的新生儿中听力与基因联合筛查流行病学特点，，并分析研究遗传和环境因素与筛查结果的相关性与差异。研究获得了新生儿全国总体与13省市的听力与基因联合筛查数据，118106例新生儿听力与基因联合筛查均通过100740例，即联合筛查通过率为85.30%。未通过17366例，即联合筛查未通过率为14.70%，其中，听力与基因均未通过867例，听力筛查通过而基因未通过2215例，听力筛查未通过而基因通过14284例。长江以南各省市听力筛查未通过率一般明显高于长江以北的城市，13个省市听力初筛未通过率在0%-25.72%之间，总体为12.83%。7个省市间听力复筛OAE未通过率在1.32%-19.20%之间，总体听力复筛未通过率约为2.40%。13个省市间比较，耳聋高危因素发生率、NICU住院患儿比例、新生儿听力初筛和复筛未通过情况，GJB2基因突变率、SLC26A4基因突变率均存在明显地域差异（P0.01）。经过卡方检验及相关性分析，发现有高危因素者、聋病易感基因异常者、存在GJB2、SLC26A4异常者在筛查人群中的构成比不同是各地区筛查结果差异的主要原因。本研究对不同听力复筛方式及联合筛查与单纯听力筛查间均进行了统计分析，发现选择DPOAE联合AABR的方式进行复筛，听力与基因联合筛查明显优于单纯采用听力筛查可明显提高检出率（P0.01）。通过听力与基因联合筛查结果，我们将全国118106例新生儿分为四类人群进行不同的随访和干预策略。（1）进入目前成熟的0-6岁听力筛查随访流程的新生儿100740例，约占全部新生儿中的85.30%。（2）立即进入听力学、医学及遗传学联合诊断流程的新生儿867例，约占全部新生儿的0.73%。（3）进入终生高度预警流程的新生儿2215例，约占全部新生儿的1.88%。（4）需进行听力学诊断流程的新生儿14284例，约占全部新生儿的12.09%，为新基因研究重点人群。本研究发现存在耳聋高危因素新生儿听力筛查与基因筛查的未通过率均明显高于无高危因素新生儿，听力筛查为33.68%：10.29%；基因筛查为4.25%：2.41%。对目前公认的13种耳聋高危因素在普遍人群新生儿中进行了相关和回归分析，发现明确危险因素8种，按其风险增加倍数依次为临床上存在或怀疑有与听力障碍有关的综合征或遗传病（2.978倍）、高胆红素血症达到换血要求（1.879倍）、巨细胞病毒、风疹病毒、疱疹病毒、梅毒或弓形体病等引起的宫内感染（1,757倍）、新生儿重症监护病房（NICU）住院超过5天（1.122倍）、早产儿呼吸窘迫综合征（0.928倍）、儿童期永久性听力障碍家族史（0.770倍）、新生儿窒息Apgar评分1分钟0-4分或5分钟0-6分（0.659倍）、颅面畸形（0.659倍）、基因异常（0.279倍）。发现出生体重低于1500克、病毒性或细菌性脑膜炎、体外膜肺氧合治疗、机械通气超过48小时等4种因素可能为危险因素。第二部分中国NICU新生儿耳聋高危因素的多中心研究本研究以NICU经历的活产新生儿为研究对象，同时随机选取同时期、同地区正常产房新生儿为对照，实施统一的新生儿听力与基因联合筛查，进行多中心、前瞻性的临床对照研究，以获得中国耳聋高危人群NICU新生儿听力与基因联合筛查的流行病学特征，分析NICU新生儿与普通产房新生儿之间耳聋发病特点的差异。研究发现：NICU新生儿听力筛查与基因筛查未通过率明显高于普通产房新生儿。4个常见耳聋基因20个热点突变的基因筛查方案在提高检出率方面优于4个位点的方案。 NICU新生儿初筛DPOAE未通过率约为14.92%，普通产房的新生儿未通过率为8.90%，两组间未通过率差异有统计学意义（P0.05），前者为后者的1.68倍。AABR听力初筛NICU组未通过率约为8.06%，普通产房新生儿未通过率为0.05%，差异有统计学意义（P0.01），NICU新生儿AABR初筛未通过率为普通产房的161.2倍。NICU新生儿基因筛查突变检出率约为11.32%；其中，GJB2突变检出率为5.83%，SLC26A4突变检出率为3.77%，GJB3突变检出率为0.51%，MTRNR1突变检出率为0.69%。普通产房新生儿基因筛查突变检出率约为4.45%；其中，GJB2突变检出率为1.93%；SLC26A4突变检出率为1.98%；GJB3突变检出率为0.43%；MTRNR1突变检出率为0.11%。NICU新生儿的基因突变携带率、GJB2突变携带率、SLC26A4突变携带率与普通产房新生儿间有显著性差异（P0.01）。而GJB3和MTRNR1突变两组间无差异（P0.05）。第三部分听神经病谱系障碍的流行病学特征与高危因素分析本研究针对10093例（16993耳）感音神经性聋患者、5134例新生儿及1406例外院上转需进行听力学诊断婴幼儿，回顾性分析听神经病谱系障碍（ANSD）的流行病学特征，并对其相关因素进行初步分析。研究发现：ANSD在感音神经性聋患者中发病率最高，其次为上转婴幼儿，新生儿中发病率最低，发病率分别为2.259%，1.067%，0.156%（Χ2=15644.151，P0.001）。在感音神经性聋人群中ANSD患者年龄3个月-73岁，平均17.7岁；病程1个月-20年，平均3.4年。男女发病率无差异（Χ2=1.262，P0.05）。双侧发病率约为3.043%，单侧约为0.564%，单双侧发病比例为1:11.67；左侧发病率为0.307%，右侧约为0.830%，单双侧间（Χ2=60.793，P0.01）、左侧与右侧间（Χ2=3.891，P0.05）发病率均有显著性差异。0-6岁ANSD发病率约为4.900%，7-12岁约为2.222%，13-18岁约为3.297%，19-30岁约为5.432%，31-60岁约为0.705%，60岁以上约为0.168%，不同年龄组发病率间有非常显著性差异（Χ2=197.482，P0.01）。听力损失轻度者发病率约为2.246%，中度约为2.750%，重度约为4.738%，极重度约为1.682%，四组发病率间差异有统计学意义（Χ2=84.903，P0.01）；听力损失严重程度与ANSD发病率间存在相关性（r=0.19，P0.05）。ANSD患者纯音听力曲线以低频上升型最常见（48.122%，不同曲线类型间P0.01）；鼓室图曲线以A型为主（78.879%，不同鼓室图间P0.01），镫骨肌反射多引不出（76.724%）；CM可引出率约为57.895%。患者年龄及病程分别与PTA、ASSR阈值、言语识别率具有相关性（P0.01），与AERP无明显相关性（P0.05）。在相同病程水平，PTA与ASSR均值间存在显著性差异（P0.05）。耳聋高危因素存在率约为11.842%，以高胆红素血症、家族史、早产多见。在新生儿人群中ANSD发病率约为0.156%。不同性别间和不同分娩方式间发病率无显著性差异（P0.05）。DPOAE初筛通过的新生儿中ANSD的发病率约为0.087%，未通过者约为0.765%，二者间存在非常显著性差异（P0.01）。AABR复筛未通过者的ANSD的发病率约为10.127%，通过者约为0.160%，二者间有非常显著性差异（P0.01）。DPOAE初筛未通过（r=-0.052，P0.01）和AABR复筛未通过（r=-0.316，P0.01）是新生儿ANSD的危险因素；ANSD在具有耳聋高危因素新生儿中发病率为约为0.255%，在早产儿中的发病率约为0.429%，早产与ANSD无明显相关性（r=0.015，P0.05）。在上转进行听力学诊断的婴幼儿中听神经病患儿ANSD发病率为1.067%。男女间无差异（P0.05）。听力损失均为重度和极重度，其中重度聋婴幼儿中发病率约占5.263%，极重度约为6.686%，二者间差异有统计学意义（P0.05）。无NICU住院史上转婴幼儿发病率约为0.394%，有NICU住院史者约为1.136%，NICU住院史与ANSD发病间无明显相关性（r=0.030，P0.05）。无耳聋高危因素上转婴幼儿ANSD发病率约为0.933%，存在高危因素者发病率约为2.469%，早产低体重儿ANSD发病率约为5.882%，高胆红素血症患儿ANSD发病率为2.326%，但早产低体重、高胆红素血症均与ANSD无明显相关性（P0.05）。第四部分中国聋病基因库的建立与样本管理本研究在王秋菊教授1999-2002博士论文《遗传性耳聋家系的收集收集、保存及基因定位研究》成果和保存的聋病资源基础之上，建立了中国聋病基因库，实现了聋病信息与样本资源的信息化和自动化管理。共收集耳聋和进行听力学检查患者资料580778例次，保存听力学资料212951例次，血样241405份，DNA32371份。其中，听觉障碍大小家系及散发病例8028例，听神经病谱系障碍331例，是国际上该领域听觉障碍遗传资源最为丰富的研究小组之一。同时，收集了118106例新生儿听力与基因联合筛查、1406例上转进行听力学诊断的婴幼儿的信息及样本资源、对2880例聋校学生进行了基因筛查，收集感音神经性聋15588例，突发性耳聋1120例及40万例次以上的临床听力学聋病患者资料，为进一步聋病基因研究及遗传和环境的复杂互做与患病危险的相关研究奠定基础。
[Abstract]:According to the estimated 278 million deafness in WHO2005 and 4.6% of the world's total population, it has become a worldwide public health problem and has brought a heavy burden to the family and society. As a big country in the world, the problem of deaf mutes is particularly prominent in our country. Early diagnosis of deafness, early intervention and early intervention have become the key to deafness and deafness. As a basis for formulating the corresponding strategies and measures, it is very important to accurately reflect the epidemiological characteristics of the deafness and the correlation data between the environment and the genetic risk factors and the deafness.
This study was based on the promotion and implementation of neonatal hearing and gene screening throughout the country. The epidemiological studies on the genetic and environmental risk factors of large-scale deafness were carried out in the newborns of the general population as the NICU newborns of the high risk population, and the auditory neuropathy with special phenotypes was carried out in different populations. At the same time, on the basis of the collection and collection of the hereditary deafness family, the results of conservation and gene localization, and the preservation of the deafness resources, Professor Wang Qiuju, Professor Wang Qiuju, established a Chinese deafness gene bank for further deafness research and the complex interaction and disease of heredity and environment. The risk related research lays the foundation.
This study is divided into four parts: Part One: high risk factors and epidemiological characteristics of hearing loss combined with genetic screening in newborns
118106 newborns with neonatal hearing and gene screening in March -2014 in December 2006 were selected as screening subjects. The epidemiological characteristics of hearing and gene screening in the whole country were analyzed, and the correlation and difference between genetic and environmental factors and screening results were analyzed.
The study obtained the data of hearing and gene screening in the whole country of the whole country and 13 provinces and cities. 118106 cases of newborn hearing and gene screening were all passed through 100740 cases, that is, the rate of 85.30%. was not passed in 17366 cases, that is, the failure rate of joint screening was 14.70%, of which 867 cases of hearing and gene were not passed and hearing screening was passed. The hearing screening was not passed in 2215 cases, and the hearing screening was not passed in 14284 cases. The rate of hearing screening was generally higher than that of the north of the Yangtze River in the south of the Yangtze River. The hearing loss rate was between the 13 provinces and cities in the 13 provinces and cities. The overall hearing loss rate was between the 12.83%.7 provinces and cities, the total hearing loss rate was between the 1.32%-19.20% and the overall hearing. The rate of non passing of rescreening was about 2.40%.13 provinces and cities, the incidence of high risk factors of deafness, the proportion of NICU hospitalized children, newborn hearing screening and rescreening, the mutation rate of GJB2 gene and the mutation rate of SLC26A4 gene had obvious regional difference (P0.01). After chi square examination and correlation analysis, it was found that people with high risk factors were susceptible to deafness. Among the abnormal gene users, the difference in the constituent ratio between the GJB2 and SLC26A4 abusers in the screening population is the main reason for the difference in screening results.
In this study, the statistical analysis of different hearing screening methods, combined screening and simple hearing screening was carried out. It was found that the selection of DPOAE combined with AABR for rescreening, hearing and gene screening were obviously better than those with simple hearing screening (P0.01). 118106 newborns were divided into four groups to carry out different follow-up and intervention strategies. (1) 100740 newborns entered the mature 0-6 year old hearing screening process, accounting for about 85.30%. (2) of all newborns entering audiology, 867 cases of newborns with medical and genetics diagnostic flow, accounting for about 0.73%. (3) of all newborns. 2215 newborns entered the lifetime early warning process, accounting for about 1.88%. (4) of all newborns, 14284 cases of newborns requiring audiological diagnosis process, accounting for 12.09% of all newborn babies, as the key population of new gene research.
This study found that the rate of hearing screening and gene screening in newborn infants with high risk of deafness was significantly higher than that of newborns without high risk factors. Hearing screening was 33.68%:10.29%, and gene screening was 4.25%:2.41%. for 13 high-risk factors of deafness in the general population. 8 kinds of risk factors were identified, and the multiplier of the risk increased in order of clinical existence or suspected of hearing impairment related syndrome or hereditary disease (2.978 times), hyperbilirubinemia reached the demand for change of blood (1.879 times), cytomegalovirus, rubella virus, herpes virus, syphilis or toxoplasmosis (1757 times), severe neonatal severe The intensive care unit (NICU) was hospitalized for more than 5 days (1.122 times), premature infant respiratory distress syndrome (0.928 times), family history of childhood permanent hearing impairment (0.770 times), neonatal asphyxia Apgar score of 1 minutes, 0-4 or 5 minutes 0-6 (0.659 times), craniofacial malformation (0.659 times), and genetic abnormalities (0.279 times). The birth weight was less than 1500, viral or bacterial 4 factors, including meningitis, extracorporeal membrane oxygenation, mechanical ventilation for more than 48 hours, may be a risk factor.
The second part is a multicenter study on the high risk factors of NICU deafness in China.
In this study, the live birth neonates experienced by NICU were studied at the same time. At the same time, the same period was selected and compared with the normal delivery room newborns in the region. A unified neonatal hearing and gene screening was carried out, and a multicenter, prospective clinical control study was carried out to obtain a combined hearing and gene screening for NICU neonates at high risk of hearing loss in China. Epidemiological characteristics were analyzed to analyze the difference of deafness between NICU neonates and neonates in delivery room.
The study found that the unpassed rate of NICU newborn hearing screening and gene screening was significantly higher than that of the.4 common deafness gene mutation screening program in the normal delivery room, which was better than the 4 loci in improving the detection rate.
The rate of initial screening of DPOAE in NICU newborn was about 14.92%, the rate of non passing of newborns in the ordinary delivery room was 8.90%, and the difference between the two groups was statistically significant (P0.05). The former was 1.68 times of the latter, the failure rate of NICU group in the NICU group was about 8.06%, and the rate of failure in the general delivery room newborns was 0.05%, and the difference was statistically significant (P0.01), NICU The rate of mutation detection of the 161.2 times.NICU newborn gene screening in the normal delivery room was about 161.2 times that of the normal delivery room. The detection rate of GJB2 mutation was 5.83%, the detection rate of SLC26A4 mutation was 3.77%, the detection rate of GJB3 mutation was 0.51%, and the detection rate of MTRNR1 mutation was about 4.45% in the 0.69%. general delivery room. Among them, GJB2 mutation detection rate was 1.93%, SLC26A4 mutation detection rate was 1.98%, GJB3 mutation detection rate was 0.43%, MTRNR1 mutation detection rate was 0.11%.NICU neonatal gene mutation carrying rate, GJB2 mutation carrier rate, SLC26A4 mutation carrier rate and normal delivery room newborns have significant difference (P0.01). GJB3 and MTRNR1 mutation two groups were not. Differences (P0.05).
The third part is the epidemiological characteristics and risk factors of auditory neuropathy spectrum disorders.
In this study, 10093 cases (16993 ears) of sensorineural deafness, 5134 cases of newborns and 1406 exceptions for audiology diagnosis of infants, the epidemiological characteristics of auditory neuropathy pedigree disorder (ANSD) were analyzed retrospectively, and the related factors were analyzed.
The study found that the incidence of ANSD was the highest in patients with sensorineural deafness, followed by upturn infants and the lowest incidence in newborns, with the incidence of 2.259%, 1.067%, and 0.156% respectively (2=15644.151, P0.001).
Among the people with sensorineural hearing loss, ANSD patients were aged 3 months -73 years old, with an average of 17.7 years of age; the course of disease was 1 months -20, averaging 3.4 years. There was no difference between male and female (2=1.262, P0.05). The incidence of bilateral incidence was about 3.043%, unilateral was 0.564%, the incidence of unilateral and bilateral was 1:11.67; Zuo Cefa's disease rate was 0.307%, and the right was about 0.830%, single and bilateral (2=60.793). There was a significant difference in the incidence of 2=3.891, P0.05 between the left and the right (P0.01). The incidence of ANSD was about 4.900% at the age of.0-6, about 2.222% at the age of 7-12, 3.297% in 13-18, 5.432% in 19-30, 0.705% in 31-60, and about 60 years of age. The incidence of hearing loss in different age groups was very significant (2=197.482, P0.01). Hearing loss was light. The incidence of the disease was about 2.246%, the moderate was about 2.750%, the severity was about 4.738%, and the extreme severity was about 1.682%. The difference between the four groups was statistically significant (2=84.903, P0.01); there was a correlation between the severity of hearing loss and the incidence of ANSD (r=0.19, P0.05), the most common (48.122%, different tune) of the pure tone audiometric curve in the patients with.ANSD. P0.01 between line types); the tympanoplasty curve was mainly A type (78.879%, different tympanum P0.01), stapes muscle reflex was not more than (76.724%); CM elicitation rate was about 57.895%. patients with PTA, ASSR threshold, speech recognition rate correlation (P0.01), and no significant correlation with AERP (P0.05). In the same course level, PTA and ASSR There was a significant difference between the mean (P0.05). The high risk factor for deafness was about 11.842%, with hyperbilirubinemia, family history and premature birth.
In newborns, the incidence of ANSD was about 0.156%. between different sexes and different modes of delivery (P0.05), the incidence of ANSD was about 0.087% in the newborns passing through the.DPOAE screening, and about 0.765% of those who failed to pass, and there was a very significant difference between the two (P0.01) the incidence of ANSD of the.AABR rescreening was about 1 (P0.01). 0.127%, through about 0.160%, there is a very significant difference between the two (P0.01).DPOAE screening (r=-0.052, P0.01) and AABR rescreening (r=-0.316, P0.01) is a risk factor for neonatal ANSD; ANSD in high-risk neonates with deafness is about 0.255%, the incidence of premature infants is about 0.429%, preterm and ANSD There was no significant correlation (r=0.015, P0.05).
The incidence of ANSD in children with audiological diagnosis of auditory neuropathy was 1.067%. between men and women (P0.05). The hearing loss was both severe and severe, among them, the incidence of severe deafness was about 5.263%, and the extreme severity was about 6.686%. The difference between the two was statistically significant (P0.05). The incidence of infants and young children in the history of NICU was not transferred to infants. The rate was about 0.394%, the history of NICU hospitalization was about 1.136%. There was no significant correlation between the history of NICU hospitalization and the incidence of ANSD (r=0.030, P0.05). The incidence of ANSD in infants with no high risk factors for hearing loss was about 0.933%, the incidence of high-risk factors was about 2.469%, the rate of ANSD onset in premature infants with low birth weight was about 5.882%, and the incidence of ANSD in children with hyperbilirubinemia was ANSD. 2.326%, but premature birth, low body weight and hyperbilirubinemia were not significantly correlated with ANSD (P0.05).
The fourth part is the establishment of Chinese Deaf gene pool and sample management.
In this study, on the basis of the collection, collection and collection of hereditary deafness of Professor Wang Qiuju's 1999-2002 doctoral thesis, the results of the preservation and gene localization study and the preservation of the deafness resources, the Chinese deafness gene bank was established, and the information and automatic management of the information and sample resources of the deafness were realized. There were 580778 cases, 212951 cases of audiology, 241405 blood samples and DNA32371. Among them, 8028 cases of hearing impairment and 8028 sporadic cases and 331 cases of acoustic neuropathic disorder were one of the most abundant research groups in the field of hearing disorder in the world. At the same time, 118106 cases of newborn hearing and genes were collected. Combined screening, 1406 cases of information and sample resources for audiological diagnosis of infants, 2880 cases of deaf students were screened by gene screening, 15588 cases of sensorineural hearing loss, 1120 cases of sudden deafness and 400 thousand cases more than 400 thousand cases of hearing deafness, for further genetic research of deafness and the complexity of heredity and environment Mutual research lays the foundation for the related research on the risk of disease.
【学位授予单位】：中国人民解放军医学院
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R764.43

【相似文献】