【作者】 涂运输；

【导师】 阴正勤；

【作者基本信息】 第三军医大学 ， 眼科学， 2006， 博士

【摘要】 原发性闭角型青光眼(Primary angle closure glaucoma, PACG)简称闭青(Angle closure glaucoma, ACG),是由于房水在前房角引流不畅而致眼内压升高,压迫视神经、视网膜而致失明。PACG具有种族特异性,是由遗传因素与共同作用造成的,因而PACG遗传研究是其发病机制的重要组成部分。通过对中国人PACG的流行病学调查,爱斯基摩人双生子方法分析,认为PACG属于多基因遗传的复杂性疾病,其易感因素主要为浅前房、窄房角、短眼轴,并提出中国人PACG的遗传度为65%,爱斯基摩人的浅前房遗传度为70%。随着分子生物学和分子遗传学技术的进步,使PACG易感基因的染色体定位成为可能。由于种族特异性以及其他种种原因,国内外尚未对PACG的遗传学以及易感基因进行过进一步的研究。本研究主要包括以下几个方面1.通过遗传流行病调查,更深入的探索和分析PACG的表型特征。2.收集PACG家系,对PACG的易感因素进行遗传分析。3.利用PACG家系,初步对11号染色体,以及其他染色体上与PACG可能相关的候选基因,进行微卫星位点进行连锁分析,为进一步研究PACG的易感基因及分子遗传学打下基础。主要结果如下:检查鉴定116个家系428名家庭成员856只眼,发现PACG患者与正常未受累者比较,年龄较大(p<0.001),女性发病较多(4.1 vs 1.5),远视(p<0.001),中央前房浅(p<0.001),周边前房浅(p<0.001),房角窄( p<0.001),晶状体厚(p<0.001),眼轴短(p<0.001).眼压高(p<0.001)。PACG患者及家系成员表型特征(前房深度,房角宽窄程度)为连续数量性状变化。可疑者成员数量性状的变化位于正常和患者之间,属于中间数量表型,但可疑者与受累者的眼轴长度无明显的差别(P>0.05),均为短眼轴。PACG先证者一级亲属浅前房相对风险率(λs值)为7.91,一级亲属加权平均遗传度为92.6%±5.87,女性先证者一级亲属浅前房遗传为115.24%±7.94。浅前房遗传方式为:男性同胞浅前房符合常染色体隐性遗传(P>0.05),女性同胞浅前房常染色体显性遗传(P>0.05);婚配型U×A分离分析接受常染色体显性遗传假设(P>0.05),婚配型U×U既不接受常染色体隐性遗传的假设,也不接受常染色体显性遗传的假设。从第二部分114个家系中选择5个慢性PACG家系,共计75例成员,并提取DNA样本。选取13个候选基因,利用其基因内或附近的微卫星DNA标记,进行多点非参数连锁分析,结果LOD值在-0.17—0.96之间,p值在0.02-0.8之间,不支持连锁。11号染色体基因组扫描及连锁分析结果显示,16个微卫星11号染色体16个标记,平均距离9.18cM。采用多点非参数连锁分析,结果发现D11S4146的LOD值为1.16,p=0.01,D11S902的LOD值为1.02,p=0.02,支持连锁。其他位点LOD值在0-0.96之间,p值在0.5-0.02之间,不支持连锁。结论:PACG患者及家系成员表型特征(前房深度,房角宽窄程度)为连续数量性状变化。可疑者成员数量性状的变化位于正常和患者之间,属于中间数量表型。短眼轴及浅前房可能是PACG形成的主要遗传易感因素。PACG一级亲属有较高的浅前房发生风险,有较高的遗传度,女性浅前房遗传可能存在一个显性主基因,浅前房的遗传方式随不同的性别及婚配类型而表现出不同的遗传方式即遗传异质性。PACG易感基因可能与下列候选基因无关:NNO1、MRCS、PAX6、VMD2、MFRP、NNO2、ROM1、CHX10、MCOP1、MCOPCB2、PITX2、FOXC1、MAF。PACG易感基因可能与11号染色体微卫星位标记D11S4146及D11S902有关。更多还原

【Abstract】 Primary angle closure glaucoma(PACG) or angle closure glaucoma(ACG) is retina and optic nerve damage due to a closed anterior angle and increased IOP. The race difference in rate of PACG between white race and yellow race reveals that inherited facts and certain environmental facts are the reason for PACG. Therefore genetics research of PACG is one of important parts in pathogenesis of this disorder.Epidemiological survey in Chinese and Eskimo shows that PACG is called complex genetic diseases, and the heritability value of PACG is 65% in China, 70% of shallow anterior chamber(AC) in Eskimo. Its susceptible facts are shallow AC, narrowing AC angle and short axial length. We known little abaut PACG genetics and its susceptible gene due to the race difference and other reason worldwide, nevertheless, with the development of biology and molecular genetics,it become possible to localizate PACG genes.The purpose of this study include as follows: 1. to furthermore explore phenotypic features of PACG by epidemiological survey. 2.to analyse inherited patterns of PACG susceptibility by collect PACG families. 3. to primarily study chromosome 11 and some of candidate genes on other chromosomes to identify whether or not PACG is related to those chromosome 11 and candidate genes by way of short tandem repeats (STR) linkage analysis.Result428 individu als from 116 families were examined. The affected individuals were older (p<0.01) than the unaffected ones, moreover, the female/male ratio was higher in the affected group than the unaffected group (4.1 vs 1.5). Compared to the unaffected individuals, the affected ones were hyperopic (p<0.01), had shallow peripheral (p<0.01) and central anterior chamber depths, narrow angles (p<0.01), high intraocular pressure (p<0.01), thick lens (p<0.01), and short axial length (p<0.01).Phenotypic features of PACG patients and their family membership such as the depth of anterior chamber and the degree of angle narrow showed consecutively quantitative trait. The quantitative trait of suspect was intermediate phenotypes between unaffected and affected, and did not show statistic difference between affected and unaffected in axial length(p>0.05).The relateive risk of first degree relative was 7.91, and the estimated heritability value of shallow AC was 92.6%±5.87, and the heritability value of female relatives was 115.24%±7.94%.The inherited patterns of shallow AC with males sibs accorded with autosomal recessive heredity, while (P>0.05), while females sibs accorded with autosomal dominant heredity (P>0.05). the genetic pattern of U×A exhibited autosomal dominant inheritance trait, and the genetic pattern of U×U showed neither autosomal recessive heredity nor dominant inheritance traits(P>0.05).75 individuals of 5 chronicPACG families were selected from 114 families and DNA samples were extracted. STR markers within 13 candidate genes or near locus were selected to perform multipoint nonparametric linkage analysis (NPL). LOD score were from -0.17 to 0.96 and p value ranged from 0.02 to 0.8. These results did not support linkange possibility of PACG genes with above candidate genes.16 STR markers, average interval 9.18 cM, on chromosome 11 were scaned and multipoint nonparametric linkage analysis (NPL) were performed. LOD score of 1.16 was obtained at D11S4146(p=0.01),. 1.02 (p=0.02) at D11S902. These results supported linkage with our PACG. pedigrees. LOD score of other STR on chromosome 11 were from -0.17 to 0.96 and p value ranged from 0.02 to 0.8. These results did not support linkange possibility of PACG genes with those locus.Conclusion:Phenotypic features of PACG patients and their family membership such as the depth of anterior chamber and the degree of angle narrow show consecutively quantitative variety. The quantitative trait of suspect was intermediate phenotypes between unaffected and affected.Short axial length and shallow AC may be mostly inherited susceptibile facts. Shallow AC exist more heritability value. First relative of PACG demonistrate may demonstrate more relateive risk to cause shallow AC and there may exist dominant major gene in female relative. The inherited patterns of Shallow AC may be different in gender and mating types.PACG susceptibile gene may not be associated with as below: NNO1、MRCS、PAX6、VMD2、MFRP、NNO2、ROM1、CHX10、MCOP1、MCOPCB2、PITX2、FOXC1、MAF。PACG susceptibile gene may be associated with D11S4146 and D11S902 on chromosome 11.更多还原