年龄相关性黄斑变性的遗传标记物和环境因素的易感性评估
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摘要
第一章LOC387715/HTRA1区域与晚期AMD的关联性分析
目的：探讨染色体10q26上LOC387715/HTRA1区域的2个单核苷酸多态性(Single Nucleotide Polymorphism, SNP)与晚期年龄相关性黄斑变性(Age-related Macular Degeneration, AMD)的关联性,为晚期AMD风险预测模型的建立奠定基础。
方法：1.以1844名高加索人群作为研究对象,包括1335名晚期AMD患者和509名种族、年龄相匹配的对照组人群,采集血样并提取DNA。2.选取染色体10q26上LOC387715/HTRA1区域的SNPrs10490924和rs11200638,通过单核苷酸引物延伸法对晚期AMD患者和对照组人群进行基因分型。3.采用卡方检验和Fisher精确检验,分析2个SNP与晚期AMD的关联性。
结果：1.SNP rs10490924和rs11200638在晚期AMD两种表现型,地图状萎缩(Geographic Atrophy, GA,干性AMD)和脉络膜新生血管形成(Choroidal Neovascularization, CNV,湿性AMD),与对照组基因分型的比较中均有统计学上的显著性差异(p<1.0E-17)。2.SNP rs10490924和rs11200638的次要等位基因T和A,在GA组、CNV组,以及全部晚期AMD组与对照组比较的比值比(Odds Ratio,OR)和95%可信区间(Confidence Interval, CI)的下限均大于1。3.SNPrs10490924和rs11200638在GA和CNV两种表现型间的比较中没有明显的统计学差异。4. LOC387715/HTRA1区域上的2个SNP具有几乎完全的连锁不平衡。
结论：1.染色体10q26上LOC387715/HTRA1区域的SNPrs10490924和rs11200638与晚期AMD的2种表现型均具有极其显著的关联性。2.SNP rs10490924和rs11200638的次要等位基因T和A,分别是2个SNP在AMD发病过程中的危险性等位基因。3. LOC387715/HTRA1区域是晚期AMD的主要遗传标记物之一。
第二章CFH、C3、CFB和C2基因与晚期AMD的关联性分析
目的：探讨补体系统4个基因CFH、C3、CFB和C2上的6个SNP与晚期AMD的关联性,为晚期AMD风险预测模型的建立奠定基础。
方法：1.以1844名高加索人群作为研究对象,包括1335名晚期AMD患者和509名种族、年龄相匹配的对照组人群,采集血样并提取DNA。2.选取来自基因CFH的SNP rs1061170,rs2274700和rs1410996,C3的rs2230199,CFB的rs641153,以及C2的rs9332739,通过单核苷酸引物延伸法对晚期AMD患者和对照组人群进行基因分型。3.用卡方检验和Fisher精确检验,分析6个SNP与AMD的关联性。
结果：1.CFH rs1061170,rs2274700和rs1410996,C3rs2230199,CFB rs641153,以及C2rs9332739在晚期AMD两种表现型与对照组基因分型的比较中均具有统计学上的显著性差异(p<0.05),其中以CFH3个SNP的统计学差异最显著(P值<1.0E-30)。2.SNP rs1061170、rs2274700、rs1410996和rs2230199的等位基因C、C、C、G,在GA组、CNV组,以及全部晚期AMD组与对照组比较的OR值和95%CI的下限均大于1, rs641153和rs9332739的等位基因T和C,在GA组、CNV组,以及全部晚期AMD组与对照组比较的OR值和95%CI的上限均小于1。3.除了SNP rs2230199, SNP rs1061170、rs2274700、rs1410996、rs641153和rs9332739在GA与CNV两种表现型的比较中均没有明显的统计学差异。4.CFH上的3个SNP具有几乎完全的连锁不平衡。
结论：1.补体系统4个基因CFH、C3、CFB和C2上的6个SNP,CFH rs1061170、CFH rs2274700、CFH rs1410996、C3rs2230199、 CFB rs641153,以及C2rs9332739,与晚期AMD的2种表现型均具有显著的关联性。2.SNP rs1061170、rs2274700、rs1410996和rs2230199在AMD发病过程中的危险性等位基因分别为C、C、C、G,而rs641153和rs9332739的保护性等位基因分别为T和C。3.CFH、C3、CFB和C2基因均为晚期AMD的主要遗传标记物,补体系统的替代途径和经典激活途径很可能是大部分AMD患者发病过程中的关键作用途径。
第三章多个AMD遗传标记物和环境因素的易感性评估
目的：评估多个与晚期AMD相关的遗传因素和环境因素在AMD发病过程中的单独或联合的效应,使用这些易感因素构建AMD风险预测模型。
方法：1.收集1844名研究对象的基本个人信息和环境影响因素,包括年龄、性别、吸烟状况和体重指数(Body Mass Index, BMI)。2.选取5个基因上的8个SNP,LOC387715rs10490924,HTRA1rs11200638,CFHrs1061170、rs2274700、rs1410996,C3rs2230199,CFB rs641153,以及C2rs9332739,对所有研究对象进行基因分型。3.采用多因素非条件logistic回归,分析所有与AMD相关的SNP基因分型以及多个环境风险因素单独或联合作用于AMD的效应,构建最佳的AMD风险预测模型。
结果：1.在晚期AMD患者单、双眼发病的比较中,CFH的rs2274700和rs1410996与GA组的单双眼发病有关,而LOC387715/HTRA1的rs10490924和rs11200638与CNV组的单双眼发病有关。2.吸烟状况与晚期AMD有着独立的关联性,曾吸烟者OR=1.80,95%CI=1.32-2.45；现在吸烟者OR=3.71,95%CI=2.02-6.80。BMI在晚期AMD组显示出临界的关联性(P=0.093和0.081),而在CNV组P=-0.038和0.03,具有统计学上的显著性差异。3.任一SNP基因型与吸烟状况或BMI均没有明显的交互作用。SNP基因型之间的交互作用分析显示,仅rs1061170-CT×rs10490924-TT以及rs2274700-CT×rs10490924-TG,2组基因型表现出较弱的交互作用,P值分别为0.029和0.027。4.AMD风险预测模型的建立显示,具有基因型rs2274700-CC、rs2230199-GG、rs10490924-TT的现在吸烟者,其AMD发病的相对危险度约为基因型rs2274700-TT、rs2230199-CC、rs10490924-GG不吸烟者的450倍。5.ROC曲线显示在0.73的分割点处,灵敏度和特异度均约为75%,此时的模型具有78%的精确区分度。
结论：1.CFH基因可能主要参与到晚期AMD GA的发病过程,而LOC387715/HTRA1基因主要参与CNV的发病过程。2.吸烟状况是AMD发病过程中的一个独立环境危险因素。BMI也是AMD的危险因素之一,但相较于吸烟状况,影响明显较小。3.吸烟状况、BMI以及各SNP基因型间均没有明显的交互作用。4.使用年龄、吸烟状况、以及6个遗传标记物(CFH rs1061170,CFH rs2274700,C2rs9332739,CFB rs641153,LOC387715/HTRA1rs10490924,C3rs2230199)基因分型结果的乘法模型可以构建AMD风险预测模型,使今后个体化的AMD风险预测可能成为现实。
第四章HTRA1:基因敲除小鼠视网膜结构的改变
目的：探讨HTRA1基因在小鼠视网膜形成过程中的作用,分析该基因表达缺失对小鼠视网膜结构的影响。
方法：1.从HTRA1基因敲除小鼠(HTRA1-/-),野生型C57BL/6小鼠(Wild Type,WT)及其后代的组织中提取DNA,通过聚合酶链式反应对其进行基因分型。2.将不同年龄组HTRA1-/-小鼠和WT小鼠的眼球摘除,行视网膜铺片免疫荧光染色,检测HTRA1基因表达缺失时小鼠视网膜结构改变的状态和程度。
结果：HTRA1-/-小鼠视网膜的螺旋状交通动脉明显减少,走行僵直,深层血管网稀疏。这种改变在1月龄小鼠中表现不明显,在3月和6月龄小鼠可以明显观察到。
结论：1.HTRA1-/-小鼠模型的建立为HTRA1基因功能研究的开展奠定了基础。2.HTRA1基因可能在视网膜血管正常形态、功能的维持及其病理改变过程中具有某种关键性作用。
Chapter1Association analysis of LOC387715/HTRA1region with Age-related Macular Degeneration
Objective:To investigate the association of2single nucleotide polymorphisms (SNPs) in the LOC387715/HTRA1region at Chromosome10q26with different phenotypes of Advanced AMD and lay the foundation for the prediction model for prevalence and incidence of advanced AMD.
Methods:1. All1844participants were recruited from Caucasian cohort, including1335advanced AMD patients and509age and ethnicity matched normal controls. DNA was extracted from their blood.2. Two SNPs rs10490924and rs11200638, in the LOC387715/HTRA1region at Chromosome10q26, were genotyped in all participants.3. The chi-squared test and Fisher exact tests over alleles were performed to assess evidence for association.
Results:1. SNP rs10490924and rs11200638were found significant associations with both forms of advanced AMD (GA and CNV) with the p<1.0E-17.2. The minor alleles of SNP rs10490924and rs11200638were T and A respectively. The Odd Ratios and the minimum of95%CI of these2minor alleles in each case group were greater than1.3. Neither rs10490924nor rs11200638was found significant difference between GA and CNV.4. SNP rs10490924and rs11200638in the LOC387715/HTRA1region show almost complete linkage disequilibrium.
Conclusions:1. Two SNPs rs10490924and rs11200638, in the LOC387715/HTRA1region at Chromosome10q26, show significant association with both forms of advanced AMD.2. The minor alleles, also the risk alleles in the pathogenesis of AMD, of SNP rs10490924and rs11200638are T and A respectively.3. The LOC387715/HTRA1region is the major genetic marker of advanced AMD.
Chapter2Association analysis of CFH, C3, CFB and C2gene with Age-related Macular Degeneration
Objective:To investigate the association of6SNPs in4genes of CFH, C3, CFB and C2with different phenotypes of Advanced AMD and lay the foundation for the prediction model for prevalence and incidence of advanced AMD.
Methods:1. All1844participants were recruited from Caucasian cohort, including1335advanced AMD patients and509age and ethnicity matched normal controls. DNA was extracted from their blood.2. SNP rs1061170, rs2274700and rs1410996from CFH, rs2230199from C3, rs641153from CFB, and rs9332739from C2were chosen and genotyped in all participants.3. The chi-squared test and Fisher exact tests over alleles were performed to assess evidence for association.
Results:1. SNP rs1061170, rs2274700and rs1410996from CFH, rs2230199from C3, rs641153from CFB, and rs9332739from C2were found significant associations with both forms of advanced AMD with the p<0.05.2. The risk alleles of SNP rs1061170, rs2274700, rs1410996and rs2230199were C, C, C and G respectively. The Odd Ratios and the minimum of95%CI of these4risk alleles in each case group were greater than1. The protective alleles of SNP rs641153and rs9332739were T and C respectively. The Odd Ratios and the maximum of95%CI of these2protective alleles in each case group were less than1.3. Except SNP rs2230199, SNP rs1061170, rs2274700, rs1410996, rs641153and rs9332739was found no significant difference between GA and CNV.4. Three SNPs in CFH gene show almost complete linkage disequilibrium.
Conclusions:1. Six SNP from4genes, CFH rs1061170, CFH rs2274700, CFH rs1410996, C3rs2230199, CFB rs641153and C2rs9332739, show significant association with both forms of advanced AMD.2. The risk alleles of SNP rs1061170, rs2274700, rs1410996and rs2230199are C, C, C and G respectively. The protective alleles of SNP rs641153and rs9332739are T and C respectively.3. CFH, C3, CFB and C2genes are the major genetic markers of advance AMD. The alternative complement pathway and the classical complement pathway of the complement system may play the important roles in the pathogenesis of AMD.
Chapter3Assessing susceptibility to Age-related Macular Degeneration with multiple genetic markers and environmental factors
Objective:To evaluate the independent and joint effects of multiple genetic factors and environmental variables on AMD and to develop a predictive model with both genetic and environmental factors included.
Methods:1. All1844participants were recruited from Caucasian cohort. Demographic information, including enroll age, smoking status and BMI, was collected.2. DNA was evaluated for eight variants in five genes related to AMD, including SNP rs10490924from LOC387715, rs11200638from HTRA1, rs1061170, rs2274700and rs1410996from CFH, rs2230199from C3, rs641153from CFB, and rs9332739from C2.3. Unconditional logistic regression analyses were performed to evaluate the independent and joint effects of multiple genetic factors and environmental variables related to AMD and generate the risk predictive model.
Results:1. SNP rs10490924and rs11200638in LOC387715/HTRA1region show significant association only between bilateral CNV and unilateral CNV, while SNP rs2274700and rs1410996on CFH show significant association only between bilateral GA and unilateral GA.2. Smoking status was independently associated with advanced AMD (for former smokers OR=1.80,95%CI=1.32-2.45; for current smokers OR=3.71,95%CI=2.02-6.80). BMI was shown boundary association (P=0.093and0.081) with combined AMD, although it was barely significant (P=0.038and0.03) in CNV subgroup.3. No significant interaction was found among any of the genotypes, smoking or BMI. In terms of interaction between genotypes, only rs1061170-CT× rs10490924-TT and rs2274700-CT×rs10490924-TG were found weak effect of interaction, with the P=0.029and0.027respectively.4. The risk model of AMD showed that the odds ratio of a current smoker with the genotype of rs2274700-CC, rs2230199-GG, rs10490924-TT was as about450times as the odds ratio of a non-smoker with the genotype of rs2274700-TT, rs2230199-CC, rs10490924-GG.5. The ROC curve showed that the cutoff of0.73yielded approximately75%of sensitivity and75%of specificity as well. The model has78%discrimination accuracy.
Conclusions:1. CFH may play a more important role in the pathogenesis of GA than CNV and so does LOC387715/HTRA1in CNV than GA.2. Smoking is as an independently risk factor in the pathogenesis of AMD. BMI, as another risk factor, shows much weaker contribution than smoking to the occurrence of AMD.3. There is no significant interaction among smoking, BMI and any of the genotypes.4. The best fit model is achieved with age, smoking and six genetic markers (CFH rs1061170, CFH rs2274700, C2rs9332739, CFB rs641153, LOC387715/HTRA1rs10490924, and C3rs2230199) with multiplicative model. It indicates that the potential for individual prediction of risk for AMD may become reality.
Chapter4Retinal structural changes of the HTRA1Knockout Mice
Objective:To investigate the function of HTRA1gene in the formation of mice retina and analysis the influence of gene deletion to the structure of mice retina.
Methods:1. HTRA1knockout mice and C57BL/6wild type mice were collocted. DNA was extracted from their tails. PCR was used to genotype the mice.2. The eyeballs of HTRA1knockout mice and C57BL/6wild type mice in different age groups were enucleated. Retinal flat-mount immunofluorescence was performed to compare the changes of the retinal structure in each group.
Results:The communicating arteries in the retina of the HTRA1 knockout mice were found obviously decreased by comparing with the wild type mice. It was observed in3and6-month old mice, but not in1-month old mice.
Conclusions:1. HTRA1knockout mice are important animal models for investigating the role of HTRA1gene and lay the foundation of further study of HTRA1gene.2. HTRA1gene may have the function of maintaining the normal appearance of the retinal vessels and playing a key role in their pathological changes.
目的：探讨染色体10q26上LOC387715/HTRA1区域的2个单核苷酸多态性(Single Nucleotide Polymorphism, SNP)与晚期年龄相关性黄斑变性(Age-related Macular Degeneration, AMD)的关联性,为晚期AMD风险预测模型的建立奠定基础。
方法：1.以1844名高加索人群作为研究对象,包括1335名晚期AMD患者和509名种族、年龄相匹配的对照组人群,采集血样并提取DNA。2.选取染色体10q26上LOC387715/HTRA1区域的SNPrs10490924和rs11200638,通过单核苷酸引物延伸法对晚期AMD患者和对照组人群进行基因分型。3.采用卡方检验和Fisher精确检验,分析2个SNP与晚期AMD的关联性。
结果：1.SNP rs10490924和rs11200638在晚期AMD两种表现型,地图状萎缩(Geographic Atrophy, GA,干性AMD)和脉络膜新生血管形成(Choroidal Neovascularization, CNV,湿性AMD),与对照组基因分型的比较中均有统计学上的显著性差异(p<1.0E-17)。2.SNP rs10490924和rs11200638的次要等位基因T和A,在GA组、CNV组,以及全部晚期AMD组与对照组比较的比值比(Odds Ratio,OR)和95%可信区间(Confidence Interval, CI)的下限均大于1。3.SNPrs10490924和rs11200638在GA和CNV两种表现型间的比较中没有明显的统计学差异。4. LOC387715/HTRA1区域上的2个SNP具有几乎完全的连锁不平衡。
结论：1.染色体10q26上LOC387715/HTRA1区域的SNPrs10490924和rs11200638与晚期AMD的2种表现型均具有极其显著的关联性。2.SNP rs10490924和rs11200638的次要等位基因T和A,分别是2个SNP在AMD发病过程中的危险性等位基因。3. LOC387715/HTRA1区域是晚期AMD的主要遗传标记物之一。
第二章CFH、C3、CFB和C2基因与晚期AMD的关联性分析
目的：探讨补体系统4个基因CFH、C3、CFB和C2上的6个SNP与晚期AMD的关联性,为晚期AMD风险预测模型的建立奠定基础。
方法：1.以1844名高加索人群作为研究对象,包括1335名晚期AMD患者和509名种族、年龄相匹配的对照组人群,采集血样并提取DNA。2.选取来自基因CFH的SNP rs1061170,rs2274700和rs1410996,C3的rs2230199,CFB的rs641153,以及C2的rs9332739,通过单核苷酸引物延伸法对晚期AMD患者和对照组人群进行基因分型。3.用卡方检验和Fisher精确检验,分析6个SNP与AMD的关联性。
结果：1.CFH rs1061170,rs2274700和rs1410996,C3rs2230199,CFB rs641153,以及C2rs9332739在晚期AMD两种表现型与对照组基因分型的比较中均具有统计学上的显著性差异(p<0.05),其中以CFH3个SNP的统计学差异最显著(P值<1.0E-30)。2.SNP rs1061170、rs2274700、rs1410996和rs2230199的等位基因C、C、C、G,在GA组、CNV组,以及全部晚期AMD组与对照组比较的OR值和95%CI的下限均大于1, rs641153和rs9332739的等位基因T和C,在GA组、CNV组,以及全部晚期AMD组与对照组比较的OR值和95%CI的上限均小于1。3.除了SNP rs2230199, SNP rs1061170、rs2274700、rs1410996、rs641153和rs9332739在GA与CNV两种表现型的比较中均没有明显的统计学差异。4.CFH上的3个SNP具有几乎完全的连锁不平衡。
结论：1.补体系统4个基因CFH、C3、CFB和C2上的6个SNP,CFH rs1061170、CFH rs2274700、CFH rs1410996、C3rs2230199、 CFB rs641153,以及C2rs9332739,与晚期AMD的2种表现型均具有显著的关联性。2.SNP rs1061170、rs2274700、rs1410996和rs2230199在AMD发病过程中的危险性等位基因分别为C、C、C、G,而rs641153和rs9332739的保护性等位基因分别为T和C。3.CFH、C3、CFB和C2基因均为晚期AMD的主要遗传标记物,补体系统的替代途径和经典激活途径很可能是大部分AMD患者发病过程中的关键作用途径。
第三章多个AMD遗传标记物和环境因素的易感性评估
目的：评估多个与晚期AMD相关的遗传因素和环境因素在AMD发病过程中的单独或联合的效应,使用这些易感因素构建AMD风险预测模型。
方法：1.收集1844名研究对象的基本个人信息和环境影响因素,包括年龄、性别、吸烟状况和体重指数(Body Mass Index, BMI)。2.选取5个基因上的8个SNP,LOC387715rs10490924,HTRA1rs11200638,CFHrs1061170、rs2274700、rs1410996,C3rs2230199,CFB rs641153,以及C2rs9332739,对所有研究对象进行基因分型。3.采用多因素非条件logistic回归,分析所有与AMD相关的SNP基因分型以及多个环境风险因素单独或联合作用于AMD的效应,构建最佳的AMD风险预测模型。
结果：1.在晚期AMD患者单、双眼发病的比较中,CFH的rs2274700和rs1410996与GA组的单双眼发病有关,而LOC387715/HTRA1的rs10490924和rs11200638与CNV组的单双眼发病有关。2.吸烟状况与晚期AMD有着独立的关联性,曾吸烟者OR=1.80,95%CI=1.32-2.45；现在吸烟者OR=3.71,95%CI=2.02-6.80。BMI在晚期AMD组显示出临界的关联性(P=0.093和0.081),而在CNV组P=-0.038和0.03,具有统计学上的显著性差异。3.任一SNP基因型与吸烟状况或BMI均没有明显的交互作用。SNP基因型之间的交互作用分析显示,仅rs1061170-CT×rs10490924-TT以及rs2274700-CT×rs10490924-TG,2组基因型表现出较弱的交互作用,P值分别为0.029和0.027。4.AMD风险预测模型的建立显示,具有基因型rs2274700-CC、rs2230199-GG、rs10490924-TT的现在吸烟者,其AMD发病的相对危险度约为基因型rs2274700-TT、rs2230199-CC、rs10490924-GG不吸烟者的450倍。5.ROC曲线显示在0.73的分割点处,灵敏度和特异度均约为75%,此时的模型具有78%的精确区分度。
结论：1.CFH基因可能主要参与到晚期AMD GA的发病过程,而LOC387715/HTRA1基因主要参与CNV的发病过程。2.吸烟状况是AMD发病过程中的一个独立环境危险因素。BMI也是AMD的危险因素之一,但相较于吸烟状况,影响明显较小。3.吸烟状况、BMI以及各SNP基因型间均没有明显的交互作用。4.使用年龄、吸烟状况、以及6个遗传标记物(CFH rs1061170,CFH rs2274700,C2rs9332739,CFB rs641153,LOC387715/HTRA1rs10490924,C3rs2230199)基因分型结果的乘法模型可以构建AMD风险预测模型,使今后个体化的AMD风险预测可能成为现实。
第四章HTRA1:基因敲除小鼠视网膜结构的改变
目的：探讨HTRA1基因在小鼠视网膜形成过程中的作用,分析该基因表达缺失对小鼠视网膜结构的影响。
方法：1.从HTRA1基因敲除小鼠(HTRA1-/-),野生型C57BL/6小鼠(Wild Type,WT)及其后代的组织中提取DNA,通过聚合酶链式反应对其进行基因分型。2.将不同年龄组HTRA1-/-小鼠和WT小鼠的眼球摘除,行视网膜铺片免疫荧光染色,检测HTRA1基因表达缺失时小鼠视网膜结构改变的状态和程度。
结果：HTRA1-/-小鼠视网膜的螺旋状交通动脉明显减少,走行僵直,深层血管网稀疏。这种改变在1月龄小鼠中表现不明显,在3月和6月龄小鼠可以明显观察到。
结论：1.HTRA1-/-小鼠模型的建立为HTRA1基因功能研究的开展奠定了基础。2.HTRA1基因可能在视网膜血管正常形态、功能的维持及其病理改变过程中具有某种关键性作用。
Chapter1Association analysis of LOC387715/HTRA1region with Age-related Macular Degeneration
Objective:To investigate the association of2single nucleotide polymorphisms (SNPs) in the LOC387715/HTRA1region at Chromosome10q26with different phenotypes of Advanced AMD and lay the foundation for the prediction model for prevalence and incidence of advanced AMD.
Methods:1. All1844participants were recruited from Caucasian cohort, including1335advanced AMD patients and509age and ethnicity matched normal controls. DNA was extracted from their blood.2. Two SNPs rs10490924and rs11200638, in the LOC387715/HTRA1region at Chromosome10q26, were genotyped in all participants.3. The chi-squared test and Fisher exact tests over alleles were performed to assess evidence for association.
Results:1. SNP rs10490924and rs11200638were found significant associations with both forms of advanced AMD (GA and CNV) with the p<1.0E-17.2. The minor alleles of SNP rs10490924and rs11200638were T and A respectively. The Odd Ratios and the minimum of95%CI of these2minor alleles in each case group were greater than1.3. Neither rs10490924nor rs11200638was found significant difference between GA and CNV.4. SNP rs10490924and rs11200638in the LOC387715/HTRA1region show almost complete linkage disequilibrium.
Conclusions:1. Two SNPs rs10490924and rs11200638, in the LOC387715/HTRA1region at Chromosome10q26, show significant association with both forms of advanced AMD.2. The minor alleles, also the risk alleles in the pathogenesis of AMD, of SNP rs10490924and rs11200638are T and A respectively.3. The LOC387715/HTRA1region is the major genetic marker of advanced AMD.
Chapter2Association analysis of CFH, C3, CFB and C2gene with Age-related Macular Degeneration
Objective:To investigate the association of6SNPs in4genes of CFH, C3, CFB and C2with different phenotypes of Advanced AMD and lay the foundation for the prediction model for prevalence and incidence of advanced AMD.
Methods:1. All1844participants were recruited from Caucasian cohort, including1335advanced AMD patients and509age and ethnicity matched normal controls. DNA was extracted from their blood.2. SNP rs1061170, rs2274700and rs1410996from CFH, rs2230199from C3, rs641153from CFB, and rs9332739from C2were chosen and genotyped in all participants.3. The chi-squared test and Fisher exact tests over alleles were performed to assess evidence for association.
Results:1. SNP rs1061170, rs2274700and rs1410996from CFH, rs2230199from C3, rs641153from CFB, and rs9332739from C2were found significant associations with both forms of advanced AMD with the p<0.05.2. The risk alleles of SNP rs1061170, rs2274700, rs1410996and rs2230199were C, C, C and G respectively. The Odd Ratios and the minimum of95%CI of these4risk alleles in each case group were greater than1. The protective alleles of SNP rs641153and rs9332739were T and C respectively. The Odd Ratios and the maximum of95%CI of these2protective alleles in each case group were less than1.3. Except SNP rs2230199, SNP rs1061170, rs2274700, rs1410996, rs641153and rs9332739was found no significant difference between GA and CNV.4. Three SNPs in CFH gene show almost complete linkage disequilibrium.
Conclusions:1. Six SNP from4genes, CFH rs1061170, CFH rs2274700, CFH rs1410996, C3rs2230199, CFB rs641153and C2rs9332739, show significant association with both forms of advanced AMD.2. The risk alleles of SNP rs1061170, rs2274700, rs1410996and rs2230199are C, C, C and G respectively. The protective alleles of SNP rs641153and rs9332739are T and C respectively.3. CFH, C3, CFB and C2genes are the major genetic markers of advance AMD. The alternative complement pathway and the classical complement pathway of the complement system may play the important roles in the pathogenesis of AMD.
Chapter3Assessing susceptibility to Age-related Macular Degeneration with multiple genetic markers and environmental factors
Objective:To evaluate the independent and joint effects of multiple genetic factors and environmental variables on AMD and to develop a predictive model with both genetic and environmental factors included.
Methods:1. All1844participants were recruited from Caucasian cohort. Demographic information, including enroll age, smoking status and BMI, was collected.2. DNA was evaluated for eight variants in five genes related to AMD, including SNP rs10490924from LOC387715, rs11200638from HTRA1, rs1061170, rs2274700and rs1410996from CFH, rs2230199from C3, rs641153from CFB, and rs9332739from C2.3. Unconditional logistic regression analyses were performed to evaluate the independent and joint effects of multiple genetic factors and environmental variables related to AMD and generate the risk predictive model.
Results:1. SNP rs10490924and rs11200638in LOC387715/HTRA1region show significant association only between bilateral CNV and unilateral CNV, while SNP rs2274700and rs1410996on CFH show significant association only between bilateral GA and unilateral GA.2. Smoking status was independently associated with advanced AMD (for former smokers OR=1.80,95%CI=1.32-2.45; for current smokers OR=3.71,95%CI=2.02-6.80). BMI was shown boundary association (P=0.093and0.081) with combined AMD, although it was barely significant (P=0.038and0.03) in CNV subgroup.3. No significant interaction was found among any of the genotypes, smoking or BMI. In terms of interaction between genotypes, only rs1061170-CT× rs10490924-TT and rs2274700-CT×rs10490924-TG were found weak effect of interaction, with the P=0.029and0.027respectively.4. The risk model of AMD showed that the odds ratio of a current smoker with the genotype of rs2274700-CC, rs2230199-GG, rs10490924-TT was as about450times as the odds ratio of a non-smoker with the genotype of rs2274700-TT, rs2230199-CC, rs10490924-GG.5. The ROC curve showed that the cutoff of0.73yielded approximately75%of sensitivity and75%of specificity as well. The model has78%discrimination accuracy.
Conclusions:1. CFH may play a more important role in the pathogenesis of GA than CNV and so does LOC387715/HTRA1in CNV than GA.2. Smoking is as an independently risk factor in the pathogenesis of AMD. BMI, as another risk factor, shows much weaker contribution than smoking to the occurrence of AMD.3. There is no significant interaction among smoking, BMI and any of the genotypes.4. The best fit model is achieved with age, smoking and six genetic markers (CFH rs1061170, CFH rs2274700, C2rs9332739, CFB rs641153, LOC387715/HTRA1rs10490924, and C3rs2230199) with multiplicative model. It indicates that the potential for individual prediction of risk for AMD may become reality.
Chapter4Retinal structural changes of the HTRA1Knockout Mice
Objective:To investigate the function of HTRA1gene in the formation of mice retina and analysis the influence of gene deletion to the structure of mice retina.
Methods:1. HTRA1knockout mice and C57BL/6wild type mice were collocted. DNA was extracted from their tails. PCR was used to genotype the mice.2. The eyeballs of HTRA1knockout mice and C57BL/6wild type mice in different age groups were enucleated. Retinal flat-mount immunofluorescence was performed to compare the changes of the retinal structure in each group.
Results:The communicating arteries in the retina of the HTRA1 knockout mice were found obviously decreased by comparing with the wild type mice. It was observed in3and6-month old mice, but not in1-month old mice.
Conclusions:1. HTRA1knockout mice are important animal models for investigating the role of HTRA1gene and lay the foundation of further study of HTRA1gene.2. HTRA1gene may have the function of maintaining the normal appearance of the retinal vessels and playing a key role in their pathological changes.
引文
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