目的利用两样本孟德尔随机化(MR)分析阿尔茨海默病(AD)与年龄相关性黄斑变性(AMD)之间存在的潜在因果关联。方法使用IEU Open GWAS数据库AD和干性AMD、湿性AMD全基因组关联研究的汇总统计数据,使用单核苷酸多态性(SNP)作为因果推断的工...目的利用两样本孟德尔随机化(MR)分析阿尔茨海默病(AD)与年龄相关性黄斑变性(AMD)之间存在的潜在因果关联。方法使用IEU Open GWAS数据库AD和干性AMD、湿性AMD全基因组关联研究的汇总统计数据,使用单核苷酸多态性(SNP)作为因果推断的工具变量,进行两样本MR分析。采用逆方差加权法(IVW)评估AD与湿性AMD、干性AMD的是否存在因果关联,同时采用MR-Egger回归法、加权中位数法(WME)、异质性检验及敏感性分析对结果进行补充分析。结果(1)筛选结果:暴露因素中,AD、湿性AMD、干性AMD均筛选出13个SNP。(2)AD与湿性AMD:AD与湿性AMD发生的强相关因素,有统计学意义[OR=0.883,95%CI(0.784,0.885),F=34.848,P=0.000],MR-Egger回归法显示不存在水平多效性(P>0.05),且AD与湿性AMD散点图斜率为负,表明二者存在因果关系。(3)AD与干性AMD:AD与干性AMD发生的强相关因素,有统计学意义[OR=0.875,95%CI(0.828,0.925),F=22.563,P=0.000],MR-Egger回归法显示不存在水平多效性(P>0.05),且AD与干性AMD散点图斜率为负,表明二者存在因果关系。结论AD与AMD存在潜在联系。由于AMD具有高致盲性,认识和控制AMD危险因素,阐明这两种疾病的共同致病途径将有助于其预防、治疗的研究。展开更多
Progressive photoreceptor cell death is one of the main pathological features of age-related macular degeneration and eventually leads to vision loss.Ferroptosis has been demonstrated to be associated with retinal deg...Progressive photoreceptor cell death is one of the main pathological features of age-related macular degeneration and eventually leads to vision loss.Ferroptosis has been demonstrated to be associated with retinal degenerative diseases.However,the molecular mechanisms underlying ferroptosis and photoreceptor cell death in age-related macular degeneration remain largely unexplored.Bioinformatics and biochemical analyses in this study revealed xC^(–),solute carrier family 7 member 11-regulated ferroptosis as the predominant pathological process of photoreceptor cell degeneration in a light-induced dry age-related macular degeneration mouse model.This process involves the nuclear factor-erythroid factor 2-related factor 2-solute carrier family 7 member 11-glutathione peroxidase 4 signaling pathway,through which cystine depletion,iron ion accumulation,and enhanced lipid peroxidation ultimately lead to photoreceptor cell death and subsequent visual function impairment.We demonstrated that solute carrier family 7 member 11 overexpression blocked this process by inhibiting oxidative stress in vitro and in vivo.Conversely,solute carrier family 7 member 11 knockdown or the solute carrier family 7 member 11 inhibitor sulfasalazine and ferroptosis-inducing agent erastin aggravated H_(2)O_(2)-induced ferroptosis of 661W cells.These findings indicate solute carrier family 7 member 11 may be a potential therapeutic target for patients with retinal degenerative diseases including age-related macular degeneration.展开更多
文摘目的利用两样本孟德尔随机化(MR)分析阿尔茨海默病(AD)与年龄相关性黄斑变性(AMD)之间存在的潜在因果关联。方法使用IEU Open GWAS数据库AD和干性AMD、湿性AMD全基因组关联研究的汇总统计数据,使用单核苷酸多态性(SNP)作为因果推断的工具变量,进行两样本MR分析。采用逆方差加权法(IVW)评估AD与湿性AMD、干性AMD的是否存在因果关联,同时采用MR-Egger回归法、加权中位数法(WME)、异质性检验及敏感性分析对结果进行补充分析。结果(1)筛选结果:暴露因素中,AD、湿性AMD、干性AMD均筛选出13个SNP。(2)AD与湿性AMD:AD与湿性AMD发生的强相关因素,有统计学意义[OR=0.883,95%CI(0.784,0.885),F=34.848,P=0.000],MR-Egger回归法显示不存在水平多效性(P>0.05),且AD与湿性AMD散点图斜率为负,表明二者存在因果关系。(3)AD与干性AMD:AD与干性AMD发生的强相关因素,有统计学意义[OR=0.875,95%CI(0.828,0.925),F=22.563,P=0.000],MR-Egger回归法显示不存在水平多效性(P>0.05),且AD与干性AMD散点图斜率为负,表明二者存在因果关系。结论AD与AMD存在潜在联系。由于AMD具有高致盲性,认识和控制AMD危险因素,阐明这两种疾病的共同致病途径将有助于其预防、治疗的研究。
基金supported by the National Natural Science Foundation of China,Nos.82171076(to XS)and U22A20311(to XS),82101168(to TL)Shanghai Science and technology Innovation Action Plan,No.23Y11901300(to JS)+1 种基金Science and Technology Commission of Shanghai Municipality,No.21ZR1451500(to TL)Shanghai Pujiang Program,No.22PJ1412200(to BY)。
文摘Progressive photoreceptor cell death is one of the main pathological features of age-related macular degeneration and eventually leads to vision loss.Ferroptosis has been demonstrated to be associated with retinal degenerative diseases.However,the molecular mechanisms underlying ferroptosis and photoreceptor cell death in age-related macular degeneration remain largely unexplored.Bioinformatics and biochemical analyses in this study revealed xC^(–),solute carrier family 7 member 11-regulated ferroptosis as the predominant pathological process of photoreceptor cell degeneration in a light-induced dry age-related macular degeneration mouse model.This process involves the nuclear factor-erythroid factor 2-related factor 2-solute carrier family 7 member 11-glutathione peroxidase 4 signaling pathway,through which cystine depletion,iron ion accumulation,and enhanced lipid peroxidation ultimately lead to photoreceptor cell death and subsequent visual function impairment.We demonstrated that solute carrier family 7 member 11 overexpression blocked this process by inhibiting oxidative stress in vitro and in vivo.Conversely,solute carrier family 7 member 11 knockdown or the solute carrier family 7 member 11 inhibitor sulfasalazine and ferroptosis-inducing agent erastin aggravated H_(2)O_(2)-induced ferroptosis of 661W cells.These findings indicate solute carrier family 7 member 11 may be a potential therapeutic target for patients with retinal degenerative diseases including age-related macular degeneration.
