Purpose:To identify plasma proteins that are causally related to primary open-angle glaucoma(POAG)for potential therapeutic targeting.Methods:Summary statistics of plasma protein quantitative trait loci(pQTL)were deri...Purpose:To identify plasma proteins that are causally related to primary open-angle glaucoma(POAG)for potential therapeutic targeting.Methods:Summary statistics of plasma protein quantitative trait loci(pQTL)were derived from two extensive genome-wide analysis study(GWAS)datasets and one systematic review,with over 100 thousand participants covering thousands of plasma proteins.POAG data were sourced from the largest FinnGen study,comprising 8,530 DR cases and 391,275 European controls.A two-sample MR analysis,supplemented by bidirectional MR,Bayesian co-localization analysis,and phenotype scanning,was conducted to examine the causal relationships between plasma proteins and POAG.The analysis was validated by identifying associations between plasma proteins and POAG-related traits,including intraocular pressure(IOP),retinal nerve fibre layer(RNFL),and ganglion cell and inner plexiform layer(GCIPL).By searching druggable gene lists,the ChEMBL database,and the ClinicalTrials.gov database,the druggability and clinical development activity of the identified proteins were systematically evaluated.Results:Eighteen proteins were identified with significant associations with POAG risk after multiple comparison adjustments.The ORs per standard deviation increase in protein levels ranged from 0.39(95%CI:0.24–0.62;P=7.70×10^(-5))for phospholipase C gamma 1(PLCG1)to 1.29(95%CI:1.16–1.44;P=6.72×10^(-6))for nidogen-1(NID1).Bidirectional MR indicated that reverse causality did not interfere with the results of the main MR analyses.Five proteins exhibited strong co-localization evidence(PH4≥0.8):protein sel-1 homolog 1(SEL1L),tyrosine-protein kinase receptor UFO(AXL),nidogen-1(NID1)and FAD-linked sulfhydryl oxidase ALR(GFER)were negatively associated with POAG risk,while roundabout homolog 1(ROBO1)showed a positive association.The phenotype scanning did not reveal any confounding factors between pQTLs and POAG.Further,validation analyses identified nine proteins causally related to POAG traits,with five proteins including interleukin-18 receptor 1(IL18R1),interleukin-1 receptor type 1(IL1R1),phospholipase C gamma 1(PLCG1),ribonuclease pancreatic(RNASE1),serine protease inhibitor Kazal-type 6(SPINK6)revealing consistent directional associations.In addition,18 causal proteins were highlighted for their druggability,of which 5 proteins are either already approved drugs or in clinical trials and 13 proteins are novel drug targets.Conclusions:This study identifies 18 plasma proteins as potential therapeutic targets for POAG,particularly emphasizing the role of genomic and proteomic integration in drug discovery.Future experimental and clinical studies should be conducted to validate the efficacy of these proteins and to conduct more comprehensive proteomic explorations,thus taking a significant leap toward innovative POAG treatments.展开更多
目的采用Cirrus HD OCT测量近视人群的青光眼诊断参数差异性及近视人群的特征。方法选取2016年1月至2017年8月,就诊于我院的18~35岁不同近视程度的患者共95例(190只眼)。记录患者性别、年龄,采集其眼轴、医学验光屈光度(等效球镜)、视...目的采用Cirrus HD OCT测量近视人群的青光眼诊断参数差异性及近视人群的特征。方法选取2016年1月至2017年8月,就诊于我院的18~35岁不同近视程度的患者共95例(190只眼)。记录患者性别、年龄,采集其眼轴、医学验光屈光度(等效球镜)、视盘周围视网膜神经纤维层厚度(cpRNFL)包括平均、上下方,颞鼻侧5个参数、黄斑部神经节细胞和内丛状层(GCIPL)厚度包括平均、最小、上下方、鼻颞侧6个参数。根据屈光度分为A组(-0.25~3.0D);B组(-3.25^-6.0D);C组(>-6.0D),采用单因素方差分析进行所有参数的组间比较。采用Pear-son相关性分析不同屈光度与眼轴、GCIPL厚度、cpRNFL厚度的相关性及GCIPL厚度与cpRNFL厚度之间相关性。结果各组的性别及年龄无统计学差异。但各组间平均屈光度差异有统计学意义(F=521.963,P=0.000),眼轴和屈光度之间呈显著负相关(相关系数-0.706,P=0.000)。根据屈光度分组,所有参数各组之间均有显著差异(F=3.396~16.305,P<0.05)。cpRNFL厚度除颞侧外均与屈光度呈负相关(相关系数-0.316^-0.212,P<0.05),GCLIP厚度各参数均与屈光度呈负相关(相关系数-0.205^-0.384,P<0.05)。两种参数之间除颞侧外,其余参数均具呈正相关性(相关系数0.222~0.559),GCIPL与cpRNFL厚度在近视人群中均随屈光度发生一定的改变。结论近视眼cpRNFL厚度上下方及鼻侧象限均随屈光度增大逐渐变薄,颞侧变厚。GCIPL厚度各参数均随屈光度增大逐渐变薄,二者具有很好的一致性。近视人群采用此两种方法评估青光眼损害时,均需要考虑近视程度对参数的影响。展开更多
基金supported by the Hainan Province Clinical Medical Center,the National Natural Science Foundation of China(82171084,82371086).
文摘Purpose:To identify plasma proteins that are causally related to primary open-angle glaucoma(POAG)for potential therapeutic targeting.Methods:Summary statistics of plasma protein quantitative trait loci(pQTL)were derived from two extensive genome-wide analysis study(GWAS)datasets and one systematic review,with over 100 thousand participants covering thousands of plasma proteins.POAG data were sourced from the largest FinnGen study,comprising 8,530 DR cases and 391,275 European controls.A two-sample MR analysis,supplemented by bidirectional MR,Bayesian co-localization analysis,and phenotype scanning,was conducted to examine the causal relationships between plasma proteins and POAG.The analysis was validated by identifying associations between plasma proteins and POAG-related traits,including intraocular pressure(IOP),retinal nerve fibre layer(RNFL),and ganglion cell and inner plexiform layer(GCIPL).By searching druggable gene lists,the ChEMBL database,and the ClinicalTrials.gov database,the druggability and clinical development activity of the identified proteins were systematically evaluated.Results:Eighteen proteins were identified with significant associations with POAG risk after multiple comparison adjustments.The ORs per standard deviation increase in protein levels ranged from 0.39(95%CI:0.24–0.62;P=7.70×10^(-5))for phospholipase C gamma 1(PLCG1)to 1.29(95%CI:1.16–1.44;P=6.72×10^(-6))for nidogen-1(NID1).Bidirectional MR indicated that reverse causality did not interfere with the results of the main MR analyses.Five proteins exhibited strong co-localization evidence(PH4≥0.8):protein sel-1 homolog 1(SEL1L),tyrosine-protein kinase receptor UFO(AXL),nidogen-1(NID1)and FAD-linked sulfhydryl oxidase ALR(GFER)were negatively associated with POAG risk,while roundabout homolog 1(ROBO1)showed a positive association.The phenotype scanning did not reveal any confounding factors between pQTLs and POAG.Further,validation analyses identified nine proteins causally related to POAG traits,with five proteins including interleukin-18 receptor 1(IL18R1),interleukin-1 receptor type 1(IL1R1),phospholipase C gamma 1(PLCG1),ribonuclease pancreatic(RNASE1),serine protease inhibitor Kazal-type 6(SPINK6)revealing consistent directional associations.In addition,18 causal proteins were highlighted for their druggability,of which 5 proteins are either already approved drugs or in clinical trials and 13 proteins are novel drug targets.Conclusions:This study identifies 18 plasma proteins as potential therapeutic targets for POAG,particularly emphasizing the role of genomic and proteomic integration in drug discovery.Future experimental and clinical studies should be conducted to validate the efficacy of these proteins and to conduct more comprehensive proteomic explorations,thus taking a significant leap toward innovative POAG treatments.
文摘目的采用Cirrus HD OCT测量近视人群的青光眼诊断参数差异性及近视人群的特征。方法选取2016年1月至2017年8月,就诊于我院的18~35岁不同近视程度的患者共95例(190只眼)。记录患者性别、年龄,采集其眼轴、医学验光屈光度(等效球镜)、视盘周围视网膜神经纤维层厚度(cpRNFL)包括平均、上下方,颞鼻侧5个参数、黄斑部神经节细胞和内丛状层(GCIPL)厚度包括平均、最小、上下方、鼻颞侧6个参数。根据屈光度分为A组(-0.25~3.0D);B组(-3.25^-6.0D);C组(>-6.0D),采用单因素方差分析进行所有参数的组间比较。采用Pear-son相关性分析不同屈光度与眼轴、GCIPL厚度、cpRNFL厚度的相关性及GCIPL厚度与cpRNFL厚度之间相关性。结果各组的性别及年龄无统计学差异。但各组间平均屈光度差异有统计学意义(F=521.963,P=0.000),眼轴和屈光度之间呈显著负相关(相关系数-0.706,P=0.000)。根据屈光度分组,所有参数各组之间均有显著差异(F=3.396~16.305,P<0.05)。cpRNFL厚度除颞侧外均与屈光度呈负相关(相关系数-0.316^-0.212,P<0.05),GCLIP厚度各参数均与屈光度呈负相关(相关系数-0.205^-0.384,P<0.05)。两种参数之间除颞侧外,其余参数均具呈正相关性(相关系数0.222~0.559),GCIPL与cpRNFL厚度在近视人群中均随屈光度发生一定的改变。结论近视眼cpRNFL厚度上下方及鼻侧象限均随屈光度增大逐渐变薄,颞侧变厚。GCIPL厚度各参数均随屈光度增大逐渐变薄,二者具有很好的一致性。近视人群采用此两种方法评估青光眼损害时,均需要考虑近视程度对参数的影响。
