Aims:To identify plasma proteins with causal links to diabetic retinopathy (DR) for potential therapeutic targets.

Materials and methods:Summary statistics of plasma protein quantitative trait loci (pQTL) were derived from two extensive GWAS datasets and onesystematicreview, with over 100 thousand participants covering thousands of plasma proteins. DR data were sourced from the largest FinnGen study, comprising 10,413 DR cases and 308,633 European controls. Two-sample MR approach was utilized to investigate the causality of plasma proteins with DR, followed by bidirectional MR, Bayesian Co-localization analysis, and phenotype scanning to ensure the robustness of the MR results. Druggabilityand enrichment analysisof the identified proteins were systematically evaluated. 

Results:Genetically predicted levels of 24 proteins were significantly associated with DR risk after multiple testing corrections. For each standard deviation increase in plasm protein levels, the odds ratio (OR) for DR varied from 0.51 (95% CI: 0.36-0.73; P=2.22×10^-5) for Tubulin Polymerization-Promoting Protein Family Member 3 (TPPP3) to 2.02 (95% CI: 1.44-2.83; P=5.01×10^-5) for Olfactomedin like 3 (OLFML3). Four proteins exhibited strong co-localization evidence (PH4 ≥0.8): WARS, ACRBP, and ICAM1 were negatively associated with DR risk, while NOTCH2 showed a positive association. Drugability assessments highlighted these 24 proteins as potential DR targets, with two of them currently in phase I clinical trials.

Conclusions:Twenty-four promising drug targets for DR were identified, including four plasma proteins with particular promise. These findings offer new insights into DR's etiology and therapeutic targeting, exemplifying the value of genomic and proteomic data in drug target discovery.

Aims:To identify plasma proteins with causal links to diabetic retinopathy (DR) for potential therapeutic targets.

Materials and methods:Summary statistics of plasma protein quantitative trait loci (pQTL) were derived from two extensive GWAS datasets and onesystematicreview, with over 100 thousand participants covering thousands of plasma proteins. DR data were sourced from the largest FinnGen study, comprising 10,413 DR cases and 308,633 European controls. Two-sample MR approach was utilized to investigate the causality of plasma proteins with DR, followed by bidirectional MR, Bayesian Co-localization analysis, and phenotype scanning to ensure the robustness of the MR results. Druggabilityand enrichment analysisof the identified proteins were systematically evaluated. 

Results:Genetically predicted levels of 24 proteins were significantly associated with DR risk after multiple testing corrections. For each standard deviation increase in plasm protein levels, the odds ratio (OR) for DR varied from 0.51 (95% CI: 0.36-0.73; P=2.22×10^-5) for Tubulin Polymerization-Promoting Protein Family Member 3 (TPPP3) to 2.02 (95% CI: 1.44-2.83; P=5.01×10^-5) for Olfactomedin like 3 (OLFML3). Four proteins exhibited strong co-localization evidence (PH4 ≥0.8): WARS, ACRBP, and ICAM1 were negatively associated with DR risk, while NOTCH2 showed a positive association. Drugability assessments highlighted these 24 proteins as potential DR targets, with two of them currently in phase I clinical trials.

Conclusions:Twenty-four promising drug targets for DR were identified, including four plasma proteins with particular promise. These findings offer new insights into DR's etiology and therapeutic targeting, exemplifying the value of genomic and proteomic data in drug target discovery.

目的：探讨无糖尿病性视网膜病变(diabetic retinopathy，DR)的糖尿病人群中，糖尿病与近视对黄斑区节细胞-内丛状层(ganglion cell layer and inner plexiform layer，GCIPL)厚度纵向变化的影响。方法：纳入广州糖尿病眼病研究中1165名基线无视网膜病变的糖尿病和正常对照者，纵向随访2年。根据是否存在近视[等效球镜(spherical equivalent，SE)≤-3屈光度(diopter，D)]和糖尿病分为健康组(n=508)、糖尿病组(n=525)及糖尿病合并近视组(n=132)。扫频光学相干断层成像(swept source-optical coherence tomography，SS-OCT)技术测量并比较三组间GCIPL厚度的变化，以确定糖尿病和近视的影响，三组间差异使用协方差分析，采用线性混合模型分析评估GCIPL厚度与相关因素的关系。结果：对照组的SE为(1.07±1.06) D，糖尿病组为(1.02±1.00) D，糖尿病合并近视组为(-5.36±2.30) D，组间差异有统计学意义(P<0.001)。对照组基线GCIPL厚度为(71.1±0.3) μm，糖尿病组为(74.4±0.2)μm，糖尿病合并近视组为(71.7±0.5) μm。在2年随访过程中，对照组GCIPL厚度下降-0.10(95%CI：-2.03~0.05) μm/年，糖尿病组GCIPL厚度下降的速度为对照组的12倍[-1.21(95%CI：-24.04~0.05) μm/年，P<0.001]，糖尿病合并近视组GCIPL厚度下降的速度为对照组的22倍[-2.17(95%CI：-21.63~0.10)μm/年，P<0.001]。结论：近视是无DR的糖尿病患者中GCIPL加速变薄的危险因素，糖尿病和近视在GCIPL损伤中可能存在协同作用。

Objective: To investigate the association between myopia and ganglion cell layer and inner plexiform layer (GCIPL) in diabetic population without diabetic retinopathy (DR). Methods: In this Guangzhou Diabetic Eye study, a total of 1 165 patients aged 30–80 years were recruited followed up longitudinally for 2 years. According to the presence or absence of myopia [spherical equivalence (SE)≤-3 diopter (D)] and diabetics, the patients were divided into a healthy group (n=508), a diabetes mellitus group (n=525), and a diabetes mellitus + myopia group (n=132). GCIPL was measured via swept-source optical coherence tomography. Univariable and multivariable mixed models were used to show the association of GCIPL change and baseline parameters. Results: SE was (1.07±1.06) D in the healthy group, (1.02±1.00) D in the diabetes mellitus group and (-5.36±2.30) D in the diabetes mellitus + myopia group (P<0.001). The baseline GCIPL thickness were (71.1±0.3), (74.4±0.2), and (71.7±0.5) μm, respectively. The slope of GCIPL thickness was -0.10 (95% CI: -2.03 to 0.05) μm/year in the healthy group, which was 12 folds faster than those in the diabetes mellitus group [-1.21(95% CI: -24.04 to 0.05 μm/year, P<0.001] and 22 folds higher among those in diabetes mellitus + myopia group [-2.17 (95% CI: -21.63 to 0.10) μm/year, P=0.009]. Conclusion: Both myopia and diabetes status accelerate macular ganglion cell layer and inner plexiform layer thinning in diabetic patients without diabetic retinopathy.

目的：探讨无糖尿病性视网膜病变(diabetic retinopathy，DR)的糖尿病人群中，糖尿病与近视对黄斑区节细胞-内丛状层(ganglion cell layer and inner plexiform layer，GCIPL)厚度纵向变化的影响。方法：纳入广州糖尿病眼病研究中1 165名基线无视网膜病变的糖尿病和正常对照者，纵向随访2年。根据是否存在近视[等效球镜(spherical equivalent，SE)≤-3 屈光度(diopter，D)]和糖尿病分为健康组(n =508)、糖尿病组(n =525)及糖尿病合并近视组(n =132)。扫频光学相干断层成像(swept source-optical coherence tomography，SS-OCT)技术测量并比较三组间GCIPL厚度的变化，以确定糖尿病和近视的影响，三组间差异使用协方差分析，采用线性混合模型分析评估GCIPL厚度与相关因素的关系。结果：对照组的SE为(1.07±1.06) D，糖尿病组为(1.02±1.00) D，糖尿病合并近视组为(-5.36±2.30D)，组间差异有统计学意义(P<0.001)。对照组基线GCIPL厚度为(71.1±0.3) μm，糖尿病组为(74.4±0.2) μm，糖尿病合并近视组为(71.7±0.5) μm。在2年随访过程中，对照组GCIPL厚度下降-0.10(95%CI：0.05~-2.03) μm/年，糖尿病组GCIPL厚度下降的速度为对照组的12倍[-1.21(95%CI：0.05~?24.04) μm/年，P<0.001]，糖尿病合并近视组GCIPL厚度下降的速度为对照组的22倍[-2.17(95%CI：0.10~-21.63) μm/年，P<0.001]。结论：近视是无DR的糖尿病患者中GCIPL加速变薄的危险因素，糖尿病和近视GCIPL损伤中可能存在协同作用。

Objective: To investigate the association between myopia and ganglion cell layer and inner plexiform layer(GCIPL) in diabetic population without diabetic retinopathy (DR). Methods: In this Guangzhou Diabetic Eyestudy, a total of 1165 patients aged 30–80 years were recruited followed up longitudinally for 2 years. According tothe presence or absence of myopia [spherical equivalence (SE)≤-3 diopter (D)] and diabetics, the patients weredivided into a healthy group (n=508), a diabetes mellitus group (n=525), and a diabetes mellitus + myopia group(n=132). GCIPL was measured via swept-source optical coherence tomography. Univariable and multivariablemixed models were used to show the association of GCIPL change and baseline parameters. Results: SE was(1.07±1.06) D in the healthy group, (1.02±1.00) D in the diabetes mellitus group and (-5.36±2.30) D in thediabetes mellitus + myopia group (P<0.001). The baseline GCIPL thickness were (71.1±0.3), (74.4±0.2), and(71.7±0.5) μm, respectively. The slope of GCIPL thickness was ?0.10 (95% CI: 0.05 to -2.03) μm/year in the healthy group, which was 12 folds faster than those in the diabetes mellitus group [-1.21(95% CI: 0.05 to-24.04) μm/year, P<0.001] and 22 folds higher among those in diabetes mellitus + myopia group [-2.17 (95%CI: 0.10 to ?21.63) μm/year, P=0.009]. Conclusion: Both myopia and diabetes status accelerate macular ganglioncell layer and inner plexiform layer thinning in diabetic patients without diabetic retinopathy.

剥脱性青光眼是剥脱综合征继发的一类青光眼，临床上少见。本文报告2例患者，患眼瞳孔缘可见灰白色碎屑样物质沉积，散大瞳孔后可见晶状体前囊周边部混浊带，房角镜下可见Sampaolesi线。认识其临床特征，将有助于提高其诊治率。

Exfoliation glaucoma is a category of glaucoma secondary to exfoliation syndrome, which is rarely encountered in clinical practice. We reported 2 cases with deposits of white material on the pupillary border of the iris. Opacity band could be observed surrounding the anterior lens capsule after pupil dilation, and the Sampaolesi line was seen under gonioscope. Understanding the clinical characteristics contribute to improving the diagnosis and treatment of exfoliation glaucoma.

剥脱性青光眼是剥脱综合征继发的一类青光眼，临床上少见。本文报告2例患者，患眼瞳孔缘可见灰白色碎屑样物质沉积，散大瞳孔后可见晶状体前囊周边部混浊带，房角镜下可见Sampaolesi线。认识其临床特征，将有助于提高其诊治率。

Exfoliation glaucoma is a category of glaucoma secondary to exfoliation syndrome, which is rarely encountered in clinical practice. We reported 2 cases with deposits of white material on the pupillary border of the iris. Opacity band could be observed surrounding the anterior lens capsule after pupil dilation, and the Sampaolesi line was seen under gonioscope. Understanding the clinical characteristics contribute to improving the diagnosis and treatment of exfoliation glaucoma.