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Войти в исследования Translational vision science & technology · 2025
Systematic Druggable-Proteome-Wide Mendelian Randomization Identifies Potential Therapeutic Targets for Allergic Conjunctivitis.
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Chen Jianqi, Zhuo Xiaohua, Ling Yuyao, Zhu Yingting, Li Yangyang, Shen Xinyue, Zhuo Yehong, Tan Hongmei, Li Zhidong
Аннотация
PURPOSE: Allergic conjunctivitis (AC) is a prevalent ocular inflammatory condition. In this study, we aimed to identify novel therapeutic targets for AC by integrating druggable proteomic analyses.
METHODS: We sourced druggable protein abundance data from quantitative trait loci studies, including the deCODE Genetics Consortium (discovery) and UK Biobank Pharma Proteomics Project (replication). Genetic associations with AC were obtained from the FinnGen Project. We applied summary data-based Mendelian randomization (MR) and colocalization techniques to identify and prioritize potential therapeutic targets. Additionally, we conducted phenome-wide MR analysis to evaluate potential co-therapeutic benefits and adverse effects of identified candidate targets and performed protein-protein interaction analysis for functional validation.
RESULTS: Overall, 106 druggable proteins were significantly associated with AC. After false discovery rate (FDR) correction and eliminating associations potentially attributed to pleiotropy, CD36 and HSPA1B were identified as tier 1 and IL6R as tier 2 therapeutic targets. Genetically predicted higher levels of CD36 (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.7-0.88, PFDR = 0.003) and HSPA1B (OR, 0.33; 95% CI, 0.22-0.52; PFDR < 0.001) were associated with a reduced risk of AC. Higher levels of IL6R (OR, 1.05; 95% CI, 1.03-1.07; PFDR < 0.001) were linked to an increased risk of AC. Colocalization was confirmed for CD36 (posterior probability H4 [PPH4] = 0.974) and HSPA1B (PPH4 = 0.974). In the phenome-wide MR analysis, targeting CD36 in patients with AC indicated no significant side effects after FDR correction.
CONCLUSIONS: We identified three potential therapeutic targets, with CD36 being the most promising.
TRANSLATIONAL RELEVANCE: These findings enhance our understanding of AC pathophysiology, driving the development of innovative treatment strategies.
METHODS: We sourced druggable protein abundance data from quantitative trait loci studies, including the deCODE Genetics Consortium (discovery) and UK Biobank Pharma Proteomics Project (replication). Genetic associations with AC were obtained from the FinnGen Project. We applied summary data-based Mendelian randomization (MR) and colocalization techniques to identify and prioritize potential therapeutic targets. Additionally, we conducted phenome-wide MR analysis to evaluate potential co-therapeutic benefits and adverse effects of identified candidate targets and performed protein-protein interaction analysis for functional validation.
RESULTS: Overall, 106 druggable proteins were significantly associated with AC. After false discovery rate (FDR) correction and eliminating associations potentially attributed to pleiotropy, CD36 and HSPA1B were identified as tier 1 and IL6R as tier 2 therapeutic targets. Genetically predicted higher levels of CD36 (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.7-0.88, PFDR = 0.003) and HSPA1B (OR, 0.33; 95% CI, 0.22-0.52; PFDR < 0.001) were associated with a reduced risk of AC. Higher levels of IL6R (OR, 1.05; 95% CI, 1.03-1.07; PFDR < 0.001) were linked to an increased risk of AC. Colocalization was confirmed for CD36 (posterior probability H4 [PPH4] = 0.974) and HSPA1B (PPH4 = 0.974). In the phenome-wide MR analysis, targeting CD36 in patients with AC indicated no significant side effects after FDR correction.
CONCLUSIONS: We identified three potential therapeutic targets, with CD36 being the most promising.
TRANSLATIONAL RELEVANCE: These findings enhance our understanding of AC pathophysiology, driving the development of innovative treatment strategies.