Systemic inflammatory regulators and proliferative diabetic retinopathy: A bidirectional Mendelian randomization study
BackgroundIncreasing evidence shows that systemic inflammation is an embedded mechanism of proliferative diabetic retinopathy (PDR). However, the specific systemic inflammatory factors involved in this process remained obscure. The study aimed to identify the upstream and downstream systemic regulat...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1088778/full |
| _version_ | 1811167116122914816 |
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| author | Qiqin Shi Qiangsheng Wang Zhenqian Wang Jiawen Lu Ruobing Wang |
| author_facet | Qiqin Shi Qiangsheng Wang Zhenqian Wang Jiawen Lu Ruobing Wang |
| author_sort | Qiqin Shi |
| collection | DOAJ |
| description | BackgroundIncreasing evidence shows that systemic inflammation is an embedded mechanism of proliferative diabetic retinopathy (PDR). However, the specific systemic inflammatory factors involved in this process remained obscure. The study aimed to identify the upstream and downstream systemic regulators of PDR by using Mendelian randomization (MR) analyses.MethodsWe performed a bidirectional two-sample MR analysis implementing the results from genome-wide association studies for 41 serum cytokines from 8,293 Finnish individuals, and PDR from FinnGen consortium (2,025 cases vs. 284,826 controls) and eight cohorts of European ancestry (398 cases vs. 2,848 controls), respectively. The inverse-variance-weighted method was adopted as the main MR method, and four additional MR methods (MR-Egger, weighted-median, MR-pleiotropy residual sum and outlier (MR-PRESSO), and MR-Steiger filtering methods) were used for the sensitivity analyses. Results from FinnGen and eight cohorts were pooled into a meta-analysis.ResultsOur results showed that genetically predicted higher stem cell growth factor-β (SCGFb) and interleukin-8 were positively associated with an elevated risk of PDR, with a combined effect of one standard deviation (SD) increase in SCGFb and interleukin-8 causing 11.8% [95% confidence interval (CI): 0.6%, 24.2%]) and 21.4% [95% CI: 3.8%, 41.9%]) higher risk of PDR, respectively. In contrast, genetically predisposition to PDR showed a positive association with the increased levels of growth-regulated oncogene-α (GROa), stromal cell-derived factor-1 alpha (SDF1a), monocyte chemotactic protein-3 (MCP3), granulocyte colony-stimulating factor (GCSF), interleukin-12p70, and interleukin-2 receptor subunit alpha (IL-2ra).ConclusionsOur MR study identified two upstream regulators and six downstream effectors of PDR, providing opportunities for new therapeutic exploitation of PDR onset. Nonetheless, these nominal associations of systemic inflammatory regulators and PDR require validation in larger cohorts. |
| first_indexed | 2024-04-10T16:04:48Z |
| format | Article |
| id | doaj.art-67795602675d47f1a9a46dfea3a4909f |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-10T16:04:48Z |
| publishDate | 2023-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-67795602675d47f1a9a46dfea3a4909f2023-02-10T06:32:59ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-02-011410.3389/fimmu.2023.10887781088778Systemic inflammatory regulators and proliferative diabetic retinopathy: A bidirectional Mendelian randomization studyQiqin Shi0Qiangsheng Wang1Zhenqian Wang2Jiawen Lu3Ruobing Wang4Department of Ophthalmology, Ningbo Hangzhou Bay Hospital, Ningbo, Zhejiang, ChinaDepartment of Haematology, Ningbo Hangzhou Bay Hospital, Ningbo, Zhejiang, ChinaSchool of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, Guangdong, ChinaSchool of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, Guangdong, ChinaDepartment of Ophthalmology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, ChinaBackgroundIncreasing evidence shows that systemic inflammation is an embedded mechanism of proliferative diabetic retinopathy (PDR). However, the specific systemic inflammatory factors involved in this process remained obscure. The study aimed to identify the upstream and downstream systemic regulators of PDR by using Mendelian randomization (MR) analyses.MethodsWe performed a bidirectional two-sample MR analysis implementing the results from genome-wide association studies for 41 serum cytokines from 8,293 Finnish individuals, and PDR from FinnGen consortium (2,025 cases vs. 284,826 controls) and eight cohorts of European ancestry (398 cases vs. 2,848 controls), respectively. The inverse-variance-weighted method was adopted as the main MR method, and four additional MR methods (MR-Egger, weighted-median, MR-pleiotropy residual sum and outlier (MR-PRESSO), and MR-Steiger filtering methods) were used for the sensitivity analyses. Results from FinnGen and eight cohorts were pooled into a meta-analysis.ResultsOur results showed that genetically predicted higher stem cell growth factor-β (SCGFb) and interleukin-8 were positively associated with an elevated risk of PDR, with a combined effect of one standard deviation (SD) increase in SCGFb and interleukin-8 causing 11.8% [95% confidence interval (CI): 0.6%, 24.2%]) and 21.4% [95% CI: 3.8%, 41.9%]) higher risk of PDR, respectively. In contrast, genetically predisposition to PDR showed a positive association with the increased levels of growth-regulated oncogene-α (GROa), stromal cell-derived factor-1 alpha (SDF1a), monocyte chemotactic protein-3 (MCP3), granulocyte colony-stimulating factor (GCSF), interleukin-12p70, and interleukin-2 receptor subunit alpha (IL-2ra).ConclusionsOur MR study identified two upstream regulators and six downstream effectors of PDR, providing opportunities for new therapeutic exploitation of PDR onset. Nonetheless, these nominal associations of systemic inflammatory regulators and PDR require validation in larger cohorts.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1088778/fullbidirectionalsystemic inflammatory regulatorsMendelian randomizationproliferative diabetic retinopathymeta-analysis |
| spellingShingle | Qiqin Shi Qiangsheng Wang Zhenqian Wang Jiawen Lu Ruobing Wang Systemic inflammatory regulators and proliferative diabetic retinopathy: A bidirectional Mendelian randomization study Frontiers in Immunology bidirectional systemic inflammatory regulators Mendelian randomization proliferative diabetic retinopathy meta-analysis |
| title | Systemic inflammatory regulators and proliferative diabetic retinopathy: A bidirectional Mendelian randomization study |
| title_full | Systemic inflammatory regulators and proliferative diabetic retinopathy: A bidirectional Mendelian randomization study |
| title_fullStr | Systemic inflammatory regulators and proliferative diabetic retinopathy: A bidirectional Mendelian randomization study |
| title_full_unstemmed | Systemic inflammatory regulators and proliferative diabetic retinopathy: A bidirectional Mendelian randomization study |
| title_short | Systemic inflammatory regulators and proliferative diabetic retinopathy: A bidirectional Mendelian randomization study |
| title_sort | systemic inflammatory regulators and proliferative diabetic retinopathy a bidirectional mendelian randomization study |
| topic | bidirectional systemic inflammatory regulators Mendelian randomization proliferative diabetic retinopathy meta-analysis |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1088778/full |
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