No causal relationship between SARS-CoV-2 infection and retinal vascular occlusion: evidence from two-sample mendelian randomization studies_Chinese Journal of Ocular Fundus Diseases

Authors：

Wei Xixiang ,  Yang Hui , Yin Xue , Fu Zheng , Xiong Weiwei

Department of Ophthalmology, Xiamen Children's Hospital (Children's Hospital of Fudan University at Xiamen), Xiamen 361000, China;

Corresponding author：

Yang Hui, Email: 805992715@qq.com

Keywords：

SARS-CoV-2; Mendelian randomization; Retinal artery occlusion; Retinal vein occlusion; Single nucleotide polymorphism

DOI：

10.3760/cma.j.cn511434-20240530-00213

Video：

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Objective To analyze the causal relationship between SARS-CoV-2 infection and retinal vascular obstruction by mendelian randomization (MR). Methods A two-sample MR analysis utilizing summary statistics from genome-wide association studies (GWAS) in European populations was conducted. The GWAS data for SARS-CoV-2 infection comprised cases of common infection (2 597 856), hospitalized infection (2 095 324), and severe infection (1 086 211). Data on retinal vascular obstruction were obtained from the FinnGen database, which included 203 269 cases of retinal artery obstruction and 182 945 cases of retinal vein obstruction (RVO). Inverse variance weighting (IVW), random effects models, weighted median (WM), MR-Egger regression, simple models, and weighted models were used to analyze the bidirectional causal relationship between different SARS-CoV-2 infection phenotypes and retinal obstruction. The Q statistic was used to assess heterogeneity among single nucleotide polymorphisms (SNP), while MR-Presso was utilized to detect SNP outliers, and MR-Egger intercept tests were performed to evaluate horizontal pleiotropy. Results The MR analysis, using IVW, random effects models, MR-Egger, WM, and weighted models, indicated no significant association between common SARS-CoV-2 infection, hospitalized infection, severe infection, and retinal vascular obstruction (P＞0.05). Additionally, retinal vascular obstruction did not show a significant association with the various SARS-CoV-2 infection phenotypes (P＞0.05). In the simple model, a significant association was found between severe SARS-CoV-2 infection and RVO (P＜0.05), as well as between RVO and common SARS-CoV-2 infection (P＜0.05). No heterogeneity was observed in the IVW and MR-Egger analyses (P＞0.05). The MR-Egger test provided no evidence of horizontal pleiotropy (P＞0.05), and MR-Presso detected no outlier SNP. Conclusion The findings of this study do not support a causal relationship between SARS-CoV-2 infection and the occurrence of retinal vascular obstruction.

Citation： Wei Xixiang, Yang Hui, Yin Xue, Fu Zheng, Xiong Weiwei. No causal relationship between SARS-CoV-2 infection and retinal vascular occlusion: evidence from two-sample mendelian randomization studies. Chinese Journal of Ocular Fundus Diseases, 2024, 40(11): 860-868. doi: 10.3760/cma.j.cn511434-20240530-00213 Copy

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14.	Power GM, Sanderson E, Pagoni P, et al. Methodological approaches, challenges, and opportunities in the application of Mendelian randomisation to lifecourse epidemiology: a systematic literature review[J]. Eur J Epidemiol, 2024, 39(5): 501-520. DOI: 10.1007/s10654-023-01032-1.
15.	Boehm FJ, Zhou X. Statistical methods for Mendelian randomization in genome-wide association studies: a review[J]. Comput Struct Biotechnol J, 2022, 20: 2338-2351. DOI: 10.1016/j.csbj.2022.05.015.
16.	Burgess S, Scott RA, Timpson NJ, et al. Using published data in mendelian randomization: a blueprint for efficient identification of causal risk factors[J]. Eur J Epidemiol, 2015, 30(7): 543-552. DOI: 10.1007/s10654-015-0011-z.
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19.	Palmer T, Lawlor D, Harbord R, et al. Using multiple genetic variants as instrumental variables for modifiable risk factors[J]. Stat Methods Med Res, 2012, 21(3): 223-242. DOI: 10.1177/0962280210394459.
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21.	Bowden J, Smith GD, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression[J]. Int J Epidemiol, 2015, 44(2): 512-525. DOI: 10.1093/ije/dyv080.
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24.	Bowden J, Del Greco MF, Minelli C, et al. Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption[J]. Int J Epidemiol, 2019, 48(3): 728-742. DOI: 10.1093/ije/dyy258.
25.	Verbanck M, Chen C, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases[J]. Nat Genet, 2018, 50(5): 693-698. DOI: 10.1038/s41588-018-0099-7.
26.	Heidarzadeh HR, Abrishami M, Shariati MM, et al. Atypical central retinal artery occlusion following COVID-19 infection: a case report[J]. Case Rep Ophthalmol, 2023, 14(1): 405-410. DOI: 10.1159/000532108.
27.	Sunny CLA, Callie KLK. Prevalence of SARS-CoV-2 among central retinal artery occlusion patients: a case series-HORA study report No. 3[J]. J Acute Dis, 2021, 10(4): 147-149. DOI: 10.4103/2221-6189.318644.
28.	Ashkenazy N, Patel NA, Sridhar J, et al. Hemi- and central retinal vein occlusion associated with COVID-19 infection in young patients without known risk factors[J]. Ophthalmol Retina, 2022, 6(6): 520-530. DOI: 10.1016/j.oret.2022.02.004.
29.	Al-Moujahed A, Boucher N, Fernando R, et al. Incidence of retinal artery and vein occlusions during the COVID-19 pandemic[J]. Ophthalmic Surg Lasers Imaging Retina, 2022, 53(1): 22-30. DOI: 10.3928/23258160-20211209-01.
30.	Modjtahedi BS, Do D, Luong T, et al. Changes in the incidence of retinal vascular occlusions after COVID-19 diagnosis[J]. JAMA Ophthalmol, 2022, 140(5): 523-537. DOI: 10.1001/jamaophthalmol.2022.0632.

1. Merrill J, Erkan D, Winakur J, et al. Emerging evidence of a COVID-19 thrombotic syndrome has treatment implications[J]. Nat Rev Rheumatol, 2020, 16(10): 581-589. DOI: 10.1038/s41584-020-0474-5.
2. Ali M, Spinler S. COVID-19 and thrombosis: from bench to bedside[J]. Trends Cardiovasc Med, 2021, 31(3): 143-160. DOI: 10.1016/j.tcm.2020.12.004.
3. Mir T, Almas T, Kaur J, et al. Coronavirus disease 2019 (COVID-19): multisystem review of pathophysiology[J/OL]. Ann Med Surg (Lond), 2021, 69: 102745[2021-08-23]. https://pubmed.ncbi.nlm.nih.gov/34457265/. DOI: 10.1016/j.amsu.2021.102745.
4. Sharma A, Parachuri N, Kumar N, et al. Myths and truths of the association of retinal vascular occlusion with COVID-19[J]. Retina, 2022, 42(3): 413-416. DOI: 10.1097/iae.0000000000003371.
5. Shiroma H, Lima L, Shiroma Y, et al. Retinal vascular occlusion in patients with the Covid-19 virus[J]. Int J Retina Vitreous, 2022, 8(1): 45. DOI: 10.1186/s40942-022-00371-7.
6. Invernizzi A, Pellegrini M, Messenio D, et al. Impending central retinal vein occlusion in a patient with coronavirus disease 2019 (COVID-19)[J]. Ocul Immunol Inflamm, 2020, 28(8): 1290-1292. DOI: 10.1080/09273948.2020.1807023.
7. Rego Lorca D, Rouco Fernandez A, Jimenez Santos M, et al. Bilateral retinal vein occlusion and diabetic retinopathy after COVID-19[J/OL]. Acta Ophthalmol, 2021, 99(7): e1246-e1248[2020-12-23]. https://pubmed.ncbi.nlm.nih.gov/33354904/. DOI: 10.1111/aos.14718.
8. Walinjkar J, Makhija S, Sharma H, et al. Central retinal vein occlusion with COVID-19 infection as the presumptive etiology[J]. Indian J Ophthalmol, 2020, 68(11): 2572-2574. DOI: 10.4103/ijo.IJO_2575_20.
9. Lee MY, Bae ON, Chung SM, et al. Enhancement of platelet aggregation and thrombus formation by arsenic in drinking water: a contributing factor to cardiovascular disease[J]. Toxicol Appl Pharmacol, 2002, 179(2): 83-88. DOI: 10.1006/taap.2001.9356.
10. Okoroh E, Hooper W, Atrash H, et al. Is polycystic ovary syndrome another risk factor for venous thromboembolism? United States, 2003-2008[J]. Am J Obstet Gynecol, 2012, 207(5): 377. DOI: 10.1016/j.ajog.2012.08.007.
11. Finn A, Khurana R, Chang L. Hemi-retinal vein occlusion in a young patient with COVID-19[J/OL]. Am J Ophthalmol Case Rep, 2021, 22: 101046[2021-04-05]. https://pubmed.ncbi.nlm.nih.gov/33688598/. DOI: 10.1016/j.ajoc.2021.101046.
12. Venkatesh R, Reddy N, Agrawal S, et al. COVID-19-associated central retinal vein occlusion treated with oral aspirin[J/OL]. BMJ Case Rep, 2021, 14(5): e242987[2021-05-19]. https://pubmed.ncbi.nlm.nih.gov/34011649/. DOI: 10.1136/bcr-2021-242987.
13. Raval N, Djougarian A, Lin J. Central retinal vein occlusion in the setting of COVID-19 infection[J]. J Ophthalmic Inflamm Infect, 2021, 11(1): 10. DOI: 10.1186/s12348-021-00241-7.
14. Power GM, Sanderson E, Pagoni P, et al. Methodological approaches, challenges, and opportunities in the application of Mendelian randomisation to lifecourse epidemiology: a systematic literature review[J]. Eur J Epidemiol, 2024, 39(5): 501-520. DOI: 10.1007/s10654-023-01032-1.
15. Boehm FJ, Zhou X. Statistical methods for Mendelian randomization in genome-wide association studies: a review[J]. Comput Struct Biotechnol J, 2022, 20: 2338-2351. DOI: 10.1016/j.csbj.2022.05.015.
16. Burgess S, Scott RA, Timpson NJ, et al. Using published data in mendelian randomization: a blueprint for efficient identification of causal risk factors[J]. Eur J Epidemiol, 2015, 30(7): 543-552. DOI: 10.1007/s10654-015-0011-z.
17. Skrivankova VW, Richmond RC, Woolf BAR, et al. Strengthening the reporting of observational studies in epidemiology using mendelian randomization: the STROBE-MR Statement[J]. JAMA, 2021, 326(16): 1614-1621. DOI: 10.1001/jama.2021.18236.
18. Kurki MI, Karjalainen J, Palta P, et al. FinnGen provides genetic insights from a well-phenotyped isolated population[J]. Nature, 2023, 613(7944): 508-518. DOI: 10.1038/s41586-022-05473-8.
19. Palmer T, Lawlor D, Harbord R, et al. Using multiple genetic variants as instrumental variables for modifiable risk factors[J]. Stat Methods Med Res, 2012, 21(3): 223-242. DOI: 10.1177/0962280210394459.
20. Burgess S, Dudbridge F, Thompson S. Combining information on multiple instrumental variables in Mendelian randomization: comparison of allele score and summarized data methods[J]. Stat Med, 2016, 35(11): 1880-1906. DOI: 10.1002/sim.6835.
21. Bowden J, Smith GD, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression[J]. Int J Epidemiol, 2015, 44(2): 512-525. DOI: 10.1093/ije/dyv080.
22. Bowden J, Smith GD, Haycock PC, et al. Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator[J]. Genet Epidemiol, 2016, 40(4): 304-314. DOI: 10.1002/gepi.21965.
23. Hemani G, Zhengn J, Elsworth B, et al. The Mr-Base platform supports systematic causal inference across the human phenome[J/OL]. Elife, 2018, 7: e34408[2018-05-30]. https://pubmed.ncbi.nlm.nih.gov/29846171/. DOI: 10.7554/eLife.34408.
24. Bowden J, Del Greco MF, Minelli C, et al. Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption[J]. Int J Epidemiol, 2019, 48(3): 728-742. DOI: 10.1093/ije/dyy258.
25. Verbanck M, Chen C, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases[J]. Nat Genet, 2018, 50(5): 693-698. DOI: 10.1038/s41588-018-0099-7.
26. Heidarzadeh HR, Abrishami M, Shariati MM, et al. Atypical central retinal artery occlusion following COVID-19 infection: a case report[J]. Case Rep Ophthalmol, 2023, 14(1): 405-410. DOI: 10.1159/000532108.
27. Sunny CLA, Callie KLK. Prevalence of SARS-CoV-2 among central retinal artery occlusion patients: a case series-HORA study report No. 3[J]. J Acute Dis, 2021, 10(4): 147-149. DOI: 10.4103/2221-6189.318644.
28. Ashkenazy N, Patel NA, Sridhar J, et al. Hemi- and central retinal vein occlusion associated with COVID-19 infection in young patients without known risk factors[J]. Ophthalmol Retina, 2022, 6(6): 520-530. DOI: 10.1016/j.oret.2022.02.004.
29. Al-Moujahed A, Boucher N, Fernando R, et al. Incidence of retinal artery and vein occlusions during the COVID-19 pandemic[J]. Ophthalmic Surg Lasers Imaging Retina, 2022, 53(1): 22-30. DOI: 10.3928/23258160-20211209-01.
30. Modjtahedi BS, Do D, Luong T, et al. Changes in the incidence of retinal vascular occlusions after COVID-19 diagnosis[J]. JAMA Ophthalmol, 2022, 140(5): 523-537. DOI: 10.1001/jamaophthalmol.2022.0632.

Chinese Journal of Ocular Fundus Diseases

No causal relationship between SARS-CoV-2 infection and retinal vascular occlusion: evidence from two-sample mendelian randomization studies

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