According to the current literature, our study is the first study to discuss the causal relationship between glaucoma and RVO at the genetic level. Glaucoma has been considered as a risk factor for the development of RVO3. However, it is uncertain whether glaucoma has a causal relationship with RVO. We carried out four different estimating methods (inverse-variance weighted method, weighted median method, MR‐Egger regression and weighted mode) for MR analyses. Two previous studies on risk factors in patients with RVO have used this method, making the feasibility of this study obvious. Zheng et al. found a causal relationship between lipids and RVO by MR and concluded that HDL-C is a significant risk factor for the development of to RVO compared to other lipid types5. Meanwhile, using this method, Huang found that T2DM is a risk factor for RVO24. Our study indicated that the associations between glaucoma and RVO may be causal. Although the MR estimates using IVW, MR Egger, weighted median and weighted mode analysis were not consistent, IVW and weighted mode analysis support a causal association between glaucoma and RVO. Considering that compared to the MR‐Egger analysis, the IVW estimator has the advantage of retaining greater precision in the estimates, this MR analysis indicates a potential causal role of glaucoma in the risk of RVO. In addition, the beta values calculated by all four MR methods were positive and in the same direction, which also proved that glaucoma is a risk factor for the occurrence of RVO. Thus, our study corroborates the association found in previous observational studies.
A meta-analysis showed that glaucoma is a significant risk factor for RVO. It was indicated that OAG (POAG/COAG) could increase the incidence of RVO, particularly for CRVO. Meanwhile, there was less association between PACG and RVO, especially for BRVO7, but heterogeneity was unavoidable. On the other hand, there was one cross-sectional study confirming the non-association between glaucoma and RVO: the Korean National Health and Nutritional Examination Survey25. Thus, previous studies of glaucoma and RVO have yielded correlations, but the existence of an association between the two remains fraught with controversy. Furthermore, this is the first study to discuss the causal relationship between glaucoma and RVO at the genetic level. Călugăru D et al11 described the mechanisms involved in the development of RVO in glaucoma patients from a pathohistological perspective. In eyes with narrow angles, intermittent angle closure episodes may trigger the onset of venous occlusion from collapse of the vein, and, as a result, endothelial lesions may lead to intimal proliferation at the level of the lamina cribrosa26. Călugăru M once elaborated three risk factors for central/hemicentral RVO are angle closure27,a permanently high IOP, and glaucomatous cupping of the optic disc28. These risk factors can corroborate that glaucoma patients need to be on high alert for RVO.
Beaumont PE studied the association between glaucoma and RVO from an anatomical point of view and concluded: RVOs with optic nerve head swelling within the optic nerve head behind the lamina cribrosa have not been associated with high values of IOP, cup-to-disc ratio or prevalence of POAG. The appearance of the optic nerve head swelling in RVOs shows that the venous occlusion caused
sufficient ischemia immediately behind the lamina cribrosa to block axoplasmic transport29. Mohammadi M et al. explored the mechanisms involved from a cell biological perspective: Cell proliferation in the lumen of the vein at the level of the lamina cribrosa and displacement of the vessel in the anterior portion of the optic nerve have been suggested to be causes of central/hemicentral RVOs30. In recent years, as the study of biomechanics in ocular diseases has been gradually deepened, the biomechanical mechanisms associated with RVO have been gradually revealed31. The physical obstruction of the retinal venous system is generally induced by thrombosis, deformation of the vein wall, and external biomechanical compression secondary to glaucoma32. Mechanically, it is postulated that the elevated intraocular pressure compresses the lamina cribrosa and optic disc, thereby leading to the stretching and weakening of the vessel wall, which further predisposes the retinal vein to occlusion33. Meanwhile, the direct biomechanical insult of intraocular pressure obstructs the retinal vein drainage and induces venous stasis, consequently exacerbating the intimal proliferation in the vein34. None of the above studies have argued for a causal relationship between glaucoma and RVO.
MR minimises the bias inherent in observational studies35. However, MR studies are susceptible to pleiotropy (the association of genetic variants with more than one variable). Genetic variants may be associated with multiple phenotypes, a phenomenon known as pleiotropy, which can confound MR estimates and lead to biased causality estimates21. Although the inclusion of more than one variant in MR analyses generally improves statistical power, it may also lead to the inclusion of pleiotropic genetic variants that are not valid IVs. Therefore, sensitivity analyses are needed to test the validity of MR findings. To eliminate pleiotropy, we used weighted mode estimation, which provides valid estimates even if 50% of the SNPs are not valid instruments, and MR-Egger regression to test for unbalanced pleiotropy and to provide causal estimates of the effect of exposure on outcomes in the presence of pleiotropy. The results of these four methods were inconsistent. Our data support previous observational studies showing an association between glaucoma and RVO. The current findings may provide an opportunity to identify the mechanisms by which glaucoma affects the risk of RVO.
To the best of our knowledge, this is the first study to clarify a causal associations between glaucoma and RVO risk using the MR method. However, our MR study does have several limitations that should not be ignored. The greatest concern in MR studies is the horizontal pleiotropy, which occurs when thegenetic variants influence the outcome of more than one pathway15.Furthermore, both glaucoma and RVO summary statistics were obtained from individuals of European ancestry. This reduced population structure bias, but limited the generalizability of our finding to other ethnicities. A causal relationship between genetically predicted glaucoma and RVO should be further evaluated in Asians when relevantdata are available. In addition, we did not separately assess genetic prediction of associations between different types of glaucoma and RVO because the gene pool currently lacks this information. It is worth noting that although common risk factors for RVO were adjusted for in our analyses, we could not completely exclude the influence of other unexplored factors.