Causal inference between serum bilirubin levels and juvenile idiopathic arthritis-associated uveitis: A bidirectional Mendelian randomization study.

Background: Several observational studies have suggested an association between low serum bilirubin levels and Behçet's disease uveitis. However, the causal inference between bilirubin level and juvenile idiopathic arthritis-associated uveitis (JIAU) remains ambiguous. We investigated the potential causal relationship between serum bilirubin levels and JIAU using a bidirectional two-sample Mendelian randomization (MR) framework. Methods: We systemically integrated summary-level data from published large-scale genome-wide association studies on bilirubin level and JIAU in a Caucasian British population. To determine the causal effect of bilirubin level on JIAU, we constructed strong instrumental variables using 47 and 80 single-nucleotide polymorphisms (SNPs) specific to direct bilirubin and total bilirubin levels, respectively. For reverse causal inference, seven SNPs associated with JIAU were included in our study. Multiple complementary methods were further performed to evaluate the robustness of MR estimates. Results: The inverse-variance weighted estimate did not show any significant causal associations of genetically predicted serum direct or total bilirubin level with the risk of JIAU (odds ratio [OR]: 1.010, 95% confidence interval [CI]: 0.750-1.359, p = 0.947; OR: 0.867, 95% CI: 0.688-1.093; p = 0.227, respectively). MR-Egger and weighted median methods also obtained similar associations. Additionally, the results of reverse MR analyses using JIAU as exposure showed no associations of genetically predicted risk of JIAU with serum bilirubin levels (p > 0.05). In sensitivity analysis, the causal estimate between serum bilirubin levels and JIAU did not differ when SNPs associated with possible confounders were omitted. Conclusion: Genetic evidence from our bidirectional analysis did not support a causal association between serum bilirubin levels and JIAU risk in the Caucasian British population. Future large-scale studies should be conducted to validate these findings and explore any causal effects on the disease process.

Investigating the Causal Relationship Between Sleep Behaviors and Primary Open-Angle Glaucoma: A Bidirectional Two-Sample Mendelian Randomization Study.

Background: Although previous studies of sleep-related behaviors in relation to primary open-angle glaucoma (POAG) have been noted, the causal relationship remains unclear. The purpose of our present study was to investigate the relationships of genetically predicted sleep traits with POAG using a two-sample bidirectional Mendelian randomization (MR) method. Methods: Summary-level data collected from publicly available genome-wide association studies (GWAS) of European decent were applied for the bidirectional MR analysis. After quality control steps, independent single-nucleotide polymorphisms for eight sleep behaviors and POAG were selected as the genetic instruments. The inverse-variance weighted (IVW) approach was adopted as the primary method, which was complemented by a series of sensitivity analyses to assess the robustness of the results by estimating heterogeneity and pleiotropy. Multivariable MR (MVMR) was used to assess the direct effect of sleep traits on POAG, after adjusting for several confounding factors. Results: Our investigation revealed a positive correlation between genetically predicted ease of getting up in the morning and sleep duration and POAG using the IVW method (odds ratio (OR)=1.78, 95% confidence interval (CI):1.29-2.46, P = 4.33× 10-4; OR = 1.66, 95% CI:1.18-2.34, P = 3.38×10-3, respectively). Other supplementary MR methods also confirmed similar results. Moreover, the MVMR results also revealed that the adverse effects of these two sleep traits on POAG persisted after adjusting for body mass index, smoking, drinking, and education (all P < 0.05). Conversely, the relationships between genetic liability of POAG and different sleep behaviors were not statistically significant in the reverse-direction MR estimate (all P > 0.05). Conclusion: Our study demonstrated that genetic prediction of getting up easily in the morning or sleep duration were associated with a higher risk of POAG, but not vice versa, in a European population. Further validation and clinical interventions are required to offer potential strategies to prevent and manage POAG.

Genetically predicted retinal vascular occlusion in relation to cardiovascular diseases: A bidirectional two-sample Mendelian randomization analysis.

INTRODUCTION: Increasing evidence implicates retinal vascular occlusions as a susceptibility factor for cardiovascular diseases (CVDs), whereas inconsistent results on the relationship were reported in previous observational studies. This research using a bidirectional two-sample Mendelian randomization (MR) analysis aimed to investigate the potential association between genetically determined central/branch retinal artery and retinal vein occlusions (CRAO/BRAO/RVO) and the risk of CVD. METHODS: Summary statistics of retinal vascular occlusions from the largest available genome-wide association study of European descent were used to investigate their relationship with CVDs, and vice versa. Primary analyses were conducted using the common inverse-variance weighted approach. Several complementary sensitivity analyses were performed to verify the reliability of our results. RESULTS: Inverse variance weighted method showed suggestive effects of genetically determined RVO on ischemic stroke (IS) (odds ratio [OR] = 1.021, 95% confidence [CI] = 1.004-1.037, p = 0.012), a genetic liability to CRAO increased the risk of myocardial infarction (MI) (OR = 1.014, 95% CI = 1.006-1.023, p = 7.0 × 10-4). In addition, genetic predisposition to BRAO had a positive effect on stroke (OR = 1.008, 95% CI = 1.002-1.013, p = 0.011), IS (OR = 1.007, 95% CI = 1.001-1.014, p = 0.022), and cardioembolic stroke (CES) (OR = 1.018, 95% CI = 1.006-1.031, p = 0.004). The point estimates from sensitivity analyses were in the same direction. Reverse MR analyses found no significant evidence for the effect of CVDs on retinal vascular occlusions. CONCLUSION: Our MR study provides potential evidence that retinal vascular occlusions are causally linked to increased risk of CVDs including IS, MI, stroke, and CES. This supports the need for clinical CVD screening in individuals with retinal vascular occlusions. Further investigations are warranted to clarify the effects of CVDs on ocular comorbidities.

Application of Femtosecond Laser + Piggyback Multifocal Intraocular Lens Implantation in Patients with Super-High Myopia Complicated with Cataract.

OBJECTIVE: To observe the clinical effect of piggyback multifocal intraocular lens (IOL) implantation in treating patients with high myopia complicated with cataract. METHODS: This was a prospective controlled study. We compared 32 eyes of 32 patients who underwent femtosecond laser-assisted cataract surgery with piggyback IOL implantation (two IOLs were implanted into the capsule) with 32 eyes of 32 patients who also underwent the same surgery (one IOL implanted into the capsule) due to high myopia complicated with cataract at the Wuhan Aier Eye Expert Hospital between January 2019 and October 2020. All patients were followed up for three months after surgery. Uncorrected distance visual acuity (UCDVA), uncorrected intermediate visual acuity (UCIVA), uncorrected near visual acuity (UCNVA), best-corrected distance visual acuity, distance-corrected intermediate visual acuity (DCIVA), distance-corrected near visual acuity (DCNVA), postoperative spectacle independence, postoperative visual interference, equivalent spherical lens, defocus curve, and IOL tilt and eccentricity were evaluated. RESULTS: Three months after surgery, the patients' UCIVA, UCNVA, DCIVA, and DCNVA were 0.49 ± 0.07, 0.38 ± 0.15, 0.47 ± 0.09, and 0.36 ± 0.12, respectively, in the research group and 0.56 ± 0.18, 0.72 ± 0.22, 0.55 ± 0.13, and 0.69 ± 0.15, respectively, in the control group; the differences between the two groups were statistically significant (P < .05). The spectacle independence rate was higher in the research group (93%) than in the control group (13%). The overall satisfaction regarding postoperative visual quality was also higher in the research group than in the control group. The absolute mean value of the spherical equivalents was 0.48 ± 0.28 D in the research group and 0.62 ± 0.33 D in the control group; the difference between the two groups was statistically significant (P < .05). CONCLUSION: Piggyback multifocal IOL implantation can expand the multifocal IOL application range, and satisfy the desire of patients with high myopia complicated with cataract to see both near and far.

Causal analysis of serum polyunsaturated fatty acids with juvenile idiopathic arthritis and ocular comorbidity.

BACKGROUND & OBJECTIVE: To investigate the causal effects of plasma Polyunsaturated fatty acids (PUFAs) on the risk of juvenile idiopathic arthritis (JIA) and ocular comorbidity through Mendelian randomization (MR) analysis. METHODS: Genetic variants (formerly single nucleotide polymorphisms, SNPs) that are strongly associated with PUFAs levels (P < 5×10-8) were selected as instrumental variables. Summary-level MR was performed with outcome estimates for JIA (n = 31,142) and JIA associated iridocyclitis (n = 94,197). The inverse variance-weighted (IVW) method was employed as the main approach to combine the estimation for each SNP. Two set of models with summary statistics were conducted and multiple sensitivity analyses were applied for testing of pleiotropic bias. RESULTS: In model 1, genetically predicted n-6 PUFAs linoleic acid (LA) and arachidonic acid (AA) were associated with lower and higher risk of JIA associated iridocyclitis using IVW (ORLA = 0.940, 95% CI: 0.895-0.988, P = 0.015; ORAA = 1.053, 95% CI: 1.007-1.101, P = 0.024). No such association was observed between each plasma PUFAs and JIA susceptibility (P > 0.05). In further MR analysis, results from model 2 also showed a consistent trend. Besides, multiple sensitivity analyses revealed that there was no obvious evidence for unknown pleiotropy (P > 0.05). CONCLUSIONS: Our MR study provides genetic evidence on the possible causality that plasma LA level might protect against JIA associated iridocyclitis, whereas AA was responsible for opposite effect.

Causal association of juvenile idiopathic arthritis-associated uveitis with depression and anxiety: a bidirectional Mendelian randomization study.

PURPOSE: The objective of this article was to examine the potential effect of juvenile idiopathic arthritis-associated uveitis (JIAU) on the risk of major depressive and anxiety disorders through Mendelian randomization (MR) study. METHODS: Genetic instrumental variables from the largest available genome-wide association study for JIAU, major depressive disorder, and anxiety disorder were applied. A set of complementary MR approaches including inverse-variance weighted (IVW) were carried out to verify the estimate association and assess horizontal pleiotropy. RESULTS: Our results indicated that genetically driven JIAU did not causally produce changes in major depressive or anxiety disorders (IVW: OR = 1.001, 95% CI = 0.997-1.006, P = 0.581; IVW: OR = 1.006, 95% CI = 0.980-1.033, P = 0.649, respectively). In addition, the risk of JIAU could not be influenced by genetically predicted major depressive or anxiety disorders (IVW: OR = 1.132, 95% CI = 0.914-1.404, P = 0.256; IVW: OR = 1.019, 95% CI = 0.548-1.896, P = 0.953, respectively). Besides, several sensitivity analyses indicated that our MR results were robust and no horizontal pleiotropy was observed (P > 0.05). CONCLUSIONS: Our MR study does not reveal sufficient evidence to support the causal association of JIAU with the development of major depressive or anxiety disorders in both directions. Further large studies are warranted to validate the undetermined relationship between JIAU and the risk of major depressive or anxiety disorders.

Meta-Analysis of the Genetic Association between PTPN22 and CTLA-4 Variants and Risk of Uveitis.

BACKGROUND: Though the risk of protein tyrosine phosphatase nonreceptor 22 (PTPN22) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) genetic variants with uveitis have been developed, the combined results still remain uncertain and controversial. OBJECTIVES: The aim of this study was to perform a meta-analysis to estimate the precise association of PTPN22 (rs2488457 and rs2476601) and CTLA-4 (rs231775, rs5742909, rs4553808, and rs3087243) polymorphisms with uveitis susceptibility. METHOD: Five electronic databases (PubMed, Embase, Web of Science, China Biomedical Database, and China National Knowledge Infrastructure) were systematically searched for relevant literature up to July 20, 2021. All statistical analyses were evaluated by Stata 12.0 software and R programming language. RESULTS: Our meta-results indicated that PTPN22 rs2488457 conferred positive susceptibility to uveitis (odds ratio [OR] = 1.18, 95% confidence interval [CI] = 1.02-1.38, p = 0.029). In stratified analysis by ethnicity, the rs2488457 C allele had a growing tendency toward uveitis in the Asian region (OR = 1.21, 95% CI = 1.00-1.45, p = 0.046). For CTLA-4 rs231775, subgroup analysis based on ethnicity manifested a negative association among uveitis individuals in the Africa region (OR = 0.25, 95% CI = 0.19-0.33, p < 0.001). For CTLA-4 rs4553808, subgroup analysis by the disease type revealed that the GG genotype was associated with an elevated risk of Behcet's disease (BD) (OR = 3.22, 95% CI = 1.05-9.90, p = 0.042). CONCLUSIONS: Our research revealed that PTPN22 rs2488457 conferred strong susceptibility to uveitis in general, especially in the Asian region. CTLA-4 rs231775 conveyed protection against uveitis in African populations, and CTLA-4 rs4553808 displayed an increased risk of BD.

Meta-Analysis of the Pharmacogenetics of ARMS2 A69S Polymorphism and the Response to Advanced Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) causes irreversible vision loss, and targeted anti-vascular endothelial growth factor (VEGF) therapy is now the most common and effective treatment. The aim of this meta-analysis is to discuss whether genetic polymorphism of ARMS2 A69S could confer susceptibility to advanced AMD with the response to anti-VEGF treatment. We performed a meta-analysis of relevant published studies selected through electronic databases. A total of 21 preferred studies regarding the association between ARMS2 gene and anti-VEGF treatment response in advanced AMD were generally included in the meta-analysis. The pooled results demonstrated that the carriage of G allele for ARMS2 A69S presented a better clinical prognosis for advanced AMD treated with anti-VEGF drugs (OR = 1.38, 95% CI = 1.13-1.69, p = 0.002). In addition, in the subgroup analysis based on ethnicity, ARMS2 polymorphisms were more likely to be a positive responder for East Asian patients (OR = 1.67, 95% CI = 1.29-2.16, p < 0.001). This meta-analysis through a series of rigorous methodology data demonstrated a significant association between ARMS2 A69S polymorphism and the anti-VEGF treatment response in advanced AMD, especially among East Asian population. Numerous well-designed, randomized, multicenter clinical trials with large sample size are required to validate the association.

Factors of Retinal Re-detachment and Visual Outcome after Intraocular Silicone Oil Removal in Silicone Oil-filled Eyes.

Background: This study aims to evaluate the risk factors of retinal re-detachment and visual outcome after silicone oil removal (SOR) in silicone oil-filled eyes.Methods: A total of 57 patients who underwent pars plana vitrectomy (PPV) and silicone oil injection for retinal detachment (RD), and subsequently underwent a silicone oil removal procedure. Pre-operative examinations were performed to determine the best-corrected visual acuity (BCVA) using the Snellen chart, while Icare was used to determine the intraocular pressure (IOP). In addition, slit-lamp examination of the anterior segment and lens, fundus pre-set lens examination for the posterior segment, color fundus photography, anterior segment photography and type B-ultrasonic scans were performed.Results: In five of 57 patients (8.77%), the retina re-detached following the removal of silicone oil. The factors for re-detachment were proliferative vitreoretinopathy (PVR) (two cases), the formation of new retinal breaks (two cases), and incomplete membrane peeling (one case). The rate of retinal re-detachment (reRD) was statistically independent of the duration of silicone oil endotamponade (P = .810). BCVA significantly improved following the removal of silicone oil (P = .001). The duration of the silicone oil tamponade was significant in the development of cataract (27 eyes, 47.3%; P = .0008), emulsified oil in the anterior chamber (13 eyes, 22.8%; P = .009), and glaucoma (seven eyes, 12.2%).Conclusion: The improvement of visual acuity was discovered following the removal of the intraocular silicone oil. Although the duration of the intraocular silicone oil endotamponade had no effect on the rate of retinal attachment, a longer duration of silicone oil endotamponade can lead to the development of complications, such as cataract, emulsified oil in the anterior chamber and glaucoma, suggesting that the earlier removal of oil should be performed.

Association between genetic variation of complement C3 and the susceptibility to advanced age-related macular degeneration: a meta-analysis.

BACKGROUND: The purpose of this study is to discuss whether genetic variants (rs2230199, rs1047286, rs2230205, and rs2250656) in the C3 gene account for a significant risk of advanced AMD. METHODS: We performed a meta-analysis using electronic databases to search relevant articles. A total of 40 case-control studies from 38 available articles (20,673 cases and 20,025 controls) were included in our study. RESULTS: In our meta-analysis, the pooled results showed that the carriage of G allele for rs2230199 and the T allele for rs1047286 had a tendency to the risk of advanced AMD (OR = 1.49, 95% CI = 1.39-1.59, P < 0.001; OR = 1.45, 95% CI = 1.37-1.54, P < 0.001). Moreover, in the subgroup analysis based on ethnicity, rs2230199 and rs1047286 polymorphisms were more likely to be a predictor of response for Caucasian region (OR = 1.48, 95% CI = 1.38-1.59, P < 0.001; OR = 1.45, 95% CI = 1.37-1.54, P < 0.001). Besides, pooled results suggested that the G allele of rs2230199 could confer susceptibility to advanced AMD in Middle East (OR = 1.62, 95% CI = 1.33-1.97, P < 0.001). CONCLUSION: In our meta-analysis, C3 genetic polymorphisms unveiled a positive effect on the risk of advanced AMD, especially in Caucasians. Furthermore, numerous well-designed studies with large sample-size are required to validate this conclusion.

Effects of timing of vitrectomy performed for open-globe injury patients on the thickness of retinal nerve fiber layer.

OBJECTIVE: To study the effects of timing of vitrectomy performed for open-globe injury patients on the thickness of retinal nerve fiber layer (RNFL). METHODS: A total of 120 patients with traumatic optic neuropathy (TON) were selected and divided into a treatment group and a control group by random draw (n=60). Vitrectomy was performed within one week upon injury for treatment group and after one week for control group. The thickness of RNFL was observed by optical coherence tomography. RESULTS: All surgeries were conducted successfully, without severe complications. The best corrected visual acuity of treatment group surpassed that of control group one month after surgery, and treatment group had an obviously higher overall effective rate (95.0%) than control group did (81.7%). The incidence rate of postoperative complications in treatment group (6.7%) was significantly lower than that of control group (28.3%) (P<0.05). Logistic multivariate regression analysis showed that vitrectomy timing and postoperative complications were independent risk factors of prognosis (P<0.05). Both groups had significantly thinner RNFLs one week after surgery (P<0.05), and treatment group almost recovered within one month (P>0.05). CONCLUSION: Early vitrectomy effectively augmented the visual acuity of patients with TON, decreased complications, affected RNFL thickness reversibly, and improved prognosis.