Mendelian Randomization Shows a Causal Effect of Low Vitamin D on Non-infectious Uveitis and Scleritis Risk

center dot PURPOSE: To investigate a causal relationship between Vitamin D levels and non-infectious uveitis and scleritis using Mendelian randomization (MR) techniques.center dot DESIGN: Two-sample Mendelian randomization case -control study. center dot METHODS: The study setting was a biobank of an aca-demic, integrated health care system. The patient popu-lation comprised 375 case patients with a non-infectious uveitis and/or scleritis diagnosis and no diagnosis of infec-tious, trauma-related, or drug-induced uveitis/scleritis. In addition, there were 4167 controls with no uveitis or scle-ritis diagnosis. Causal effect estimates of low 25-hydroxy Vitamin D (25OHD) on uveitis/scleritis risk were calcu-lated. center dot RESULTS: We found an association of genetically de-creased 25OHD with uveitis/scleritis risk (odds ratio [OR] = 2.16, 95% CI = 1.01-4.64, P = .049, per SD decrease in log25OHD). In a first sensitivity MR anal-ysis excluding the genetic variants that are unlikely to have a role in biologically active 25OHD, effect esti-mates were consistent with those from the primary anal-ysis (OR = 2.38, 95% CI = 1.06-5.36, P = 0.035, per SD of log25OHD). Furthermore, in a second sen-sitivity analysis using only the 6 variants within the CYP2R1 locus (which encodes 25OHD hydroxylase, the liver enzyme responsible for converting Vitamin D to 25OHD), genetically decreased 25OHD was strongly as-sociated with increased uveitis/scleritis risk (OR = 6.42, 95% CI = 3.19-12.89, P = 1.7 x 10-7 , per SD of log25OHD).center dot CONCLUSIONS: Our findings suggest a causal relation-ship between low Vitamin D levels and higher risk of non-infectious uveitis and scleritis. Vitamin D supplementa-tion may be a low-cost, low-risk intervention to miti-gate non-infectious uveitis and scleritis risk, and should be explored in a prospective trial. (Am J Ophthalmol 2022;244: 11-18. (c) 2022 Elsevier Inc. All rights re-served.)

Automated summary

The study found a genetic association between decreased 25-hydroxy Vitamin D levels and uveitis/scleritis risk, suggesting a causal relationship between low Vitamin D levels and non-infectious uveitis and scleritis. Vitamin D supplementation may be a cost-effective, low-risk intervention to mitigate the risk of non-infectious uveitis and scleritis.