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

PURPOSE:To investigate a causal relationship between Vitamin D levels and non-infectious uveitis and scleritis using Mendelian randomization (MR) techniques. DESIGN:Two-sample Mendelian randomization case-control study. METHODS:The study setting was a biobank of an academic, integrated health care system. The patient population comprised 375 case patients with a non-infectious uveitis and/or scleritis diagnosis and no diagnosis of infectious, trauma-related, or drug-induced uveitis/scleritis. In addition, there were 4167 controls with no uveitis or scleritis diagnosis. Causal effect estimates of low 25-hydroxy Vitamin D (25OHD) on uveitis/scleritis risk were calculated. RESULTS:We found an association of genetically decreased 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 analysis excluding the genetic variants that are unlikely to have a role in biologically active 25OHD, effect estimates were consistent with those from the primary analysis (OR = 2.38, 95% CI =1.06-5.36, P = 0.035, per SD of log25OHD). Furthermore, in a second sensitivity 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 associated with increased uveitis/scleritis risk (OR = 6.42, 95% CI = 3.19-12.89, P = 1.7 × 10-7, per SD of log25OHD). CONCLUSIONS:Our findings suggest a causal relationship between low Vitamin D levels and higher risk of non-infectious uveitis and scleritis. Vitamin D supplementation may be a low-cost, low-risk intervention to mitigate non-infectious uveitis and scleritis risk, and should be explored in a prospective trial.