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Statin Use in Relation to Intraocular Pressure, Glaucoma, and Ocular Coherence Tomography Parameters in the UK Biobank

Purpose The purpose of this study was to evaluate the relationship between statin use and glaucoma-related traits. Methods In a cross-sectional study, we included 118,153 UK Biobank participants with data on statin use and corneal-compensated IOP. In addition, we included 192,283 participants (8982 cases) with data on glaucoma status. After excluding participants with neurodegenerative diseases, 41,638 participants with macular retinal nerve fiber layer thickness (mRNFL) and 41,547 participants with macular ganglion cell inner plexiform layer thickness (mGCIPL) were available for analysis. We examined associations of statin use with IOP, mRNFL, mGCIPL, and glaucoma status utilizing multivariable-adjusted regression models. We assessed whether a glaucoma polygenic risk score (PRS) modified associations. We performed Mendelian randomization (MR) experiments to investigate associations with various glaucoma-related outcomes. Results Statin users had higher unadjusted mean IOP ± SD than nonusers, but in a multivariable-adjusted model, IOP did not differ by statin use (difference = 0.05 mm Hg, 95% confidence interval [CI] = −0.02 to 0.13, P = 0.17). Similarly, statin use was not associated with prevalent glaucoma (odds ratio [OR] = 1.05, 95% CI = 0.98 to 1.13). Statin use was weakly associated with thinner mRNFL (difference = −0.15 microns, 95% CI = −0.28 to −0.01, P = 0.03) but not with mGCIPL thickness (difference = −0.12 microns, 95% CI = −0.29 to 0.05, P = 0.17). No association was modified by the glaucoma PRS (Pinteraction ≥ 0.16). MR experiments showed no evidence for a causal association between the cholesterol-altering effect of statins and several glaucoma traits (inverse weighted variance P ≥ 0.14). Conclusions We found no evidence of a protective association between statin use and glaucoma or related traits after adjusting for key confounders.


Supplementary Methods for Mendelian Randomization Experiments
Mendelian Randomization (MR) is the use of genetic variants as proxies for modifiable risk factors and therapeutics in a way that has been likened to a randomized control trial by genetic proxy. The fixed nature of genetic variants reduces bias from environment exposure and reverse causation.
As statin's cholesterol reduction and pleiotropic effects appear mediated by inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, it would be expected that if statins protect against primary open-angle glaucoma (POAG), subjects with genetically modified activity of this enzyme from birth should have a commensurate difference in risk of POAG. We conducted a MR study using 5 gene variants (rs2303152. rs17238484, rs12916, rs10066707, and rs5909) of HMG-CoA reductase to see whether these have any bearing on the genetic risk of primary open angle glaucoma (POAG), 1 intraocular pressure (IOP), 2 vertical cup-disc ratio (VCDR), 3 macular retinal nerve fiber layer (mRNFL) thickness and the macular ganglion cell inner plexiform layer (mGCIPL) thickness. 4 We performed the inverse-variance weighted (IVW) analyses accounting for correlations between the variants 5, 6 using a random-effects model. Sensitivity analyses included weighted median and egger regression. Global heterogeneity was measured using Cochran's Q and I 2 statistic. All analyses were performed using R (version 1.4.17) using R packages "TwosampleMR" 7, 8 and "MendelianRandomization" 9 .
Variants in HMG-CoA reductase were obtained from the Global Lipids Genetic Consortium (GLGC). 10 We used serum LDL as a biomarker for the effect size and scaled to one standard deviation increase in LDL-cholesterol (39mg/dl). The GLGC involved up to 188,577 individuals of European ancestry who were not on any lipidlowering medication. Six variants that are conditionally associated with LDL and are not strongly correlated (r 2 <0.2) were originally chosen by Ference et al; 11 rs2006760 was removed prior to analysis for being palindromic with intermediate allele frequencies, leaving five variants. Together, they account for 0.4% of the variance in circulating LDL. For our outcome datasets, we selected the largest published GWAS available performed in a European population and full details can be found in the source paper: POAG (n=216,257) , 1 IOP (n=139,555), 2 VCDR (n=23,899), 3 mRNFL (n=31,434) 4 and mGCIPL (n=31,434). 4 For the POAG dataset, we used the stage 1 genome-wide association study (GWAS) summary data from a recent meta-analysis that combined 18 POAG studies using ICD9/10 coding data in Europeans (16,677 POAG cases vs 199,580 controls). 1 The IOP GWAS 2 is the largest performed to date, including 139,555 participants from three cohorts: UK Biobank, 12 EPIC-Norfolk 13 and the previously reported combined results from 14 European studies in the International Glaucoma Genetics Consortium (IGGC). 3 The VCDR GWAS was performed as part of the metanalysis by the IGGC, combining multiple studies and included n = 23,899 participants of European descent. 3 The mRNFL and mGCIPL GWAS used data solely from UK Biobank. Ocular coherence tomography (OCT) macula scans that fit quality control measures were extracted from the densest populated well-mixed population within the overall dataset (n= 31,434). 4 Supplementary Table 1.

Glaucoma MTAG GRS, mean (SD)
0 (1.0) 0 (1.0) 0 (1.0) Abbreviation: MTAG GRS = multi-trait analysis of genome wide association study genetic risk score * "Statin users" were defined as anyone using statins (± other non-statin hypolipidemic drugs); while "users of non-statin hypolipidemic medication only" were defined as those not on any statins but using fibric acid agents, bile acid sequestrants, niacin-derivatives, cholesterol absorption inhibitors, omega-3 fats and other miscellaneous antihyperlipidemic agents Abbreviations: mGCIPL=macular ganglion cell inner plexiform layer; mRNFL=macular retinal nerve fiber layer thickness; ref=reference * Each model adjusted for age, age 2 , sex, ethnicity (White, Black, Asian, and Other), deprivation, spherical equivalent, smoking status, number of cigarettes (only among current smokers), alcohol, physical activity + missing indicator, coffee and tea intake, body mass index, systolic blood pressure, diabetes, cardiovascular disease, HbA1C + missing indicator, baseline systemic betablocker use, serum total cholesterol + missing indicator, serum triglyceride + missing indicator † "Statin users" were defined as anyone using statins (± other non-statin hypolipidemic drugs); while "users of non-statin hypolipidemic medication only" were defined as those not on any statins but using fibric acid agents, bile acid sequestrants, niacin-derivatives, cholesterol absorption inhibitors, omega-3 fats and other miscellaneous antihyperlipidemic agents Supplementary Table 5.

Supplementary
Multivariable-adjusted analyses* assessing whether the glaucoma MTAG GRS modified the relation between statin use and the four glaucoma related outcomes or the relation between nonstatin hypolipidemic drug use † and the four glaucoma outcomes in the UK BioBank  For the POAG dataset, we used the stage 1 GWAS summary data from a meta-analysis that combined 18 POAG studies in Europeans (16,677 POAG cases vs 199,580 controls).
The VCDR GWAS was performed as part of the metanalysis by the IGGC, combining multiple studies and included n = 23,899 participants of European descent.
The mRNFL and mGCIPL GWAS used data solely from UK Biobank: OCT data that fit quality control measures was extracted from the densest populated well-mixed population within the overall dataset (n= 31434).