Effect of antihypertensive drugs on glaucoma: a Mendelian randomization and triangulation analysis

ImportanceGlaucoma is one of the worlds leading causes of irreversible blindness and effective interventions with less side effect and less cost were still in need. ObjectiveTo investigate the potential of repurposing antihypertensive drugs to glaucoma treatment and intra ocular pressure (IOP) lowering in cost effective manners. Design, Setting and ParticipantsTwo sample Mendelian Randomization (MR) was used to investigate the genetic effect of antihypertensive drugs on glaucoma protection or IOP lowering. Two strategies (biomarker or eQTL approach) were applied to define the instrumental variable (IV). Genome-wide association study (GWAS) results on systolic blood pressure (SBP) of 526,001 European participants were used as exposure and GWAS on primary open angle glaucoma (POAG, 15,229 cases and 177,473 controls) and on IOP compromising 70832 participants in the UK Biobank were used as the outcome. All analyses were performed between April 2022 and December 2022. ExposuresThe SBP lowering effect of the antihypertensive drug targets. Main Outcomes and MeasuresPOAG or IOP measurements. ResultsUsing IVs defined by the biomarker approach, genetically-proxied lower SBP through diuretics targets was causally associated with a reduced risk of glaucoma (OR per mmHg reduction in SBP 0.87, 95% CI: 0.97-0.78, p = 0.009 for potassium-sparing diuretics [PSD] and OR=0.86, 95% CI: 0.92-0.81,p =2.67e-05 for loop diuretics [LD]). When using eQTL as IVs, the IVW-MR yielded a causal effect estimate on POAG of 0.88 (95% CI 0.79 -0.97, P = 0.011) per 1 mmHg decrease in blood pressure via PSD targets and 0.92 (95% CI 0.85 - 1, P=0.052) via LD. No consistence effects were observed among different MR methods for other antihypertensive drugs on glaucoma or IOP. After triangulation genetic evidence from MR, epidemiological evidence from observational studies and experimental evidence, the protective effect of PSD/LD on POAG was suggested. Conclusions and RelevanceWe found PSD and LD drugs hold promise as potential therapeutic agents to reduce the risk of POAG Key PointsO_ST_ABSQuestionC_ST_ABSCan antihypertensive drugs be repurposed to the treatment of ocular hypertension? FindingsDifferent Mendelian Randomization (MR) analysis strategies identified that diuretics (potassium-sparing diuretics [PSD) and loop diuretics [LD] might have a protective effect on primary open angle glaucoma (POAG). Furthermore, the triangulation analysis compared the genetic evidence from MR, epidemiological evidence from observational studies and experimental evidence and found a consistent protective effect of PSD/LD on POAG. MeaningPSD/LD may be repurposed to the treatment of POAG and they may also benefit patients with hypertension as well as POAG.