Journal of Shandong University (Health Sciences) ›› 2026, Vol. 64 ›› Issue (7): 69-80.doi: 10.6040/j.issn.1671-7554.0.2025.1059

• Public Health and Preventive Medicine • Previous Articles     Next Articles

Causal associations of antihypertensive and lipid-lowering drugs with ocular diseases: a cross-ancestry drug target Mendelian randomization study

CHEN Changhai, ZHANG Xiumei, YUAN Zhongshang, WANG Shukang   

  1. 1. Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, China;
    2. National Institute of Health and Medical Big Data, Jinan 250003, Shandong, China
  • Online:2026-07-10 Published:2026-07-21

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Abstract: Objective To investigate the causal associations between commonly used antihypertensive and lipid-lowering drugs and prevalent ocular diseases in East Asian and European populations using drug-target Mendelian randomization(MR). Methods This cross-ancestry drug-target MR study utilized publicly available genome-wide association study(GWAS)summary data from the GWAS Catalog. Five classes of antihypertensive drugs, including angiotensin-converting enzyme inhibitors(ACEIs), angiotensin II receptor blockers(ARBs), β-blockers(BBs), calcium channel blockers(CCBs), and thiazide diuretics(TDs), and three classes of lipid-lowering drugs, including 3-hydroxy-3-methylglutaryl-CoA reductase(HMGCR)inhibitors, proprotein convertase subtilisin/kexin type 9(PCSK9)inhibitors, and Niemann–Pick C1-like 1(NPC1L1)inhibitors were selected as exposures. Six common ocular diseases(senile cataract, glaucoma, dry eye syndrome, visual impairment, presbyopia, and myopia)were defined as outcomes. Inverse variance weighted(IVW)was employed as the primary analytical method, supplemented by seven additional MR methods for findings with statiscauy significant correlation. Sensitivity analyses were conducted using Cochrans Q test, MR-Egger intercept test, and leave-one-out analysis. Results In East Asian populations, ACEIs were causally associated with increased risks of myopia(OR=1.024, 95%CI: 1.010-1.038, PFDR=0.002), senile cataract(OR=1.022, 95%CI: 1.019-1.024, PFDR<0.001), and glaucoma(OR=1.017, 95%CI: 1.011-1.023, PFDR<0.001); BBs were associated with reduced risk of senile cataract(OR=0.994, 95%CI: 0.989-0.999, PFDR=0.034); PCSK9 inhibitors were associated with reduced risks of presbyopia(OR=0.993, 95%CI: 0.986-0.997, PFDR=0.003)and visual impairment(OR=0.996, 95%CI: 0.992-0.999, PFDR=0.048). In European populations, ACEIs were associated with increased glaucoma risk(OR=1.088, 95%CI: 1.029-1.152, PFDR=0.016); HMGCR inhibitors were associated with increased senile cataract risk(OR=1.194, 95%CI: 1.049-1.359, PFDR=0.022); PCSK9 inhibitors were associated with increased risks of dry eye syndrome(OR=1.106, 95%CI: 1.039-1.176, PFDR=0.004)and presbyopia(OR=1.082, 95%CI: 1.024-1.145, PFDR=0.017), but with reduced glaucoma risk(OR=0.892, 95%CI: 0.822-0.968, PFDR=0.018); NPC1L1 inhibitors were associated with reduced glaucoma risk(OR=0.706, 95%CI: 0.579-0.861, PFDR=0.002). Conclusion ACEIs may increase risks of certain ocular diseases in both East Asian and European populations. BBs may reduce senile cataract risk in East Asians. HMGCR inhibitors may increase cataract risk in Europeans, while NPC1L1 inhibitors may reduce glaucoma risk in Europeans. The effects of PCSK9 inhibitors on ocular diseases exhibit ethnic differences.

Key words: Drug target Mendelian randomization, Antihypertensive drugs, Lipid-lowering drugs, Ocular diseases

CLC Number: 

  • R77
[1] World Health Organization. World report on vision[R]. Geneva: World Health Organization, 2019:26.
[2] Klein R, Klein B E K. The prevalence of age-related eye diseases and visual impairment in aging: current estimates[J]. Invest Ophthalmol Vis Sci, 2013, 54(14): ORSF5-ORSF13.
[3] Gudayneh Y A, Shumye A F, Gelaye A T, et al. Prevalence of hypertensive retinopathy and its associated factors among adult hypertensive patients attending at Comprehensive Specialized Hospitals in northwest Ethiopia, 2024, a multicenter cross-sectional study[J]. Int J Retina Vitreous, 2025, 11(1): 17. DOI:10.1186/s40942-025-00631-2
[4] Li Y S, Xie L Y, Song W J, et al. Association between dyslipidaemia and dry eye disease: a systematic review and meta-analysis[J]. BMJ Open, 2023, 13(11): e069283. DOI:10.1136/bmjopen-2022-069283
[5] Lee J S, Cha H R, Bae H W, et al. Effect of antihyperten-sive medications on the risk of open-angle glaucoma[J]. Sci Rep, 2023, 13(1): 16224. DOI:10.1038/s41598-023-43420-3
[6] Wang Y W, Liu S D, Lin G L, et al. Association between statin use and dry eye disease in patients with hyperlipidemia: a population-based retrospective cohort study[J]. Clin Transl Sci, 2024, 17(10): e70039. DOI:10.1111/cts.70039
[7] Leuschen J, Mortensen E M, Frei C R, et al. Association of statin use with cataracts: a propensity score-matched analysis[J]. JAMA Ophthalmol, 2013, 131(11): 1427-1434.
[8] Chodick G, Heymann A D, Flash S, et al. Persistence with statins and incident cataract: a population-based historical cohort study[J]. Ann Epidemiol, 2010, 20(2): 136-142.
[9] Cheng C Y, Schache M, Ikram M K, et al. Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error[J]. Am J Hum Genet, 2013, 93(2): 264-277.
[10] Bailey J N C, Loomis S J, Kang J H, et al. Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma[J]. Nat Genet, 2016, 48(2): 189-194.
[11] Fan B H, Zhang J M, Zhao J V. Systematic review of Mendelian randomization studies on antihypertensive drugs[J]. BMC Med, 2024, 22(1): 547. DOI:10.1186/s12916-024-03760-x
[12] Gill D, Dib M J, Cronjé H T, et al. Common pitfalls in drug target Mendelian randomization and how to avoid them[J]. BMC Med, 2024, 22(1): 473. DOI:10.1186/s12916-024-03700-9
[13] Zhong A, Zhang L Y, Ma X, et al. Sex differences in albuminuria risk with metformin use: insights from a cross-sectional study and drug-target Mendelian randomization analysis[J]. Diabetes Metab J, 2025, 49(6): 1346-1348.
[14] Jee Y, Shin J W, Ryu M, et al. Causal relationship between drug target genes of LDL-cholesterol and coronary artery disease: drug target Mendelian randomization study[J]. Lipids Health Dis, 2025, 24(1): 92. DOI:10.1186/s12944-025-02502-z
[15] Buniello A, MacArthur J A L, Cerezo M, et al. The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019[J]. Nucleic Acids Res, 2019, 47(D1): D1005-D1012.
[16] Keaton J M, Kamali Z, Xie T, et al. Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits[J]. Nat Genet, 2024, 56(5): 778-791.
[17] Graham S E, Clarke S L, Wu K H, et al. The power of genetic diversity in genome-wide association studies of lipids[J]. Nature, 2021, 600(7890): 675-679.
[18] Verma A, Huffman J E, Rodriguez A, et al. Diversity and scale: genetic architecture of 2068 traits in the VA Million Veteran Program[J]. Science, 2024, 385(6706): eadj1182. DOI:10.1126/science.adj1182
[19] Aragam K G, Jiang T, Goel A, et al. Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants[J]. Nat Genet, 2022, 54(12): 1803-1815.
[20] Matsunaga H, Ito K, Akiyama M, et al. Transethnic meta-analysis of genome-wide association studies identifies three new loci and characterizes population-specific differences for coronary artery disease[J]. Circ Genom Precis Med, 2020, 13(3): e002670. DOI:10.1161/CIRCGEN.119.002670
[21] Kreutz R, Brunström M, Burnier M, et al. 2024 Euro-pean Society of Hypertension clinical practice guidelines for the management of arterial hypertension[J]. Eur J Intern Med, 2024, 126: 1-15. DOI:10.1016/j.ejim.2024.05.033
[22] 中国血脂管理指南修订联合专家委员会, 王增武, 李建军, 等. 中国血脂管理指南(基层版2024年)[J]. 中华心血管病杂志, 2024, 52(4): 330-337. Joint Committee on the Chinese Guidelines for Lipid Management, Wang Zengwu, Li Jianjun, et al. Chinese guideline for lipid management(primary care version 2024)[J]. Chinese Journal of Cardiology, 2024, 52(4): 330-337.
[23] Davies N M, Holmes M V, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians[J]. BMJ, 2018, 362: k601. DOI:10.1136/bmj.k601
[24] Skrivankova V W, Richmond R C, Woolf B A R, et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomization: the STROBE-MR statement[J]. JAMA, 2021, 326(16): 1614-1621.
[25] Lymperopoulou C, Kandarakis S A, Tzanaki I, et al. The effect of statins on ocular disorders: a systematic review of randomized controlled trials[J]. Pharmaceuticals, 2023, 16(5): 711. DOI:10.3390/ph16050711
[26] Vergroesen J E, Schuster A K, Stuart K V, et al. Association of systemic medication use with glaucoma and intraocular pressure: the European eye epidemiology consortium[J]. Ophthalmology, 2023, 130(9): 893-906.
[27] Leung G, Grant A, Garas A N, et al. A systematic review and meta-analysis of systemic antihypertensive medications with intraocular pressure and glaucoma[J]. Am J Ophthalmol, 2023, 255: 7-17. DOI:10.1016/j.ajo.2023.03.014
[28] Dai W, Tham Y C, Chee M L, et al. Systemic medications and cortical cataract: the Singapore Epidemiology of Eye Diseases Study[J]. Br J Ophthalmol, 2020, 104(3): 330-335.
[29] Lee E B, Hu W D, Singh K, et al. The association among blood pressure, blood pressure medications, and glaucoma in a nationwide electronic health records database[J]. Ophthalmology, 2022, 129(3): 276-284.
[30] Taddei S, Bortolotto L. Unraveling the pivotal role of bradykinin in ACE inhibitor activity[J]. Am J Cardiovasc Drugs, 2016, 16(5): 309-321.
[31] Bin Lim H, Lee M W, Park J H, et al. Changes in gang-lion cell-inner plexiform layer thickness and retinal microvasculature in hypertension: an optical coherence tomography angiography study[J]. Am J Ophthalmol, 2019, 199: 167-176. DOI:10.1016/j.ajo.2018.11.016
[32] Shen W, Jiang X X, Li Y W, et al. I/D polymorphism of ACE and risk of diabetes-related end-stage renal di-sease: a systematic review and meta-analysis[J]. Eur Rev Med Pharmacol Sci, 2019, 23(4): 1652-1660.
[33] Alves C, Mendes D, Batel Marques F. Statins and risk of cataracts: a systematic review and meta-analysis of observational studies[J]. Cardiovasc Ther, 2018, 36(6): e12480. DOI:10.1111/1755-5922.12480
[34] Casula M, Soranna D, Corrao G, et al. Statin use and risk of cataract: a nested case-control study within a healthcare database[J]. Atherosclerosis, 2016, 251: 153-158. DOI:10.1016/j.atherosclerosis.2016.06.020
[35] Ghouse J, Ahlberg G, Skov A G, et al. Association of common and rare genetic variation in the 3-hydroxy-3-methylglutaryl coenzyme a reductase gene and cataract risk[J]. J Am Heart Assoc, 2022, 11(12): e025361. DOI:10.1161/JAHA.122.025361
[36] Widomska J, Subczynski W K. Why is very high cholesterol content beneficial for the eye lens but negative for other organs [J]. Nutrients, 2019, 11(5): 1083. DOI:10.3390/nu11051083
[37] Qu H, Meng Y Y, Chai H, et al. The effect of statin treatment on circulating coenzyme Q10 concentrations: an updated meta-analysis of randomized controlled trials[J]. Eur J Med Res, 2018, 23(1): 57. DOI:10.1186/s40001-018-0353-6
[38] Cheng Q F, Gerald Robison W, Samuel Zigler J. Geranylgeranyl pyrophosphate counteracts the cataractogenic effect of lovastatin on cultured rat lenses[J]. Exp Eye Res, 2002, 75(5): 603-609.
[39] Aikawa T. Geographic and ethnic variations in response to lipid-lowering therapies: why do they matter [J]. Eur J Prev Cardiol, 2023, 30(11): 1118-1119.
[40] Doi T, Langsted A, Nordestgaard B G. Lipoproteins, cholesterol, and atherosclerotic cardiovascular disease in east asians and Europeans[J]. J Atheroscler Thromb, 2023, 30(11): 1525-1546.
[41] Lu X F, Li J, Li H X, et al. Coding-sequence variants are associated with blood lipid levels in 14, 473 Chinese[J]. Hum Mol Genet, 2016, 25(18): 4107-4116.
[42] Liu Y Q, Li T. Causal association between lipid-lowering drugs and glaucoma: a drug-targeted Mendelian randomization study[J]. Invest Ophthalmol Vis Sci, 2024, 65(10): 23. DOI:10.1167/iovs.65.10.23
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