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Published in: Journal of Translational Medicine 1/2024

Open Access 01-12-2024 | Diabetic Retinopathy | Research

Statins as a risk factor for diabetic retinopathy: a Mendelian randomization and cross-sectional observational study

Authors: Chengming Chen, Huan Zhang, Yanyan Lan, Weiming Yan, Sida Liu, Yixuan Chen, Tingke Xie, Jiayi Ning, Xiaolong Yan, Lei Shang, Jing Han

Published in: Journal of Translational Medicine | Issue 1/2024

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Abstract

Background

Diabetic retinopathy (DR) is the foremost cause of vision loss among the global working-age population, and statins are among the most frequently prescribed drugs for lipid management in patients with DR. The exact relationship between statins and DR has not been determined. This study sought to validate the causal association between statins usage and diabetic retinopathy.

Methods

The summary-data-based Mendelian randomization (SMR) method and inverse-variance-weighted Mendelian randomization (IVW-MR) were used to identify the causal relationship between statins and DR via the use of expression quantitative trait loci (eQTL) data for 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) (31,684 blood samples), low density lipoprotein cholesterol-related GWAS data (sample size: 440,546), and DR-related GWAS data (14,584 cases and 176,010 controls). Additionally, a cross-sectional observational study based on the data from the National Health and Nutrition Examination Survey (NHANES) was conducted to supplement the association between DR and statins (sample size: 106,911). The odds ratios (ORs) with corresponding 95% confidence intervals (CIs) was employed to evaluate the results.

Results

Based on the results of the MR analysis, HMGCR inhibitors were causally connected with a noticeably greater incidence of DR (IVW: OR = 0.54, 95% CI [0.42, 0.69], p = 0.000002; SMR: OR = 0.66, 95% CI [0.52, 0.84], p = 0.00073). Subgroup analysis revealed that the results were not affected by the severity of DR. The sensitivity analysis revealed the stability and reliability of the MR analysis results. The results from the cross-sectional study based on NHANES also support the association between not taking statins and a decreased risk of DR (OR = 0.54, 95% CI [0.37, 0.79], p = 0.001).

Conclusions

This study revealed that a significant increase in DR risk was causally related to statins use, providing novel insights into the role of statins in DR. However, further investigations are needed to verify these findings.
Appendix
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Literature
2.
go back to reference Lee R, Wong TY, Sabanayagam C. Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye Vis (Lond). 2015;2:17.PubMedCrossRef Lee R, Wong TY, Sabanayagam C. Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye Vis (Lond). 2015;2:17.PubMedCrossRef
3.
go back to reference Teo ZL, et al. Global prevalence of diabetic retinopathy and projection of burden through 2045: systematic review and meta-analysis. Ophthalmology. 2021;128(11):1580–91.PubMedCrossRef Teo ZL, et al. Global prevalence of diabetic retinopathy and projection of burden through 2045: systematic review and meta-analysis. Ophthalmology. 2021;128(11):1580–91.PubMedCrossRef
4.
go back to reference Saeedi P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9(th) edition. Diabetes Res Clin Pract. 2019;157: 107843.PubMedCrossRef Saeedi P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9(th) edition. Diabetes Res Clin Pract. 2019;157: 107843.PubMedCrossRef
5.
go back to reference Chen C, et al. Pharmacological roles of lncRNAs in diabetic retinopathy with a focus on oxidative stress and inflammation. Biochem Pharmacol. 2023;214: 115643.PubMedCrossRef Chen C, et al. Pharmacological roles of lncRNAs in diabetic retinopathy with a focus on oxidative stress and inflammation. Biochem Pharmacol. 2023;214: 115643.PubMedCrossRef
6.
go back to reference Chen C, et al. Anti-VEGF combined with ocular corticosteroids therapy versus anti-VEGF monotherapy for diabetic macular edema focusing on drugs injection times and confounding factors of pseudophakic eyes: a systematic review and meta-analysis. Pharmacol Res. 2023;196: 106904.PubMedCrossRef Chen C, et al. Anti-VEGF combined with ocular corticosteroids therapy versus anti-VEGF monotherapy for diabetic macular edema focusing on drugs injection times and confounding factors of pseudophakic eyes: a systematic review and meta-analysis. Pharmacol Res. 2023;196: 106904.PubMedCrossRef
7.
go back to reference Gauldin D, et al. Exposure of contralateral eyes to laser radiation during retinal photocoagulation. Curr Eye Res. 2021;46(9):1424–7.PubMedCrossRef Gauldin D, et al. Exposure of contralateral eyes to laser radiation during retinal photocoagulation. Curr Eye Res. 2021;46(9):1424–7.PubMedCrossRef
9.
go back to reference Fraser-Bell S, et al. Bevacizumab or dexamethasone implants for DME: 2-year results (the BEVORDEX study). Ophthalmology. 2016;123(6):1399–401.PubMedCrossRef Fraser-Bell S, et al. Bevacizumab or dexamethasone implants for DME: 2-year results (the BEVORDEX study). Ophthalmology. 2016;123(6):1399–401.PubMedCrossRef
10.
go back to reference Wong TY, et al. Guidelines on diabetic eye care: the international council of ophthalmology recommendations for screening, follow-up, referral, and treatment based on resource settings. Ophthalmology. 2018;125(10):1608–22.PubMedCrossRef Wong TY, et al. Guidelines on diabetic eye care: the international council of ophthalmology recommendations for screening, follow-up, referral, and treatment based on resource settings. Ophthalmology. 2018;125(10):1608–22.PubMedCrossRef
11.
go back to reference Taylor FC, Huffman M, Ebrahim S. Statin therapy for primary prevention of cardiovascular disease. JAMA. 2013;310(22):2451–2.PubMedCrossRef Taylor FC, Huffman M, Ebrahim S. Statin therapy for primary prevention of cardiovascular disease. JAMA. 2013;310(22):2451–2.PubMedCrossRef
12.
go back to reference Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science. 2001;292(5519):1160–4.PubMedCrossRef Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science. 2001;292(5519):1160–4.PubMedCrossRef
13.
go back to reference Nielsen SF, Nordestgaard BG. Statin use before diabetes diagnosis and risk of microvascular disease: a nationwide nested matched study. Lancet Diabetes Endocrinol. 2014;2(11):894–900.PubMedCrossRef Nielsen SF, Nordestgaard BG. Statin use before diabetes diagnosis and risk of microvascular disease: a nationwide nested matched study. Lancet Diabetes Endocrinol. 2014;2(11):894–900.PubMedCrossRef
15.
16.
17.
18.
go back to reference Lawlor DA, et al. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med. 2008;27(8):1133–63.PubMedCrossRef Lawlor DA, et al. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med. 2008;27(8):1133–63.PubMedCrossRef
19.
go back to reference Burgess S, Small DS, Thompson SG. A review of instrumental variable estimators for Mendelian randomization. Stat Methods Med Res. 2017;26(5):2333–55.PubMedCrossRef Burgess S, Small DS, Thompson SG. A review of instrumental variable estimators for Mendelian randomization. Stat Methods Med Res. 2017;26(5):2333–55.PubMedCrossRef
20.
go back to reference Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013;37(7):658–65.PubMedPubMedCentralCrossRef Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013;37(7):658–65.PubMedPubMedCentralCrossRef
21.
go back to reference Smith GD, Ebrahim S. “Mendelian randomization”: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003;32(1):1–22.PubMedCrossRef Smith GD, Ebrahim S. “Mendelian randomization”: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003;32(1):1–22.PubMedCrossRef
23.
go back to reference Võsa U, et al. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression. Nat Genet. 2021;53(9):1300–10.PubMedPubMedCentralCrossRef Võsa U, et al. Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression. Nat Genet. 2021;53(9):1300–10.PubMedPubMedCentralCrossRef
24.
go back to reference Richardson TG, et al. Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: a multivariable Mendelian randomisation analysis. PLoS Med. 2020;17(3): e1003062.PubMedPubMedCentralCrossRef Richardson TG, et al. Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: a multivariable Mendelian randomisation analysis. PLoS Med. 2020;17(3): e1003062.PubMedPubMedCentralCrossRef
27.
go back to reference Nicholls SJ, et al. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA. 2007;297(5):499–508.PubMedCrossRef Nicholls SJ, et al. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA. 2007;297(5):499–508.PubMedCrossRef
28.
go back to reference Mortensen MB, et al. Low-density lipoprotein cholesterol is predominantly associated with atherosclerotic cardiovascular disease events in patients with evidence of coronary atherosclerosis: the Western Denmark heart registry. Circulation. 2023;147(14):1053–63.PubMedCrossRef Mortensen MB, et al. Low-density lipoprotein cholesterol is predominantly associated with atherosclerotic cardiovascular disease events in patients with evidence of coronary atherosclerosis: the Western Denmark heart registry. Circulation. 2023;147(14):1053–63.PubMedCrossRef
29.
go back to reference Skrivankova VW, et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomization: the STROBE-MR statement. JAMA. 2021;326(16):1614–21.PubMedCrossRef Skrivankova VW, et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomization: the STROBE-MR statement. JAMA. 2021;326(16):1614–21.PubMedCrossRef
30.
go back to reference Boef AG, Dekkers OM, le Cessie S. Mendelian randomization studies: a review of the approaches used and the quality of reporting. Int J Epidemiol. 2015;44(2):496–511.PubMedCrossRef Boef AG, Dekkers OM, le Cessie S. Mendelian randomization studies: a review of the approaches used and the quality of reporting. Int J Epidemiol. 2015;44(2):496–511.PubMedCrossRef
31.
32.
go back to reference Burgess S, Thompson SG. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol. 2011;40(3):755–64.PubMedCrossRef Burgess S, Thompson SG. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol. 2011;40(3):755–64.PubMedCrossRef
34.
go back to reference Verbanck M, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50(5):693–8.PubMedPubMedCentralCrossRef Verbanck M, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50(5):693–8.PubMedPubMedCentralCrossRef
35.
go back to reference Hartwig FP, Davey Smith G, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol. 2017;46(6):1985–98.PubMedPubMedCentralCrossRef Hartwig FP, Davey Smith G, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol. 2017;46(6):1985–98.PubMedPubMedCentralCrossRef
36.
go back to reference Hemani G, Bowden J, Davey Smith G. Evaluating the potential role of pleiotropy in Mendelian randomization studies. Hum Mol Genet. 2018;27(R2):R195-r208.PubMedPubMedCentralCrossRef Hemani G, Bowden J, Davey Smith G. Evaluating the potential role of pleiotropy in Mendelian randomization studies. Hum Mol Genet. 2018;27(R2):R195-r208.PubMedPubMedCentralCrossRef
38.
39.
go back to reference Bowden J, et al. Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption. Int J Epidemiol. 2019;48(3):728–42.PubMedCrossRef Bowden J, et al. Improving the accuracy of two-sample summary-data Mendelian randomization: moving beyond the NOME assumption. Int J Epidemiol. 2019;48(3):728–42.PubMedCrossRef
40.
41.
go back to reference Chauquet S, et al. Association of antihypertensive drug target genes with psychiatric disorders: a mendelian randomization study. JAMA Psychiat. 2021;78(6):623–31.CrossRef Chauquet S, et al. Association of antihypertensive drug target genes with psychiatric disorders: a mendelian randomization study. JAMA Psychiat. 2021;78(6):623–31.CrossRef
42.
go back to reference Armstrong RA. When to use the Bonferroni correction. Ophthal Physiol Opt. 2014;34(5):502–8.CrossRef Armstrong RA. When to use the Bonferroni correction. Ophthal Physiol Opt. 2014;34(5):502–8.CrossRef
43.
44.
go back to reference van Leiden HA, et al. Blood pressure, lipids, and obesity are associated with retinopathy: the hoorn study. Diabetes Care. 2002;25(8):1320–5.PubMedCrossRef van Leiden HA, et al. Blood pressure, lipids, and obesity are associated with retinopathy: the hoorn study. Diabetes Care. 2002;25(8):1320–5.PubMedCrossRef
45.
go back to reference Zhong Y, et al. Association of the serum total cholesterol to triglyceride ratio with diabetic retinopathy in chinese patients with type 2 diabetes: a community-based study. Diabetes Ther. 2019;10(2):597–604.PubMedPubMedCentralCrossRef Zhong Y, et al. Association of the serum total cholesterol to triglyceride ratio with diabetic retinopathy in chinese patients with type 2 diabetes: a community-based study. Diabetes Ther. 2019;10(2):597–604.PubMedPubMedCentralCrossRef
46.
go back to reference Klein BE, et al. The Wisconsin epidemiologic study of diabetic retinopathy. XIII. Relationship of serum cholesterol to retinopathy and hard exudate. Ophthalmology. 1991;98(8):1261–5.PubMedCrossRef Klein BE, et al. The Wisconsin epidemiologic study of diabetic retinopathy. XIII. Relationship of serum cholesterol to retinopathy and hard exudate. Ophthalmology. 1991;98(8):1261–5.PubMedCrossRef
47.
go back to reference Lopes-Virella MF, et al. High concentrations of AGE-LDL and oxidized LDL in circulating immune complexes are associated with progression of retinopathy in type 1 diabetes. Diabetes Care. 2012;35(6):1333–40.PubMedPubMedCentralCrossRef Lopes-Virella MF, et al. High concentrations of AGE-LDL and oxidized LDL in circulating immune complexes are associated with progression of retinopathy in type 1 diabetes. Diabetes Care. 2012;35(6):1333–40.PubMedPubMedCentralCrossRef
48.
go back to reference Miyahara S, et al. Simvastatin inhibits leukocyte accumulation and vascular permeability in the retinas of rats with streptozotocin-induced diabetes. Am J Pathol. 2004;164(5):1697–706.PubMedPubMedCentralCrossRef Miyahara S, et al. Simvastatin inhibits leukocyte accumulation and vascular permeability in the retinas of rats with streptozotocin-induced diabetes. Am J Pathol. 2004;164(5):1697–706.PubMedPubMedCentralCrossRef
49.
50.
go back to reference Pranata R, Vania R, Victor AA. Statin reduces the incidence of diabetic retinopathy and its need for intervention: a systematic review and meta-analysis. Eur J Ophthalmol. 2021;31(3):1216–24.PubMedCrossRef Pranata R, Vania R, Victor AA. Statin reduces the incidence of diabetic retinopathy and its need for intervention: a systematic review and meta-analysis. Eur J Ophthalmol. 2021;31(3):1216–24.PubMedCrossRef
52.
go back to reference Swerdlow DI, et al. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet. 2015;385(9965):351–61.PubMedPubMedCentralCrossRef Swerdlow DI, et al. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet. 2015;385(9965):351–61.PubMedPubMedCentralCrossRef
53.
go back to reference Boucher K, et al. HMG-CoA reductase inhibitors induce apoptosis in pericytes. Microvasc Res. 2006;71(2):91–102.PubMedCrossRef Boucher K, et al. HMG-CoA reductase inhibitors induce apoptosis in pericytes. Microvasc Res. 2006;71(2):91–102.PubMedCrossRef
54.
go back to reference Eisa-Beygi S, et al. The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) pathway regulates developmental cerebral-vascular stability via prenylation-dependent signalling pathway. Dev Biol. 2013;373(2):258–66.PubMedCrossRef Eisa-Beygi S, et al. The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) pathway regulates developmental cerebral-vascular stability via prenylation-dependent signalling pathway. Dev Biol. 2013;373(2):258–66.PubMedCrossRef
55.
go back to reference Liinamaa MJ, Savolainen MJ. High vitreous concentration of vascular endothelial growth factor in diabetic patients with proliferative retinopathy using statins. Ann Med. 2008;40(3):209–14.PubMedCrossRef Liinamaa MJ, Savolainen MJ. High vitreous concentration of vascular endothelial growth factor in diabetic patients with proliferative retinopathy using statins. Ann Med. 2008;40(3):209–14.PubMedCrossRef
56.
go back to reference Simó R, Sundstrom JM, Antonetti DA. Ocular Anti-VEGF therapy for diabetic retinopathy: the role of VEGF in the pathogenesis of diabetic retinopathy. Diabetes Care. 2014;37(4):893–9.PubMedCrossRef Simó R, Sundstrom JM, Antonetti DA. Ocular Anti-VEGF therapy for diabetic retinopathy: the role of VEGF in the pathogenesis of diabetic retinopathy. Diabetes Care. 2014;37(4):893–9.PubMedCrossRef
58.
go back to reference Tomkins-Netzer O, Niederer R, Lightman S. The role of statins in diabetic retinopathy. Trends Cardiovasc Med. 2024;34(2):128–35.PubMedCrossRef Tomkins-Netzer O, Niederer R, Lightman S. The role of statins in diabetic retinopathy. Trends Cardiovasc Med. 2024;34(2):128–35.PubMedCrossRef
59.
go back to reference Chung YR, et al. Association of statin use and hypertriglyceridemia with diabetic macular edema in patients with type 2 diabetes and diabetic retinopathy. Cardiovasc Diabetol. 2017;16(1):4.PubMedPubMedCentralCrossRef Chung YR, et al. Association of statin use and hypertriglyceridemia with diabetic macular edema in patients with type 2 diabetes and diabetic retinopathy. Cardiovasc Diabetol. 2017;16(1):4.PubMedPubMedCentralCrossRef
Metadata
Title
Statins as a risk factor for diabetic retinopathy: a Mendelian randomization and cross-sectional observational study
Authors
Chengming Chen
Huan Zhang
Yanyan Lan
Weiming Yan
Sida Liu
Yixuan Chen
Tingke Xie
Jiayi Ning
Xiaolong Yan
Lei Shang
Jing Han
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2024
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-024-05097-8

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