Vitamin D Levels and Risk of Ocular Disorders: Insights from Bidirectional and Multivariable Mendelian Randomization Analysis

Overview

Journal Front Med (Lausanne)

Specialty General Medicine

Date 2024 Oct 24

PMID 39444820

Authors

Shipei Fan

Xing-Yu Shi

Xia Li

Jun Li

Song-Ping Yu

Affiliations

Soon will be listed here.

Abstract

Purpose: This study aimed to assess the causal relationships between vitamin D levels and ocular disorders.

Methods: Independent genetic variables were obtained from genome-wide association studies (GWAS) and publicly available databases. The summary statistics for 25-hydroxyvitamin D (25(OH)D) were obtained from two large-scale GWAS studies, with sample sizes of 324,105 and 417,580 European individuals. The genetic variants of myopia, primary open angle glaucoma (POAG), anterior iridocyclitis, senile cataract, diabetic retinopathy (DR), retinal vein occlusion (RVO), wet age-related macular degeneration (WAMD) and optic neuritis were extracted from the latest release of FinnGen consortium, which contains genome data from Finnish participants. Subsequently, Mendelian randomization (MR) analyses were conducted to obtain effect estimates. Additionally, we performed multivariable MR analysis and mediation analysis to validate the results.

Results: In the discovery dataset, genetically predicted vitamin D concentration was found to be causally associated with an increased risk of WAMD, (odd ratio (OR) = 1.35, 95% confidence interval (CI) = 1.09-1.67, = 0.005). However, no causal effects of genetically predisposed vitamin D levels on the risk of most types of ocular disorders were observed. Reverse MR revealed no causal relationships between the ocular diseases and vitamin D concentrations. The MR analyses of the validation dataset yielded consistent results. Additionally, the causal effect of vitamin D levels on the risk of WAMD remained significant after adjusting for potential confounders in the multivariable MR analysis (OR = 1.86, 95% CI = 1.26-2.73, = 0.002).

Conclusion: Our MR analysis results provide robust evidence of a causal relationship between genetically predicted 25(OH)D levels and an increased risk of WAMD in European population. These findings offer important insights into the management and control of ocular disorders.

References

Ma Y, Qu X, Zhu X, Xu X, Zhu J, Sankaridurg P . Age-Specific Prevalence of Visual Impairment and Refractive Error in Children Aged 3-10 Years in Shanghai, China. Invest Ophthalmol Vis Sci. 2016; 57(14):6188-6196. DOI: 10.1167/iovs.16-20243. View

Zhou X, Pardue M, Iuvone P, Qu J . Dopamine signaling and myopia development: What are the key challenges. Prog Retin Eye Res. 2017; 61:60-71. PMC: 5653403. DOI: 10.1016/j.preteyeres.2017.06.003. View

Yoon B, Lee Y, Seo J . Potential Causal Association between C-Reactive Protein Levels in Age-Related Macular Degeneration: A Two-Sample Mendelian Randomization Study. Biomedicines. 2024; 12(4). PMC: 11047998. DOI: 10.3390/biomedicines12040807. View

Arnault E, Barrau C, Nanteau C, Gondouin P, Bigot K, Vienot F . Phototoxic action spectrum on a retinal pigment epithelium model of age-related macular degeneration exposed to sunlight normalized conditions. PLoS One. 2013; 8(8):e71398. PMC: 3751948. DOI: 10.1371/journal.pone.0071398. View

Bowden J, Del Greco M F, Minelli C, Davey Smith G, Sheehan N, Thompson J . Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I2 statistic. Int J Epidemiol. 2016; 45(6):1961-1974. PMC: 5446088. DOI: 10.1093/ije/dyw220. View

Kusuhara S, Fukushima Y, Ogura S, Inoue N, Uemura A . Pathophysiology of Diabetic Retinopathy: The Old and the New. Diabetes Metab J. 2018; 42(5):364-376. PMC: 6202564. DOI: 10.4093/dmj.2018.0182. View

Longo A, Casuccio A, Pani L, Avitabile T, Cillino S, Uva M . Association of neovascular age-related macular degeneration with month and season of birth in Italy. Aging (Albany NY). 2016; 9(1):133-141. PMC: 5310660. DOI: 10.18632/aging.101137. View

Xue A, Wu Y, Zhu Z, Zhang F, Kemper K, Zheng Z . Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes. Nat Commun. 2018; 9(1):2941. PMC: 6063971. DOI: 10.1038/s41467-018-04951-w. View

Bowden J, Davey Smith G, Haycock P, Burgess S . Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol. 2016; 40(4):304-14. PMC: 4849733. DOI: 10.1002/gepi.21965. View

10.

Mutlu U, Ikram M, Hofman A, de Jong P, Uitterlinden A, Klaver C . Vitamin D and retinal microvascular damage: The Rotterdam Study. Medicine (Baltimore). 2016; 95(49):e5477. PMC: 5266000. DOI: 10.1097/MD.0000000000005477. View

11.

Mckay G, Young I, McGinty A, Bentham G, Chakravarthy U, Rahu M . Associations between Serum Vitamin D and Genetic Variants in Vitamin D Pathways and Age-Related Macular Degeneration in the European Eye Study. Ophthalmology. 2016; 124(1):90-96. DOI: 10.1016/j.ophtha.2016.09.007. View

12.

Fleckenstein M, Keenan T, Guymer R, Chakravarthy U, Schmitz-Valckenberg S, Klaver C . Age-related macular degeneration. Nat Rev Dis Primers. 2021; 7(1):31. DOI: 10.1038/s41572-021-00265-2. View

13.

Rojas-Carabali W, Pineda-Sierra J, Cifuentes-Gonzalez C, Morales M, Munoz-Vargas P, Pena-Pulgar L . Vitamin D deficiency and non-infectious uveitis: A systematic review and Meta-analysis. Autoimmun Rev. 2023; 23(2):103497. DOI: 10.1016/j.autrev.2023.103497. View

14.

Nebbioso M, Buomprisco G, Pascarella A, Pescosolido N . Modulatory effects of 1,25-dihydroxyvitamin D3 on eye disorders: A critical review. Crit Rev Food Sci Nutr. 2015; 57(3):559-565. DOI: 10.1080/10408398.2014.893504. View

15.

Rak K, Bronkowska M . Immunomodulatory Effect of Vitamin D and Its Potential Role in the Prevention and Treatment of Type 1 Diabetes Mellitus-A Narrative Review. Molecules. 2018; 24(1). PMC: 6337255. DOI: 10.3390/molecules24010053. View

16.

Li S, Li D, Shao M, Cao W, Sun X . Lack of Association between Serum Vitamin B₆, Vitamin B, and Vitamin D Levels with Different Types of Glaucoma: A Systematic Review and Meta-Analysis. Nutrients. 2017; 9(6). PMC: 5490615. DOI: 10.3390/nu9060636. View

17.

Cuellar-Partida G, Williams K, Yazar S, Guggenheim J, Hewitt A, Williams C . Genetically low vitamin D concentrations and myopic refractive error: a Mendelian randomization study. Int J Epidemiol. 2017; 46(6):1882-1890. PMC: 5837568. DOI: 10.1093/ije/dyx068. View

18.

Han X, Ong J, Hewitt A, Gharahkhani P, Macgregor S . The effects of eight serum lipid biomarkers on age-related macular degeneration risk: a Mendelian randomization study. Int J Epidemiol. 2020; 50(1):325-336. DOI: 10.1093/ije/dyaa178. View

19.

Jonas J, Aung T, Bourne R, Bron A, Ritch R, Panda-Jonas S . Glaucoma. Lancet. 2017; 390(10108):2183-2193. DOI: 10.1016/S0140-6736(17)31469-1. View

20.

Patrick P, Visintainer P, Shi Q, Weiss I, Brand D . Vitamin D and retinopathy in adults with diabetes mellitus. Arch Ophthalmol. 2012; 130(6):756-60. DOI: 10.1001/archophthalmol.2011.2749. View