Vitamin D and Cataract Risk: A Mendelian Randomisation Study

Data Availability Statement: All publicly available data used in analyses is listed within the manuscript, alongside where the data can be located. UKBB data used in this study is subject to the following licenses/restrictions: UK Biobank data is accessible to all bona fide researchers for healthrelated research that serves the public interest. Requests for access to these datasets should be directed to https://www.ukbiobank.ac.uk/enable-your-research/apply-for-accessSupplementary Material is available online at: https://ndownloader.figstatic.com/articles/29617868/versions/1 .Background: Previous observational studies have suggested an association between vitamin D levels and the risk of cataracts. Whilst this correlation has been well reported, there is a lack of causal evidence. Methods: We first conducted an observational study using UK Biobank (UKBB) data to explore the correlation between vitamin D levels and deficiency with incident cataract. To assess causality, we then performed both one-sample and two-sample Mendelian Randomisation (MR) analyses. The one-sample MR used genetic risk scores (GRS) reflecting a genetic predisposition to higher vitamin D levels and vitamin D deficiency, examining its association with incident cataract. The two-sample MR, publicly available summary statistics for vitamin D levels and deficiency were used to investigate their relationship with cataract. Sensitivity analyses using a UKBB meta-analysis for vitamin D in a two-sample MR and a gene-focused analysis using variants in genes with a known role in vitamin D metabolism. Results: The observational analysis showed a statistically significant relationship between both vitamin D levels (OR = 0.998, ln(OR)SE = 3.23x10-4, p = 6.72x10-14) and deficiency (OR = 1.237, ln(OR)SE = 0.022, p = 9.05x10-23) with incident cataract risk. However, there was insufficient evidence to suggest an association between vitamin D supplementation and cataract risk (OR = 0.971, ln(OR)SE = 0.016, p = 0.057). Furthermore, no evidence was found in our one-sample MR analysis to suggest a causal relationship between vitamin D levels (OR = 1.001, ln(OR)SE = 0.002, p = 0.541) or vitamin D deficiency (OR = 1.095, ln(OR)SE = 0.145, p = 0.534) and incident cataract. The inverse variance weighted two-sample MR analysis also showed no evidence to suggest a causal association between vitamin D levels (IVW: OR = 1.122, 95% CI: 0.968-1.301, p = 0.125) or deficiency (IVW: OR= 0.987, 95% CI: 0.959-1.015, p = 0.344) and cataract risk, with consistent results observed using a multi-ethnic cataract cohort. Some evidence was observed between vitamin D levels and increasing cataract risk (Weighted median OR = 1.076, 95% CI: 1.002–1.156, p = 0.045), however, due to sample overlap between the exposure and outcome, datasets should be interpreted with caution. Conclusion: Whilst we identified a correlative association between vitamin D levels and cataract, we found no robust evidence to support a causal relationship between vitamin D levels and deficiency with cataract risk.The authors declare no funding sources.

No Evidence That Vitamin D Levels or Deficiency Are Associated with the Risk of Open-Angle Glaucoma in Individuals of European Ancestry: A Mendelian Randomisation Analysis

Data Availability Statement: The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.Supplementary Materials are available online at: https://www.mdpi.com/2073-4425/15/8/1084#app1-genes-15-01084 .Background: Glaucoma is the second leading cause of blindness worldwide, with intraocular pressure as the only known modifiable risk factor. Vitamin D has been proposed to influence intraocular pressure and decrease retinal ganglion cell degeneration. Based on these findings, vitamin D has been suggested to prevent or reduce the severity of primary open-angle glaucoma (POAG), which is the most common form. Methods: We applied two-sample Mendelian randomisation (MR) analyses to data from the SUNLIGHT consortium and the UK Biobank to assess the causal effect of vitamin D levels and vitamin D deficiency on primary open-angle glaucoma (POAG). MR analysis, including sensitivity tests using other GWAS summary statistics from FinnGen, was also performed. We also investigated the association between single nucleotide polymorphisms (SNPs) on genes involved in vitamin D metabolic pathways and POAG. Results: We found no statistical evidence that vitamin D levels (OR = 1.146, 95% CI 0.873 to 1.504, p = 0.326) or vitamin D deficiency (OR = 0.980 (95% CI 0.928 to 1.036, p = 0.471) causally affect the risk of developing POAG. Sensitivity analyses, including the use of a more relaxed p-value threshold, and use of winter-measured samples only, replication in the FinnGen dataset, and exploration of specific genetic markers also showed no evidence of association between SNPs for genes involved in key steps of vitamin D metabolism and POAG. Conclusions: These results indicate that vitamin D may not be a significant factor in modifying POAG risk, challenging the hypothesis that vitamin D supplementation could be effective in reducing POAG risk. Further research should focus on identifying other potential risk factors for POAG prevention strategies.This research was funded by the Brunel Research Initiative and Enterprise Fund from Brunel University London, awarded to F.D. H.A.A. is the recipient of a studentship from the College of Health, Medicine and Life Sciences

Using genetics to investigate the association between lanosterol and cataract

Data availability statement: The data analyzed in this study is subject to the following licenses/restrictions: UK Biobank data are available to all bona fide researchers for all types of health-related research which is in the public interest. Requests to access these datasets should be directed to https://www.ukbiobank.ac.uk/enable-your-research/apply-for-access.Acknowledgements: The authors of the paper would like to thank the UKBB staff and participants who provide and facilitate access to their dataSupplementary material: The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fgene.2024.1231521/full#supplementary-material .Background: Cataract is one of the most prevalent causes of blindness worldwide. Whilst surgery is the primary treatment for cataracts, it is not always an available option, particularly in developing countries. Non-surgical methods of treatment would increase treatment availability for more patients. Several studies have investigated how topical application of oxysterols, such as lanosterol, may break down aggregated proteins and restore lens transparency. However, the results are conflicting and inconclusive. Aim: In this study, we focus on combining genetic evidence for associations between lanosterol related genetic variation and cataract to explore whether lanosterol is a potentially suitable drug treatment option. Method: Using data from 45,449 available cataract cases from the UK Biobank, with participant ages ranging from 40–69, we conducted a genetic association study (GWAS) to assess the risk of cataract. Cataract cases were defined using diagnostic and operation codes. We focused on genetic variants in the lanosterol synthase gene region. We also compared our results with previously published genetic associations of phytosterol-to-lanosterol ratios. Finally, we performed a genetic risk score analysis to test the association between lanosterol within the cholesterol synthesis pathway and the risk of cataract. Results: No statistically significant single nucleotide polymorphisms (SNPs) associations with cataract were observed in the gene region of lanosterol synthase at a multiple testing adjusted significance threshold of p < 0.05/13. The comparison between cataract risk and genetic association of 8 phytosterol-to-lanosterol GWAS results also showed no evidence to support lanosterol’s protective properties for cataract risk. No statistically significant association was found between the lanosterol within the cholesterol synthesis pathway genetic risk score and cataract outcomes (OR = 1.002 p = 0.568). Conclusion: There was no evidence observed for genetic associations between lanosterol and cataract risk. Our results do not support lanosterol’s potential role in treating cataracts. Further research may be needed to address the effect of lanosterol on specific cataract subtypes

MicroRNA Involvement in Immune Activation During Heart Failure

Heart failure is one of the common end stages of cardiovascular diseases, the leading cause of death in developed countries. Molecular mechanisms underlying the development of heart failure remain elusive but there is a consistent observation of chronic immune activation and aberrant microRNA (miRNA) expression that is present in failing hearts. This review will focus on the interplay between the immune system and miRNAs as factors that play a role during the development of heart failure. Several studies have shown that heart failure patients can be characterized by a sustained innate immune activation. The role of inflammatory signaling is discussed and TLR4 signaling, IL-1β, TNFα and IL-6 expression appears to coincide with the development of heart failure. Furthermore, we describe the implication of the renin angiotensin aldosteron system in immunity and heart failure. In the past decade microRNAs (miRNAs), small non-coding RNAs that translationally repress protein synthesis by binding to partially complementary sequences of mRNA, have come to light as important regulators of several kinds of cardiovascular diseases including cardiac hypertrophy and heart failure. The involvement of differentially expressed miRNAs in the inflammation that occurs during the development of heart failure is still subject of investigation. Here, we summarize and comment on the first studies in this field and hypothesize on the putative involvement of certain miRNAs in heart failure. MicroRNAs have been shown to be critical regulators of cardiac function and inflammation. Future research will have to point out if dampening the immune response, and the miRNAs associated with it, during the development of heart failure is a therapeutically plausible route to follow

Measuring single-molecule nucleic acid dynamics in solution by two-color filtered ratiometric fluorescence correlation spectroscopy

This work presents a general method for determining single-molecule intramolecular dynamics in biomolecules by using a reporter fluorophore, whose fluorescence is quenched or partially quenched as a result of intramolecular motion, and a remote observer fluorophore. These fluorophores were excited independently with two different lasers, and the ratio of the two fluorophores' fluorescence was calculated. The time-varying ratio was then filtered to reduce contributions from molecules outside the overlapped laser volume and then correlated. The rates of opening and closing of a DNA hairpin were measured by using both fluorescence correlation spectroscopy and this method for comparison. We found at 50 pM, where molecules were studied one by one as they diffused through the probe volume, we obtained accurate opening and closing rates and could also measure dynamic heterogeneity. To demonstrate applicability to a more complex biological molecule we then probed intramolecular motions in the dimer of a human telomerase RNA fragment (hTR(380-444)), in the presence of an excess of monomer. The motion was found to occur on the time scale of 180-750 μs and slowed with increasing magnesium ion concentration. Blocking experiments using complementary oligonucleotides suggested that the motion involves substantial changes in dimer tertiary structure. This method appears to be a general method for selectively studying intramolecular motion in large biomolecules or complexes