Association Between Medication-Taking and Refractive Error in a Large General Population-Based Cohort

PURPOSE. Refractive errors, particularly myopia, are common and a leading cause of blind-ness. This study aimed to explore associations between medications and refractive error in an aging adult cohort and to determine whether childhood-onset refractive errors predict future medication use to provide novel insights into disease mechanisms. METHODS. The study compared the spherical equivalent values measured in 102,318 UK Biobank participants taking the 960 most commonly used medications. The strengths of associations were evaluated against the self-reported age of spectacle wear. The causality of refractive error changes was inferred using sensitivity and Mendelian randomization analyses. RESULTS. Anti-glaucoma drugs were associated with 1 to 2 diopters greater myopic refrac-tion, particularly in subjects who started wearing correction in the first two decades of life, potentially due to the association of higher intraocular pressure since early years with both myopia and, later in life, glaucoma. All classes of pain-control medications, including paracetamol, opiates, non-steroidal antiinflammatory drugs, and gabapentinoids, were associated with greater hyperopia (+0.68-1.15 diopters), after correction for deprivation, education, and polypharmacy and sensitivity analyses for common diagnoses. Oral hypoglycemics (metformin, gliburonide) were associated with myopia, as was allopurinol, and participants using bronchodilators (ipratropium and salbutamol) were more hyperopic. CONCLUSIONS. This study finds for the first time, to our knowledge, that medication use is associated with refractive error in adults. The novel finding that analgesics are associated with hyperopic refraction, and the possibility that multisite chronic pain predisposes to hyperopia, deserves further research. Some drugs, such as antihyperglycemic or bronchodilators, may directly alter refractive error. Intraocular pressure appears causative for myopia

Plasma metabolite profile for primary open-angle glaucoma in three US cohorts and the UK Biobank

Glaucoma is a progressive optic neuropathy and a leading cause of irreversible blindness worldwide. Primary open-angle glaucoma is the most common form, and yet the etiology of this multifactorial disease is poorly understood. We aimed to identify plasma metabolites associated with the risk of developing POAG in a case-control study (599 cases and 599 matched controls) nested within the Nurses' Health Studies, and Health Professionals' Follow-Up Study. Plasma metabolites were measured with LC-MS/MS at the Broad Institute (Cambridge, MA, USA); 369 metabolites from 18 metabolite classes passed quality control analyses. For comparison, in a cross-sectional study in the UK Biobank, 168 metabolites were measured in plasma samples from 2,238 prevalent glaucoma cases and 44,723 controls using NMR spectroscopy (Nightingale, Finland; version 2020). Here we show higher levels of diglycerides and triglycerides are adversely associated with glaucoma in all four cohorts, suggesting that they play an important role in glaucoma pathogenesis

GWAS on retinal vasculometry phenotypes.

The eye is the window through which light is transmitted and visual sensory signalling originates. It is also a window through which elements of the cardiovascular and nervous systems can be directly inspected, using ophthalmoscopy or retinal imaging. Measurements of ocular parameters may therefore offer important information on the physiology and homeostasis of these two important systems. Here we report the results of a genetic characterisation of retinal vasculature. Four genome-wide association studies performed on different aspects of retinal vasculometry phenotypes, such as arteriolar and venular tortuosity and width, found significant similarities between retinal vascular characteristics and cardiometabolic health. Our analyses identified 119 different regions of association with traits of retinal vasculature, including 89 loci associated arteriolar tortuosity, the strongest of which was rs35131825 (p = 2.00×10-108), 2 loci with arteriolar width (rs12969347, p = 3.30×10-09 and rs5442, p = 1.9E-15), 17 other loci associated with venular tortuosity and 11 novel associations with venular width. Our causal inference analyses also found that factors linked to arteriolar tortuosity cause elevated diastolic blood pressure and not vice versa

GWAS on retinal vasculometry phenotypes.

The eye is the window through which light is transmitted and visual sensory signalling originates. It is also a window through which elements of the cardiovascular and nervous systems can be directly inspected, using ophthalmoscopy or retinal imaging. Measurements of ocular parameters may therefore offer important information on the physiology and homeostasis of these two important systems. Here we report the results of a genetic characterisation of retinal vasculature. Four genome-wide association studies performed on different aspects of retinal vasculometry phenotypes, such as arteriolar and venular tortuosity and width, found significant similarities between retinal vascular characteristics and cardiometabolic health. Our analyses identified 119 different regions of association with traits of retinal vasculature, including 89 loci associated arteriolar tortuosity, the strongest of which was rs35131825 (p = 2.00×10-108), 2 loci with arteriolar width (rs12969347, p = 3.30×10-09 and rs5442, p = 1.9E-15), 17 other loci associated with venular tortuosity and 11 novel associations with venular width. Our causal inference analyses also found that factors linked to arteriolar tortuosity cause elevated diastolic blood pressure and not vice versa

Importance of Non-Selective Cation Channel TRPV4 Interaction with Cytoskeleton and Their Reciprocal Regulations in Cultured Cells

BACKGROUND: TRPV4 and the cellular cytoskeleton have each been reported to influence cellular mechanosensitive processes as well as the development of mechanical hyperalgesia. If and how TRPV4 interacts with the microtubule and actin cytoskeleton at a molecular and functional level is not known. METHODOLOGY AND PRINCIPAL FINDINGS: We investigated the interaction of TRPV4 with cytoskeletal components biochemically, cell biologically by observing morphological changes of DRG-neurons and DRG-neuron-derived F-11 cells, as well as functionally with calcium imaging. We find that TRPV4 physically interacts with tubulin, actin and neurofilament proteins as well as the nociceptive molecules PKCepsilon and CamKII. The C-terminus of TRPV4 is sufficient for the direct interaction with tubulin and actin, both with their soluble and their polymeric forms. Actin and tubulin compete for binding. The interaction with TRPV4 stabilizes microtubules even under depolymerizing conditions in vitro. Accordingly, in cellular systems TRPV4 colocalizes with actin and microtubules enriched structures at submembranous regions. Both expression and activation of TRPV4 induces striking morphological changes affecting lamellipodial, filopodial, growth cone, and neurite structures in non-neuronal cells, in DRG-neuron derived F11 cells, and also in IB4-positive DRG neurons. The functional interaction of TRPV4 and the cytoskeleton is mutual as Taxol, a microtubule stabilizer, reduces the Ca2+-influx via TRPV4. CONCLUSIONS AND SIGNIFICANCE: TRPV4 acts as a regulator for both, the microtubule and the actin. In turn, we describe that microtubule dynamics are an important regulator of TRPV4 activity. TRPV4 forms a supra-molecular complex containing cytoskeletal proteins and regulatory kinases. Thereby it can integrate signaling of various intracellular second messengers and signaling cascades, as well as cytoskeletal dynamics. This study points out the existence of cross-talks between non-selective cation channels and cytoskeleton at multiple levels. These cross talks may help us to understand the molecular basis of the Taxol-induced neuropathic pain development commonly observed in cancer patients

The Role of Chromosome X in Intraocular Pressure Variation and Sex-Specific Effects

Purpose: The purpose of this study was to identify genetic variants on chromosome X associated with intraocular pressure (IOP) and determine if they possess any sex-specific effects. / Methods: Association analyses were performed across chromosome X using 102,407 participants from the UK Biobank. Replication and validation analyses were conducted in an additional 6599 participants from the EPIC-Norfolk cohort, and an independent 331,682 participants from the UK Biobank. / Results: We identified three loci associated with IOP at genomewide significance (P < 5 × 10-8), located within or near the following genes: MXRA5 (rs2107482, P = 7.1 × 10-11), GPM6B (rs66819623, P = 6.9 × 10-10), NDP, and EFHC2 (rs12558081, P = 4.9 × 10-11). Alleles associated with increased IOP were also associated with increased risk for primary open-angle glaucoma in an independent sample. Finally, our results indicate that chromosome X genetics most likely do not illicit sex-specific effects on IOP. / Conclusions: In this study, we report the results of genomewide levels of association of three loci on chromosome X with IOP, and provide a framework to include chromosome X in large-scale genomewide association analyses for complex phenotypes