Calcium Channel Blocker Use and Associated Glaucoma and Related Traits Among UK Biobank Participants.

Importance: Calcium channel blocker (CCB) use has been associated with an increased risk of glaucoma in exploratory studies. Objective: To examine the association of systemic CCB use with glaucoma and related traits among UK Biobank participants. Design, Setting, and Participants: This population-based cross-sectional study included UK Biobank participants with complete data (2006-2010) for analysis of glaucoma status, intraocular pressure (IOP), and optical coherence tomography (OCT)-derived inner retinal layer thicknesses. Data analysis was conducted in January 2023. Exposure: Calcium channel blocker use was assessed in a baseline touchscreen questionnaire and confirmed during an interview led by a trained nurse. Main Outcomes and Measures: The primary outcome measures included glaucoma status, corneal-compensated IOP, and 2 OCT-derived inner retinal thickness parameters (macular retinal nerve fiber layer [mRNFL] and macular ganglion cell-inner plexiform layer [mGCIPL] thicknesses). We performed logistic regression and linear regression analyses to test for associations with glaucoma status and IOP and OCT-derived inner retinal thickness parameters, respectively. Results: This study included 427 480 adults. Their median age was 58 (IQR, 50-63) years, and more than half (54.1%) were women. There were 33 175 CCB users (7.8%). Participants who had complete data for glaucoma status (n = 427 480), IOP (n = 97 100), and OCT-derived inner retinal layer thicknesses (n = 41 023) were eligible for respective analyses. After adjustment for key sociodemographic, medical, anthropometric, and lifestyle factors, use of CCBs (but not other antihypertensive agents) was associated with greater odds of glaucoma (odds ratio [OR], 1.39 [95% CI, 1.14 to 1.69]; P = .001). Calcium channel blocker use was also associated with thinner mGCIPL (-0.34 µm [95% CI, -0.54 to -0.15 µm]; P = .001) and mRNFL (-0.16 µm [95% CI, -0.30 to -0.02 µm]; P = .03) thicknesses but not IOP (-0.01 mm Hg [95% CI, -0.09 to 0.07 mm Hg]; P = .84). Conclusions and Relevance: In this study, an adverse association between CCB use and glaucoma was observed, with CCB users having, on average, 39% higher odds of glaucoma. Calcium channel blocker use was also associated with thinner mGCIPL and mRNFL thicknesses, providing a structural basis that supports the association with glaucoma. The lack of association of CCB use with IOP suggests that an IOP-independent mechanism of glaucomatous neurodegeneration may be involved. Although a causal relationship has not been established, CCB replacement or withdrawal may be considered should glaucoma progress despite optimal care.

The Association of Physical Activity with Glaucoma and Related Traits in the UK Biobank.

PURPOSE: To examine the association of physical activity (PA) with glaucoma and related traits, to assess whether genetic predisposition to glaucoma modified these associations, and to probe causal relationships using Mendelian randomization (MR). DESIGN: Cross-sectional observational and gene-environment interaction analyses in the UK Biobank. Two-sample MR experiments using summary statistics from large genetic consortia. PARTICIPANTS: UK Biobank participants with data on self-reported or accelerometer-derived PA and intraocular pressure (IOP; n = 94 206 and n = 27 777, respectively), macular inner retinal OCT measurements (n = 36 274 and n = 9991, respectively), and glaucoma status (n = 86 803 and n = 23 556, respectively). METHODS: We evaluated multivariable-adjusted associations of self-reported (International Physical Activity Questionnaire) and accelerometer-derived PA with IOP and macular inner retinal OCT parameters using linear regression and with glaucoma status using logistic regression. For all outcomes, we examined gene-PA interactions using a polygenic risk score (PRS) that combined the effects of 2673 genetic variants associated with glaucoma. MAIN OUTCOME MEASURES: Intraocular pressure, macular retinal nerve fiber layer (mRNFL) thickness, macular ganglion cell-inner plexiform layer (mGCIPL) thickness, and glaucoma status. RESULTS: In multivariable-adjusted regression models, we found no association of PA level or time spent in PA with glaucoma status. Higher overall levels and greater time spent in higher levels of both self-reported and accelerometer-derived PA were associated positively with thicker mGCIPL (P < 0.001 for trend for each). Compared with the lowest quartile of PA, participants in the highest quartiles of accelerometer-derived moderate- and vigorous-intensity PA showed a thicker mGCIPL by +0.57 µm (P < 0.001) and +0.42 µm (P = 0.005). No association was found with mRNFL thickness. High overall level of self-reported PA was associated with a modestly higher IOP of +0.08 mmHg (P = 0.01), but this was not replicated in the accelerometry data. No associations were modified by a glaucoma PRS, and MR analyses did not support a causal relationship between PA and any glaucoma-related outcome. CONCLUSIONS: Higher overall PA level and greater time spent in moderate and vigorous PA were not associated with glaucoma status but were associated with thicker mGCIPL. Associations with IOP were modest and inconsistent. Despite the well-documented acute reduction in IOP after PA, we found no evidence that high levels of habitual PA are associated with glaucoma status or IOP in the general population. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Associations Between HbA1c Across the Normal Range, Diagnosed, and Undiagnosed Diabetes and Retinal Layer Thickness in UK Biobank Cohort.

Purpose: The purpose of this study was to investigate the association between glycated hemoglobin (HbA1c) levels and retinal sub-layer thicknesses in people with and without diabetes. Methods: We included 41,453 UK Biobank participants aged 40 to 69 years old. Diabetes status was defined by self-report of diagnosis or use of insulin. Participants were categorized into groups: (1) those with HbA1c <48 mmol/mol were subdivided into quintiles according to normal range of HbA1c; (2) those previously diagnosed with diabetes with no evidence of diabetic retinopathy; and (3) undiagnosed diabetes: >48 mmol/mol. Total macular and retinal sub-layer thicknesses were derived from spectral-domain optical coherence tomography (SD-OCT) images. Multivariable linear regression was used to evaluate the associations between diabetes status and retinal layer thickness. Results: Compared with participants in the second quintile of the normal HbA1c range, those in the fifth quintile had a thinner photoreceptor layer thickness (-0.33 µm, P = 0.006). Participants with diagnosed diabetes had a thinner macular retinal nerve fiber layer (mRNFL; -0.58 µm, P < 0.001), photoreceptor layer thickness (-0.94 µm, P < 0.001), and total macular thickness (-1.61 µm, P < 0.001), whereas undiagnosed diabetes participants had a reduced photoreceptor layer thickness (-1.22 µm, P = 0.009) and total macular thickness (-2.26 µm, P = 0.005). Compared to participants without diabetes, those with diabetes had a thinner mRNFL (-0.50 µm, P < 0.001), photoreceptor layer thickness (-0.77 µm, P < 0.001), and total macular thickness (-1.36 µm, P < 0.001). Conclusions: Participants with higher HbA1c in the normal range had marginally thinner photoreceptor thickness, whereas those with diabetes (including undiagnosed diabetes) had meaningfully thinner retinal sublayer and total macular thickness. Translational Relevance: We showed that early retinal neurodegeneration occurs in people whose HbA1c levels are below the current diabetes diagnostic threshold; this might impact the management of pre-diabetes individuals.

The Association of Female Reproductive Factors with Glaucoma and Related Traits: A Systematic Review.

TOPIC: This systematic review summarizes evidence for associations between female reproductive factors (age at menarche, parity, oral contraceptive [OC] use, age at menopause, and postmenopausal hormone [PMH] use) and intraocular pressure (IOP) or open-angle glaucoma (OAG). CLINICAL RELEVANCE: Understanding the associations between female reproductive factors and glaucoma may shed light on the disease pathogenesis and aid clinical prediction and personalized treatment strategies. Importantly, some factors are modifiable, which may lead to new therapies. METHODS: Two reviewers independently extracted articles in MEDLINE, Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials databases to identify relevant studies. Eligibility criteria included studies with human subjects aged > 18 years; a measured outcome of either IOP or OAG; a cohort, case-control, cross-sectional, or randomized controlled trial design; a reported measure of association, such as the hazard ratio, relative risk, odds ratio, or mean difference, with an associated confidence interval; and a measured exposure of at least 1 of the following variables: age at menarche, parity, OC use, age at menopause, or PMH use. RESULTS: We included a total of 27 studies. Substantial differences in study designs, exposure and treatment levels, treatment durations, and variable reporting precluded a meaningful quantitative synthesis of the identified studies. Overall, relatively consistent associations between PMH use and a lower IOP were identified. Estrogen-only PMH use may be associated with lower OAG risk, which may be modified by race. No significant associations were found with combined estrogen-and-progesterone PMH use. No strong associations between parity or age at menarche and glaucoma were found, but a younger age at menopause was associated with an increased glaucoma risk, and adverse associations were identified with a longer duration of OC use, though no overall association with OC use was found. CONCLUSIONS: The association between PMH use and lower IOP or OAG risk is a potentially clinically relevant and modifiable risk factor and should be investigated further, although this needs to be interpreted in the context of a high risk of bias across included studies. Future research should examine associations with IOP specifically and how the relationship between genetic factors and OAG risks may be influenced by female reproductive factors.

The Association between Serum Lipids and Intraocular Pressure in 2 Large United Kingdom Cohorts.

PURPOSE: Serum lipids are modifiable, routinely collected blood test features associated with cardiovascular health. We examined the association of commonly collected serum lipid measures (total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], and triglycerides) with intraocular pressure (IOP). DESIGN: Cross-sectional study in the UK Biobank and European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohorts. PARTICIPANTS: We included 94 323 participants from the UK Biobank (mean age, 57 years) and 6230 participants from the EPIC-Norfolk (mean age, 68 years) cohorts with data on TC, HDL-C, LDL-C, and triglycerides collected between 2006 and 2009. METHODS: Multivariate linear regression adjusting for demographic, lifestyle, anthropometric, medical, and ophthalmic covariables was used to examine the associations of serum lipids with corneal-compensated IOP (IOPcc). MAIN OUTCOME MEASURES: Corneal-compensated IOP. RESULTS: Higher levels of TC, HDL-C, and LDL-C were associated independently with higher IOPcc in both cohorts after adjustment for key demographic, medical, and lifestyle factors. For each 1-standard deviation increase in TC, HDL-C, and LDL-C, IOPcc was higher by 0.09 mmHg (95% confidence interval [CI], 0.06-0.11 mmHg; P < 0.001), 0.11 mmHg (95% CI, 0.08-0.13 mmHg; P < 0.001), and 0.07 mmHg (95% CI, 0.05-0.09 mmHg; P < 0.001), respectively, in the UK Biobank cohort. In the EPIC-Norfolk cohort, each 1-standard deviation increase in TC, HDL-C, and LDL-C was associated with a higher IOPcc by 0.19 mmHg (95% CI, 0.07-0.31 mmHg; P = 0.001), 0.14 mmHg (95% CI, 0.03-0.25 mmHg; P = 0.016), and 0.17 mmHg (95% CI, 0.06-0.29 mmHg; P = 0.003). An inverse association between triglyceride levels and IOP in the UK Biobank (-0.05 mmHg; 95% CI, -0.08 to -0.03; P < 0.001) was not replicated in the EPIC-Norfolk cohort (P = 0.30). CONCLUSIONS: Our findings suggest that serum TC, HDL-C, and LDL-C are associated positively with IOP in 2 United Kingdom cohorts and that triglyceride levels may be associated negatively. Future research is required to assess whether these associations are causal in nature.

Associations of Alcohol Consumption and Smoking With Disease Risk and Neurodegeneration in Individuals With Multiple Sclerosis in the United Kingdom.

IMPORTANCE: Understanding the effects of modifiable risk factors on risk for multiple sclerosis (MS) and associated neurodegeneration is important to guide clinical counseling. OBJECTIVE: To investigate associations of alcohol use, smoking, and obesity with odds of MS diagnosis and macular ganglion cell layer and inner plexiform layer (mGCIPL) thickness. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study analyzed data from the community-based UK Biobank study on health behaviors and retinal thickness (measured by optical coherence tomography in both eyes) in individuals aged 40 to 69 years examined from December 1, 2009, to December 31, 2010. Risk factors were identified with multivariable logistic regression analyses. To adjust for intereye correlations, multivariable generalized estimating equations were used to explore associations of alcohol use and smoking with mGCIPL thickness. Finally, interaction models explored whether the correlations of alcohol and smoking with mGCIPL thickness differed for individuals with MS. Data were analyzed from February 1 to July 1, 2021. EXPOSURES: Smoking status (never, previous, or current), alcohol intake (never or special occasions only [low], once per month to ≤4 times per week [moderate], or daily/almost daily [high]), and body mass index. MAIN OUTCOMES AND MEASURES: Multiple sclerosis case status and mGCIPL thickness. RESULTS: A total of 71 981 individuals (38 685 women [53.7%] and 33 296 men [46.3%]; mean [SD] age, 56.7 [8.0] years) were included in the analysis (20 065 healthy control individuals, 51 737 control individuals with comorbidities, and 179 individuals with MS). Modifiable risk factors significantly associated with MS case status were current smoking (odds ratio [OR], 3.05 [95% CI, 1.95-4.64]), moderate alcohol intake (OR, 0.62 [95% CI, 0.43-0.91]), and obesity (OR, 1.72 [95% CI, 1.15-2.56]) compared with healthy control individuals. Compared with the control individuals with comorbidities, only smoking was associated with case status (OR, 2.30 [95% CI, 1.48-3.51]). High alcohol intake was associated with a thinner mGCIPL in individuals with MS (adjusted ß = -3.09 [95% CI, -5.70 to -0.48] µm; P = .02). In the alcohol interaction model, high alcohol intake was associated with thinner mGCIPL in control individuals (ß = -0.93 [95% CI, -1.07 to -0.79] µm; P < .001), but there was no statistically significant association in individuals with MS (ß = -2.27 [95% CI, -4.76 to 0.22] µm; P = .07). Smoking was not associated with mGCIPL thickness in MS. However, smoking was associated with greater mGCIPL thickness in control individuals (ß = 0.89 [95% CI, 0.74-1.05 µm]; P < .001). CONCLUSIONS AND RELEVANCE: These findings suggest that high alcohol intake was associated with retinal features indicative of more severe neurodegeneration, whereas smoking was associated with higher odds of being diagnosed with MS.

Alcohol, Intraocular Pressure, and Open-Angle Glaucoma: A Systematic Review and Meta-analysis.

TOPIC: This systematic review and meta-analysis summarizes the existing evidence for the association of alcohol use with intraocular pressure (IOP) and open-angle glaucoma (OAG). CLINICAL RELEVANCE: Understanding and quantifying these associations may aid clinical guidelines or treatment strategies and shed light on disease pathogenesis. The role of alcohol, a modifiable factor, in determining IOP and OAG risk also may be of interest from an individual or public health perspective. METHODS: The study protocol was preregistered in the Open Science Framework Registries (https://osf.io/z7yeg). Eligible articles (as of May 14, 2021) from 3 databases (PubMed, Embase, Scopus) were independently screened and quality assessed by 2 reviewers. All case-control, cross-sectional, and cohort studies reporting a quantitative effect estimate and 95% confidence interval (CI) for the association between alcohol use and either IOP or OAG were included. The evidence for the associations with both IOP and OAG was qualitatively summarized. Effect estimates for the association with OAG were pooled using random effects meta-analysis. Studies not meeting formal inclusion criteria for systematic review, but with pertinent results, were also appraised and discussed. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. RESULTS: Thirty-four studies were included in the systematic review. Evidence from 10 studies reporting an association with IOP suggests that habitual alcohol use is associated with higher IOP and prevalence of ocular hypertension (IOP > 21 mmHg), although absolute effect sizes were small. Eleven of 26 studies, comprising 173 058 participants, that tested for an association with OAG met inclusion criteria for meta-analysis. Pooled effect estimates indicated a positive association between any use of alcohol and OAG (1.18; 95% confidence interval [CI], 1.02-1.36; P = 0.03; I2 = 40.5%), with similar estimates for both prevalent and incident OAG. The overall GRADE certainty of evidence was very low. CONCLUSIONS: Although this meta-analysis suggests a harmful association between alcohol use and OAG, our results should be interpreted cautiously given the weakness and heterogeneity of the underlying evidence base, the small absolute effect size, and the borderline statistical significance. Nonetheless, these findings may be clinically relevant, and future research should focus on improving the quality of evidence.

Association of ambient air pollution with age-related macular degeneration and retinal thickness in UK Biobank.

AIM: To examine the associations of air pollution with both self-reported age-related macular degeneration (AMD), and in vivo measures of retinal sublayer thicknesses. METHODS: We included 115 954 UK Biobank participants aged 40-69 years old in this cross-sectional study. Ambient air pollution measures included particulate matter, nitrogen dioxide (NO2) and nitrogen oxides (NOx). Participants with self-reported ocular conditions, high refractive error (< -6 or > +6 diopters) and poor spectral-domain optical coherence tomography (SD-OCT) image were excluded. Self-reported AMD was used to identify overt disease. SD-OCT imaging derived photoreceptor sublayer thickness and retinal pigment epithelium (RPE) layer thickness were used as structural biomarkers of AMD for 52 602 participants. We examined the associations of ambient air pollution with self-reported AMD and both photoreceptor sublayers and RPE layer thicknesses. RESULTS: After adjusting for covariates, people who were exposed to higher fine ambient particulate matter with an aerodynamic diameter <2.5 µm (PM2.5, per IQR increase) had higher odds of self-reported AMD (OR=1.08, p=0.036), thinner photoreceptor synaptic region (ß=-0.16 µm, p=2.0 × 10-5), thicker photoreceptor inner segment layer (ß=0.04 µm, p=0.001) and thinner RPE (ß=-0.13 µm, p=0.002). Higher levels of PM2.5 absorbance and NO2 were associated with thicker photoreceptor inner and outer segment layers, and a thinner RPE layer. Higher levels of PM10 (PM with an aerodynamic diameter <10 µm) was associated with thicker photoreceptor outer segment and thinner RPE, while higher exposure to NOx was associated with thinner photoreceptor synaptic region. CONCLUSION: Greater exposure to PM2.5 was associated with self-reported AMD, while PM2.5, PM2.5 absorbance, PM10, NO2 and NOx were all associated with differences in retinal layer thickness.

The Association of Ambient Air Pollution With Cataract Surgery in UK Biobank Participants: Prospective Cohort Study.

Purpose: Air pollution is associated with chronic diseases of later life. Cataract is the most common cause of blindess globally. It is biologically plausible that cataract risk is increased by pollution exposure. Therefore, the relationship between air pollution and incident cataract surgery was examined. Methods: This was a prospective, observational study involving 433,727 UK Biobank participants. Ambient air pollution measures included particulates, nitrogen dioxide (NO2) and nitrogen oxides (NOx). Outdoor air pollution was estimated based on land use regression models. Participants undergoing cataract surgery in either eye were ascertained via data linkage to the National Health Service procedure statistics. Those undergoing cataract surgery within 1 year of baseline assessment and those reporting cataract at baseline were excluded. Cox proportional hazards models were used to examine the associations between air pollutants and incident cataract surgery, adjusting for sociodemographic and lifestyle factors. Results: There were 16,307 incident cases of cataract surgery. Higher exposure to PM2.5 was associated with a 5% increased risk of incident cataract surgery (per interquartile range [IQR] increase). Compared to the lowest quartile, participants with exposures to PM2.5, NO2, and NOx in the highest quartile were 14%, 11%, and 9% more likely to undergo cataract surgery, respectively. A continuous exposure-response relationship was observed, with the likelihood of undergoing cataract surgery being progressively higher with greater levels of PM2.5, NO2, and NOx (P for trend P < 0.001). Conclusions: Although the results of our study showed a 5% increased risk of future cataract surgery following an exposure to PM2.5, NO2, and NOx, the effect estimates were relatively small. Further research is required to determine if the associations identified are causal.

Detecting retinal neurodegeneration in people with diabetes: Findings from the UK Biobank.

IMPORTANCE: Efforts are underway to incorporate retinal neurodegeneration in the diabetic retinopathy severity scale. However, there is no established measure to quantify diabetic retinal neurodegeneration (DRN). OBJECTIVE: We compared total retinal, macular retinal nerve fiber layer (mRNFL) and ganglion cell-inner plexiform layer (GC-IPL) thickness among participants with and without diabetes (DM) in a population-based cohort. DESIGN/SETTING/PARTICIPANTS: Cross-sectional analysis, using the UK Biobank data resource. Separate general linear mixed models (GLMM) were created using DM and glycated hemoglobin as predictor variables for retinal thickness. Sub-analyses included comparing thickness measurements for patients with no/mild diabetic retinopathy (DR) and evaluating factors associated with retinal thickness in participants with and without diabetes. Factors found to be significantly associated with DM or thickness were included in a multiple GLMM. EXPOSURE: Diagnosis of DM was determined via self-report of diagnosis, medication use, DM-related complications or glycated hemoglobin level of ≥ 6.5%. MAIN OUTCOMES AND MEASURES: Total retinal, mRNFL and GC-IPL thickness. RESULTS: 74,422 participants (69,985 with no DM; 4,437 with DM) were included. Median age was 59 years, 46% were men and 92% were white. Participants with DM had lower total retinal thickness (-4.57 µm, 95% CI: -5.00, -4.14; p<0.001), GC-IPL thickness (-1.73 µm, 95% CI: -1.86, -1.59; p<0.001) and mRNFL thickness (-0.68 µm, 95% CI: -0.81, -0.54; p<0.001) compared to those without DM. After adjusting for co-variates, in the GLMM, total retinal thickness was 1.99 um lower (95% CI: -2.47, -1.50; p<0.001) and GC-IPL was 1.02 µm lower (95% CI: -1.18, -0.87; p<0.001) among those with DM compared to without. mRNFL was no longer significantly different (p = 0.369). GC-IPL remained significantly lower, after adjusting for co-variates, among those with DM compared to those without DM when including only participants with no/mild DR (-0.80 µm, 95% CI: -0.98, -0.62; p<0.001). Total retinal thickness decreased 0.40 µm (95% CI: -0.61, -0.20; p<0.001), mRNFL thickness increased 0.20 µm (95% CI: 0.14, 0.27; p<0.001) and GC-IPL decreased 0.26 µm (95% CI: -0.33, -0.20; p<0.001) per unit increase in A1c after adjusting for co-variates. Among participants with diabetes, age, DR grade, ethnicity, body mass index, glaucoma, spherical equivalent, and visual acuity were significantly associated with GC-IPL thickness. CONCLUSION: GC-IPL was thinner among participants with DM, compared to without DM. This difference persisted after adjusting for confounding variables and when considering only those with no/mild DR. This confirms that GC-IPL thinning occurs early in DM and can serve as a useful marker of DRN.

Alcohol Consumption and Incident Cataract Surgery in Two Large UK Cohorts.

PURPOSE: To examine the association of alcohol consumption and type of alcoholic beverage with incident cataract surgery in 2 large cohorts. DESIGN: Longitudinal, observational study. PARTICIPANTS: We included 469 387 participants of UK Biobank with a mean age of 56 years and 23 162 participants of European Prospective Investigation of Cancer (EPIC)-Norfolk with a mean age of 59 years. METHODS: Self-reported alcohol consumption at baseline was ascertained by a touchscreen questionnaire in UK Biobank and a food-frequency questionnaire in EPIC-Norfolk. Cases were defined as participants undergoing cataract surgery in either eye as ascertained via data linkage to National Health Service procedure statistics. We excluded participants with cataract surgery up to 1 year after the baseline assessment visit or those with self-reported cataract at baseline. Cox proportional hazards models were used to examine the associations of alcohol consumption with incident cataract surgery, adjusted for age, sex, ethnicity, Townsend deprivation index, body mass index (BMI), smoking, and diabetes status. MAIN OUTCOME MEASURES: Incident cataract surgery. RESULTS: There were 19 011 (mean cohort follow-up of 95 months) and 4573 (mean cohort follow-up of 193 months) incident cases of cataract surgery in UK Biobank and EPIC-Norfolk, respectively. Compared with nondrinkers, drinkers were less likely to undergo cataract surgery in UK Biobank (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.85-0.93) and EPIC-Norfolk (HR, 0.90; 95% CI, 0.84-0.97) after adjusting for covariables. Among alcohol consumers, greater alcohol consumption was associated with a reduced risk of undergoing cataract surgery in EPIC-Norfolk (P < 0.001), whereas a U-shaped association was observed in the UK Biobank. Compared with nondrinkers, subgroup analysis by type of alcohol beverage showed the strongest protective association with wine consumption; the risk of incident cataract surgery was 23% and 14% lower among those in the highest category of wine consumption in EPIC-Norfolk and UK Biobank, respectively. CONCLUSIONS: Our findings suggest a lower risk of undergoing cataract surgery with low to moderate alcohol consumption. The association was particularly apparent with wine consumption. We cannot exclude the possibility of residual confounding, and further studies are required to determine whether this association is causal in nature.

Relationships between retinal layer thickness and brain volumes in the UK Biobank cohort.

BACKGROUND AND PURPOSE: Current methods to diagnose neurodegenerative diseases are costly and invasive. Retinal neuroanatomy may be a biomarker for more neurodegenerative processes and can be quantified in vivo using optical coherence tomography (OCT), which is inexpensive and noninvasive. We examined the association of neuroretinal morphology with brain MRI image-derived phenotypes (IDPs) in a large cohort of healthy older people. METHODS: UK Biobank participants aged 40 to 69 years old underwent comprehensive examinations including ophthalmic and brain imaging assessments. Macular retinal nerve fibre layer (mRNFL), macular ganglion cell-inner plexiform layer (mGCIPL), macular ganglion cell complex (mGCC) and total macular thicknesses were obtained from OCT. Magnetic resonance imaging (MRI) IDPs assessed included total brain, grey matter, white matter and hippocampal volume. Multivariable linear regression models were used to evaluate associations between retinal layers thickness and brain MRI IDPs, adjusting for demographic factors and vascular risk factors. RESULTS: A total of 2131 participants (mean age 55 years; 51% women) with both gradable OCT images and brain imaging assessments were included. In multivariable regression analysis, thinner mGCIPL, mGCC and total macular thickness were all significantly associated with smaller total brain (p < 0.001), grey matter and white matter volume (p < 0.01), and grey matter volume in the occipital pole (p < 0.05). Thinner mGCC and total macular thicknesses were associated with smaller hippocampal volume (p < 0.02). No association was found between mRNFL and the MRI IDPs. CONCLUSIONS: Markers of retinal neurodegeneration are associated with smaller brain volumes. Our findings suggest that retinal structure may be a biomarker providing information about important brain structure in healthy older adults.

Retinal asymmetry in multiple sclerosis.

The diagnosis of multiple sclerosis is based on a combination of clinical and paraclinical tests. The potential contribution of retinal optical coherence tomography (OCT) has been recognized. We tested the feasibility of OCT measures of retinal asymmetry as a diagnostic test for multiple sclerosis at the community level. In this community-based study of 72 120 subjects, we examined the diagnostic potential of the inter-eye difference of inner retinal OCT data for multiple sclerosis using the UK Biobank data collected at 22 sites between 2007 and 2010. OCT reporting and quality control guidelines were followed. The inter-eye percentage difference (IEPD) and inter-eye absolute difference (IEAD) were calculated for the macular retinal nerve fibre layer (RNFL), ganglion cell inner plexiform layer (GCIPL) complex and ganglion cell complex. Area under the receiver operating characteristic curve (AUROC) comparisons were followed by univariate and multivariable comparisons accounting for a large range of diseases and co-morbidities. Cut-off levels were optimized by ROC and the Youden index. The prevalence of multiple sclerosis was 0.0023 [95% confidence interval (CI) 0.00229-0.00231]. Overall the discriminatory power of diagnosing multiple sclerosis with the IEPD AUROC curve (0.71, 95% CI 0.67-0.76) and IEAD (0.71, 95% CI 0.67-0.75) for the macular GCIPL complex were significantly higher if compared to the macular ganglion cell complex IEPD AUROC curve (0.64, 95% CI 0.59-0.69, P = 0.0017); IEAD AUROC curve (0.63, 95% CI 0.58-0.68, P < 0.0001) and macular RNFL IEPD AUROC curve (0.59, 95% CI 0.54-0.63, P < 0.0001); IEAD AUROC curve (0.55, 95% CI 0.50-0.59, P < 0.0001). Screening sensitivity levels for the macular GCIPL complex IEPD (4% cut-off) were 51.7% and for the IEAD (4 µm cut-off) 43.5%. Specificity levels were 82.8% and 86.8%, respectively. The number of co-morbidities was important. There was a stepwise decrease of the AUROC curve from 0.72 in control subjects to 0.66 in more than nine co-morbidities or presence of neuromyelitis optica spectrum disease. In the multivariable analyses greater age, diabetes mellitus, other eye disease and a non-white ethnic background were relevant confounders. For most interactions, the effect sizes were large (partial ω2 > 0.14) with narrow confidence intervals. In conclusion, the OCT macular GCIPL complex IEPD and IEAD may be considered as supportive measurements for multiple sclerosis diagnostic criteria in a young patient without relevant co-morbidity. The metric does not allow separation of multiple sclerosis from neuromyelitis optica. Retinal OCT imaging is accurate, rapid, non-invasive, widely available and may therefore help to reduce need for invasive and more costly procedures. To be viable, higher sensitivity and specificity levels are needed.

Ambient Air Pollution Associations with Retinal Morphology in the UK Biobank.

Purpose: Because air pollution has been linked to glaucoma and AMD, we characterized the relationship between pollution and retinal structure. Methods: We examined data from 51,710 UK Biobank participants aged 40 to 69 years old. Ambient air pollution measures included particulates and nitrogen oxides. SD-OCT imaging measured seven retinal layers: retinal nerve fiber layer, ganglion cell-inner plexiform layer, inner nuclear layer, outer plexiform layer + outer nuclear layer, photoreceptor inner segments, photoreceptor outer segments, and RPE. Multivariable regression was used to evaluate associations between pollutants (per interquartile range increase) and retinal thickness, adjusting for age, sex, race, Townsend deprivation index, body mass index, smoking status, and refractive error. Results: Participants exposed to greater particulate matter with an aerodynamic diameter of <2.5 µm (PM2.5) and higher nitrogen oxides were more likely to have thicker retinal nerve fiber layer (ß = 0.28 µm; 95% CI, 0.22-0.34; P = 3.3 × 10-20 and ß = 0.09 µm; 95% CI, 0.04-0.14; P = 2.4 × 10-4, respectively), and thinner ganglion cell-inner plexiform layer, inner nuclear layer, and outer plexiform layer + outer nuclear layer thicknesses (P < 0.001). Participants resident in areas of higher levels of PM2.5 absorbance were more likely to have thinner retinal nerve fiber layer, inner nuclear layer, and outer plexiform layer + outer nuclear layers (ß = -0.16 [95% CI, -0.22 to -0.10; P = 5.7 × 10-8]; ß = -0.09 [95% CI, -0.12 to -0.06; P = 2.2 × 10-12]; and ß = -0.12 [95% CI, -0.19 to -0.05; P = 8.3 × 10-4], respectively). Conclusions: Greater exposure to PM2.5, PM2.5 absorbance, and nitrogen oxides were all associated with apparently adverse retinal structural features.

Comparison of Associations with Different Macular Inner Retinal Thickness Parameters in a Large Cohort: The UK Biobank.

PURPOSE: To describe and compare associations with macular retinal nerve fiber layer (mRNFL), ganglion cell complex (GCC), and ganglion cell-inner plexiform layer (GCIPL) thicknesses in a large cohort. DESIGN: Cross-sectional study. PARTICIPANTS: We included 42 044 participants in the UK Biobank. The mean age was 56 years. METHODS: Spectral-domain OCT macular images were segmented and analyzed. Corneal-compensated intraocular pressure (IOPcc) was measured with the Ocular Response Analyzer (Reichert, Corp., Buffalo, NY). Multivariable linear regression was used to examine associations with mean mRNFL, GCC, and GCIPL thicknesses. Factors examined were age, sex, ethnicity, height, body mass index (BMI), smoking status, alcohol intake, Townsend deprivation index, education level, diabetes status, spherical equivalent, and IOPcc. MAIN OUTCOME MEASURES: Thicknesses of mRNFL, GCC, and GCIPL. RESULTS: We identified several novel independent associations with thinner inner retinal thickness. Thinner inner retina was associated with alcohol intake (most significant for GCIPL: -0.46 µm for daily or almost daily intake compared with special occasion only or never [95% confidence interval (CI), 0.61-0.30]; P = 1.1×10-8), greater social deprivation (most significant for GCIPL: -0.28 µm for most deprived quartile compared with least deprived quartile [95% CI, -0.42 to -0.14]; P = 6.6×10-5), lower educational attainment (most significant for mRNFL: -0.36 µm for less than O level compared with degree level [95% CI, -0.45 to 0.26]; P = 2.3×10-14), and nonwhite ethnicity (most significant for mRNFL comparing blacks with whites: -1.65 µm [95% CI, -1.86 to -1.43]; P = 2.4×10-50). Corneal-compensated intraocular pressure was associated most significantly with GCIPL (-0.04 µm/mmHg [95% CI, -0.05 to -0.03]; P = 4.0×10-10) and was not associated significantly with mRNFL (0.00 µm/mmHg [95% CI, -0.01 to 0.01]; P = 0.77). The variables examined explained a greater proportion of the variance of GCIPL (11%) than GCC (6%) or mRNFL (7%). CONCLUSIONS: The novel associations we identified may be important to consider when using inner retinal parameters as a diagnostic tool. Associations generally were strongest with GCIPL, particularly for IOP. This suggests that GCIPL may be the superior inner retinal biomarker for macular pathophysiologic processes and especially for glaucoma.

Heavy metal toxicity and the aetiology of glaucoma.

Despite recent advances, our understanding of the aetiological mechanisms underlying glaucoma remains incomplete. Heavy metals toxicity has been linked to the development of neurodegenerative diseases and various ocular pathologies. Given the similarities in pathophysiology between glaucoma and some neurodegenerative disorders, it is plausible that heavy metal toxicity may play a role in the development of glaucoma. Heavy metal exposure may be occupational, or through water or dietary contamination. In this report, we review mechanisms for systemic and neurotoxicity for arsenic, cadmium, chromium, cobalt, lead, mercury, and manganese, and weigh the evidence for an association between glaucoma and the accumulation of heavy metals either in ocular tissues or in the central nervous system.

Associations with photoreceptor thickness measures in the UK Biobank.

Spectral-domain OCT (SD-OCT) provides high resolution images enabling identification of individual retinal layers. We included 32,923 participants aged 40-69 years old from UK Biobank. Questionnaires, physical examination, and eye examination including SD-OCT imaging were performed. SD OCT measured photoreceptor layer thickness includes photoreceptor layer thickness: inner nuclear layer-retinal pigment epithelium (INL-RPE) and the specific sublayers of the photoreceptor: inner nuclear layer-external limiting membrane (INL-ELM); external limiting membrane-inner segment outer segment (ELM-ISOS); and inner segment outer segment-retinal pigment epithelium (ISOS-RPE). In multivariate regression models, the total average INL-RPE was observed to be thinner in older aged, females, Black ethnicity, smokers, participants with higher systolic blood pressure, more negative refractive error, lower IOPcc and lower corneal hysteresis. The overall INL-ELM, ELM-ISOS and ISOS-RPE thickness was significantly associated with sex and race. Total average of INL-ELM thickness was additionally associated with age and refractive error, while ELM-ISOS was additionally associated with age, smoking status, SBP and refractive error; and ISOS-RPE was additionally associated with smoking status, IOPcc and corneal hysteresis. Hence, we found novel associations of ethnicity, smoking, systolic blood pressure, refraction, IOPcc and corneal hysteresis with photoreceptor thickness.

The Relationship Between Ambient Atmospheric Fine Particulate Matter (PM2.5) and Glaucoma in a Large Community Cohort.

Purpose: Glaucoma is more common in urban populations than in others. Ninety percent of the world's population are exposed to air pollution above World Health Organization (WHO) recommended limits. Few studies have examined the association between air pollution and glaucoma. Methods: Questionnaire data, ophthalmic measures, and ambient residential area air quality data for 111,370 UK Biobank participants were analyzed. Particulate matter with an aerodynamic diameter < 2.5 µm (PM2.5) was selected as the air quality exposure of interest. Eye measures included self-reported glaucoma, intraocular pressure (IOP), and average thickness of macular ganglion cell-inner plexiform layer (GCIPL) across nine Early Treatment Diabetic Retinopathy Study (ETDRS) retinal subfields as obtained from spectral-domain optical coherence tomography. We examined the associations of PM2.5 concentration with self-reported glaucoma, IOP, and GCIPL. Results: Participants resident in areas with higher PM2.5 concentration were more likely to report a diagnosis of glaucoma (odds ratio = 1.06, 95% confidence interval [CI] = 1.01-1.12, per interquartile range [IQR] increase P = 0.02). Higher PM2.5 concentration was also associated with thinner GCIPL (ß = -0.56 µm, 95% CI = -0.63 to -0.49, per IQR increase, P = 1.2 × 10-53). A dose-response relationship was observed between higher levels of PM2.5 and thinner GCIPL (P < 0.001). There was no clinically relevant relationship between PM2.5 concentration and IOP. Conclusions: Greater exposure to PM2.5 is associated with both self-reported glaucoma and adverse structural characteristics of the disease. The absence of an association between PM2.5 and IOP suggests the relationship may occur through a non-pressure-dependent mechanism, possibly neurotoxic and/or vascular effects.

Frequency and distribution of corneal astigmatism and keratometry features in adult life: Methodology and findings of the UK Biobank study.

PURPOSE: To describe corneal astigmatism in the UK Biobank population and to look for associations with other biometric variables and socio-demographic factors. METHODS: This analysis included a subsample of 107,452 participants of the UK Biobank study who underwent an enhanced ophthalmic examination including autorefractor keratometry (Tomey RC 5000, Tomey Corp., Nagoya, Japan). Participants were recruited from across the United Kingdom between 2006 and 2010, and all were between 40 to 69 years. After quality control and applying relevant exclusions, data on corneal astigmatism on 83,751 participants were included for analysis. Potential associations were tested through univariable regression and significant parameters carried forward for multivariable analysis. RESULTS: In univariable analysis, the characteristics significantly associated with higher corneal astigmatism (P<0.001), by order of magnitude were, female gender, white ethnicity, lighter skin colour, use of UV protection, lower alcohol intake, lower corneal-compensated intraocular pressure (ccIOP), older age at completion of education, younger age, higher Townsend deprivation index, lower height and lower systolic blood pressure. After inclusion in the multivariable analysis, gender, skin colour, alcohol intake, age at completion of full-time education, ccIOP, age and Townsend deprivation score remained significant (all P<0.001). Increased corneal astigmatism was also found to be significantly associated with amblyopia or strabismus. CONCLUSIONS: This analysis confirms previous associations with astigmatism such as younger age and female gender, and identified novel risk factors including lighter skin colour, lower alcohol intake, later age having completed full time education later, lower ccIOP and higher Townsend deprivation index. Further research is needed to investigate these novel associations.

Cohort profile: design and methods in the eye and vision consortium of UK Biobank.

PURPOSE: To describe the rationale, methods and research potential of eye and vision measures available in UK Biobank. PARTICIPANTS: UK Biobank is a large, multisite, prospective cohort study. Extensive lifestyle and health questionnaires, a range of physical measures and collection of biological specimens are collected. The scope of UK Biobank was extended midway through data collection to include assessments of other measures of health, including eyes and vision. The eye assessment at baseline included questionnaires detailing past ophthalmic and family history, measurement of visual acuity, refractive error and keratometry, intraocular pressure (IOP), corneal biomechanics, spectral domain optical coherence tomography (OCT) of the macula and a disc-macula fundus photograph. Since recruitment, UK Biobank has collected accelerometer data and begun multimodal imaging data (including brain, heart and abdominal MRI) in 100 000 participants. Dense genotypic data and a panel of 20 biochemistry measures are available, and linkage to medical health records for the full cohort has begun. FINDINGS TO DATE: A total of 502 665 people aged between 40 and 69 were recruited to participate in UK Biobank. Of these, 117 175 took part in baseline assessment of vision, IOP, refraction and keratometry. A subgroup of 67 321 underwent OCT and retinal photography. The introduction of eye and vision measures in UK Biobank was accompanied by intensive training, support and a data monitoring quality control process. FUTURE PLANS: UK Biobank is one of the largest prospective cohorts worldwide with extensive data on ophthalmic diseases and conditions. Data collection is an ongoing process and a repeat of the baseline assessment including the questionnaires, measurements and sample collection will be performed in subsets of 25 000 participants every 2-3 years. The depth and breadth of this dataset, coupled with its open-access policy, will create a powerful resource for all researchers to investigate the eye diseases in later life.