Metabolite and Lipid Biomarkers Associated With Intraocular Pressure and Inner Retinal Morphology: ¹H NMR Spectroscopy Results From the UK Biobank

Purpose: The purpose of this study was to assess metabolites associated with intraocular pressure (IOP) and inner retina structure. / Methods: We cross-sectionally assessed 168 non-fasting plasma metabolites measured by nuclear magnetic resonance (NMR) spectroscopy with IOP (n = 28,195), macular retinal nerve fiber layer thickness (mRNFL; n = 10,584), and macular ganglion cell inner plexiform layer thickness (mGCIPL; n = 10,554) in the UK Biobank. We used multiple linear regression models adjusting for various covariates with probit-transformed metabolite levels as predictors for each outcome. Each estimate represents the difference in outcome variable per standard deviation increase in the probit-transformed metabolite values. We used the number of effective (NEF) tests and false discovery rate (FDR) to adjust for multiple comparisons for metabolites and metabolite classes, respectively. / Results: In individual metabolite analysis, multiple amino acids, especially branched-chain amino acids, were associated with lower IOP (-0.12 mm Hg; 95% confidence interval = -0.16 to -0.07; NEF = 2.7E-05). Albumin, 3 hydroxybutyrate, lactate, and several lipids were associated with higher IOP (range = 0.07 to 0.18 mm Hg, NEF = ≤ 0.039). In IOP-adjusted analyses, five HDL-related metabolites were associated with thinner mRNFL (-0.15 microns for all metabolites, NEF = ≤ 0.027), whereas five LDL-related metabolites were associated with thicker mGCIPL (range = 0.17 to 0.20 microns; NEF = ≤ 0.044). In metabolite class analysis, the lipid components of lipoproteins (cholesterol, triglycerides, etc.) were not associated with our outcomes (FDR > 0.2 for all); yet multiple lipoproteins were significantly (FDR < 0.05) associated with all outcomes. / Conclusions: Branched-chain amino acids were associated with lower IOP, HDL metabolites were associated with thinner mRNFL, and LDL metabolites were associated with thicker mGCIPL

Statin Use in Relation to Intraocular Pressure, Glaucoma, and Ocular Coherence Tomography Parameters in the UK Biobank

PURPOSE. The purpose of this study was to evaluate the relationship between statin use and glaucoma-related traits. METHODS. In a cross-sectional study, we included 118,153 UK Biobank participants with data on statin use and corneal-compensated IOP. In addition, we included 192,283 participants (8982 cases) with data on glaucoma status. After excluding participants with neurodegenerative diseases, 41,638 participants with macular retinal nerve fiber layer thickness (mRNFL) and 41,547 participants with macular ganglion cell inner plexiform layer thickness (mGCIPL) were available for analysis. We examined associations of statin use with IOP, mRNFL, mGCIPL, and glaucoma status utilizing multivariable-adjusted regression models. We assessed whether a glaucoma polygenic risk score (PRS) modified associations. We performed Mendelian randomization (MR) experiments to investigate associations with various glaucoma-related outcomes. RESULTS. Statin users had higher unadjusted mean IOP ± SD than nonusers, but in a multivariable-adjusted model, IOP did not differ by statin use (difference = 0.05 mm Hg, 95% confidence interval [CI] = −0.02 to 0.13, P = 0.17). Similarly, statin use was not associated with prevalent glaucoma (odds ratio [OR] = 1.05, 95% CI = 0.98 to 1.13). Statin use was weakly associated with thinner mRNFL (difference = −0.15 microns, 95% CI = −0.28 to −0.01, P = 0.03) but not with mGCIPL thickness (difference = −0.12 microns, 95% CI = −0.29 to 0.05, P = 0.17). No association was modified by the glaucoma PRS (Pinteraction ≥ 0.16). MR experiments showed no evidence for a causal association between the cholesterol-altering effect of statins and several glaucoma traits (inverse weighted variance P ≥ 0.14). CONCLUSIONS. We found no evidence of a protective association between statin use and glaucoma or related traits after adjusting for key confounders

Intraocular pressure, glaucoma and dietary caffeine consumption: a gene-diet interaction study from the UK Biobank

Objective: We examined the association of habitual caffeine intake with intraocular pressure (IOP) and glaucoma and whether these associations were modified by genetic predisposition to higher IOP. We also assessed whether genetic predisposition to higher coffee consumption was related to IOP. Design: A cross-sectional study in the UK Biobank. Participants: We included 121,374 participants (baseline ages 39-73 years) with data on coffee and tea intake (collected 2006-2010) and corneal-compensated IOP measurements in 2009. In a subset of 77,906 participants with up to five web-based 24-hour-recall food frequency questionnaires (2009-2012) we evaluated total caffeine intake. We also assessed the same relations with any glaucoma (9,286 cases and 189,763 controls). Method: We evaluated multivariable-adjusted associations with IOP using linear regression, and with glaucoma using logistic regression. For both outcomes, we examined gene-diet interactions, using a polygenic risk score (PRS), which combined the effects of 111 genetic variants associated with IOP. We also performed two-sample Mendelian Randomization (MR) using 8 genetic variants associated with coffee intake, to assess potential causal effects of coffee consumption on IOP. Main Outcome and Measures: IOP; glaucoma. Results: Mean IOP was 16.0 mmHg (Standard Deviation=3.8). MR analysis did not support a causal effect of coffee drinking on IOP (P>0.1). Greater caffeine intake was weakly associated with lower IOP: the highest (≥232mg/day) vs. lowest (480mg/day versus <80 mg/day was associated with a 0.35 mmHg higher IOP (Pinteraction=0.01). The relation between caffeine intake and glaucoma was null (P≥0.1). However, this relation was also significantly modified by IOP PRS: compared to those in the lowest IOP PRS quartile consuming no caffeine, those in the highest IOP PRS quartile consuming ≥321mg/day had a 3.90-fold higher glaucoma prevalence (Pinteraction=0.0003). Conclusions: Habitual caffeine consumption was weakly associated with lower IOP and the association between caffeine consumption and glaucoma was null. However, among participants with the strongest genetic predisposition to elevated IOP, greater caffeine consumption was associated with higher IOP and higher glaucoma prevalence

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

Family-based Genome-wide Association Study of South Indian Pedigrees Supports WNT7B as a Central Corneal Thickness Locus

Purpose To identify genetic risk factors contributing to central corneal thickness (CCT) in individuals from South India, a population with a high prevalence of ocular disorders. Methods: One hundred ninety-five individuals from 15 large South Indian pedigrees were genotyped using the Omni2.5 bead array. Family-based association for CCT was conducted using the score test in MERLIN. Results: Genome-wide association study (GWAS) identified strongest association for single nucleotide polymorphisms (SNPs) in the first intron of WNT7B and CCT (top SNP rs9330813; β = −0.57, 95% confidence interval [CI]: −0.78 to −0.36; P = 1.7 × 10−7). We further investigated rs9330813 in a Latino cohort and four independent European cohorts. A meta-analysis of these data sets demonstrated statistically significant association between rs9330813 and CCT (β = −3.94, 95% CI: −5.23 to −2.66; P = 1.7 × 10−9). WNT7B SNPs located in the same genomic region that includes rs9330813 have previously been associated with CCT in Latinos but with other ocular quantitative traits related to myopia (corneal curvature and axial length) in a Japanese population (rs10453441 and rs200329677). To evaluate the specificity of the observed WNT7B association with CCT in the South Indian families, we completed an ocular phenome-wide association study (PheWAS) for the top WNT7B SNPs using 45 ocular traits measured in these same families including corneal curvature and axial length. The ocular PheWAS results indicate that in the South Indian families WNT7B SNPs are primarily associated with CCT. Conclusions: The results indicate robust evidence for association between WNT7B SNPs and CCT in South Indian pedigrees, and suggest that WNT7B SNPs can have population-specific effects on ocular quantitative traits

Neonatal-onset multisystem inflammatory disease responsive to interleukin-1 beta inhibition

BACKGROUND:Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation.METHODS:We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist (1 to 2 mg per kilogram of body weight per day subcutaneously). In 11 patients, anakinra was withdrawn at three months until a flare occurred. The primary end points included changes in scores in a daily diary of symptoms, serum levels of amyloid A and C-reactive protein, and the erythrocyte sedimentation rate from baseline to month 3 and from month 3 until a disease flare.RESULTS:All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events.CONCLUSIONS:Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations

DNA sequence variants in the LOXL1 gene are associated with pseudoexfoliation glaucoma in a U.S. clinic-based population with broad ethnic diversity

<p>Abstract</p> <p>Background</p> <p>Pseudoexfoliation syndrome is a major risk factor for glaucoma in many populations throughout the world. Using a U.S. clinic-based case control sample with broad ethnic diversity, we show that three common SNPs in LOXL1 previously associated with pseudoexfoliation in Nordic populations are significantly associated with pseudoexfoliation syndrome and pseudoexfoliation glaucoma.</p> <p>Methods</p> <p>Three LOXL1 SNPs were genotyped in a patient sample (206 pseudoexfoliation, 331 primary open angle glaucoma, and 88 controls) from the Glaucoma Consultation Service at the Massachusetts Eye and Ear Infirmary. The SNPs were evaluation for association with pseudeoexfoliation syndrome, pseudoexfoliation glaucoma, and primary open angle glaucoma.</p> <p>Results</p> <p>The strongest association was found for the G allele of marker rs3825942 (G153D) with a frequency of 99% in pseudoexfoliation patients (with and without glaucoma) compared with 79% in controls (p = 1.6 × 10^-15; OR = 20.93, 95%CI: 8.06, 54.39). The homozygous GG genotype is also associated with pseudoexfoliation when compared to controls (p = 1.2 × 10^-12; OR = 23.57, 95%CI: 7.95, 69.85). None of the SNPs were significantly associated with primary open angle glaucoma.</p> <p>Conclusion</p> <p>The pseudoexfoliation syndrome is a common cause of glaucoma. These results indicate that the G153D LOXL1 variant is significantly associated with an increased risk of pseudoexfoliation and pseudoexfoliation glaucoma in an ethnically diverse patient population from the Northeastern United States. Given the high prevalence of pseudooexfoliation in this geographic region, these results also indicate that the G153D LOXL1 variant is a significant risk factor for adult-onset glaucoma in this clinic based population.</p

Disentangling the genetic overlap and causal relationships between primary open-angle glaucoma, brain morphology and four major neurodegenerative disorders

BACKGROUND: Primary open-angle glaucoma (POAG) is an optic neuropathy characterized by progressive degeneration of the optic nerve that leads to irreversible visual impairment. Multiple epidemiological studies suggest an association between POAG and major neurodegenerative disorders (Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Parkinson's disease). However, the nature of the overlap between neurodegenerative disorders, brain morphology and glaucoma remains inconclusive. METHOD: In this study, we performed a comprehensive assessment of the genetic and causal relationship between POAG and neurodegenerative disorders, leveraging genome-wide association data from studies of magnetic resonance imaging of the brain, POAG, and four major neurodegenerative disorders. FINDINGS: This study found a genetic overlap and causal relationship between POAG and its related phenotypes (i.e., intraocular pressure and optic nerve morphology traits) and brain morphology in 19 regions. We also identified 11 loci with a significant local genetic correlation and a high probability of sharing the same causal variant between neurodegenerative disorders and POAG or its related phenotypes. Of interest, a region on chromosome 17 corresponding to MAPT, a well-known risk locus for Alzheimer's and Parkinson's disease, was shared between POAG, optic nerve degeneration traits, and Alzheimer's and Parkinson's diseases. Despite these local genetic overlaps, we did not identify strong evidence of a causal association between these neurodegenerative disorders and glaucoma. INTERPRETATION: Our findings indicate a distinctive and likely independent neurodegenerative process for POAG involving several brain regions although several POAG or optic nerve degeneration risk loci are shared with neurodegenerative disorders, consistent with a pleiotropic effect rather than a causal relationship between these traits. FUNDING: PG was supported by an NHMRC Investigator Grant (#1173390), SM by an NHMRC Senior Research Fellowship and an NHMRC Program Grant (APP1150144), DM by an NHMRC Fellowship, LP is funded by the NEI EY015473 and EY032559 grants, SS is supported by an NIH-Oxford Cambridge Fellowship and NIH T32 grant (GM136577), APK is supported by a UK Research and Innovation Future Leaders Fellowship, an Alcon Research Institute Young Investigator Award and a Lister Institute for Preventive Medicine Award

Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary open-angle glaucoma.

Glaucoma is the leading cause of irreversible blindness globally 1 . Despite its gravity, the disease is frequently undiagnosed in the community 2 . Raised intraocular pressure (IOP) is the most important risk factor for primary open-angle glaucoma (POAG)3,4. Here we present a meta-analysis of 139,555 European participants, which identified 112 genomic loci associated with IOP, 68 of which are novel. These loci suggest a strong role for angiopoietin-receptor tyrosine kinase signaling, lipid metabolism, mitochondrial function and developmental processes underlying risk for elevated IOP. In addition, 48 of these loci were nominally associated with glaucoma in an independent cohort, 14 of which were significant at a Bonferroni-corrected threshold. Regression-based glaucoma-prediction models had an area under the receiver operating characteristic curve (AUROC) of 0.76 in US NEIGHBORHOOD study participants and 0.74 in independent glaucoma cases from the UK Biobank. Genetic-prediction models for POAG offer an opportunity to target screening and timely therapy to individuals most at risk

Genetic correlations between diabetes and glaucoma: an analysis of continuous and dichotomous phenotypes

Purpose: A genetic correlation is the proportion of phenotypic variance between traits that is shared on a genetic basis. Here we explore genetic correlations between diabetes- and glaucoma-related traits.Design: Cross-sectional study.Methods: We assembled genome-wide association study summary statistics from European-derived participants regarding diabetes-related traits like fasting blood sugar (FBS) and type 2 diabetes (T2D) and glaucoma-related traits (intraocular pressure (IOP), central corneal thickness (CCT), corneal hysteresis (CH), corneal resistance factor (CRF), cup-disc ratio (CDR), and primary open-angle glaucoma (POAG)). We included data from the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database, the UK Biobank and the International Glaucoma Genetics Consortium. We calculated genetic correlation (rg) between traits using linkage disequilibrium score regression. We also calculated genetic correlations between IOP, CCT and selected diabetes-related traits based on individual level phenotype data in two Northern European population-based samples using pedigree information and Sequential Oligogenic Linkage Analysis Routines (SOLAR).Results: Overall, there was little rg between diabetes- and glaucoma-related traits. Specifically, we found a non-significant negative correlation between T2D and POAG (rg=-0.14; p=0.16). Using SOLAR, the genetic correlations between measured IOP, CCT, FBS, fasting insulin and hemoglobin A1c, were null. In contrast, genetic correlations between IOP and POAG (rg ≥0.45; p≤3.0E-04) and between CDR and POAG were high (rg =0.57; p=2.8E-10). However, genetic correlations between corneal properties (CCT, CRF and CH) and POAG were low (rg range: -0.18 - 0.11) and non-significant (p≥0.07).Conclusion: These analyses suggest there is limited genetic correlation between diabetes- and glaucoma-related traits