PURPOSE:There have been conflicting findings on the role of leucocyte telomere length (LTL) in the risk of age-related macular degeneration (AMD). In this study, we evaluated the associations between LTL and the risk of incident AMD and explored whether age, sex and/or genetic predisposition to AMD can modify these associations. METHODS:We conducted a longitudinal cohort study involving 332 123 AMD-free participants with complete baseline covariates and LTL data from the UK Biobank. We employed multivariable Cox proportional hazards models to test the association between LTL and AMD incidence, estimating the HRs and 95% CIs. Genetic risk was assessed using polygenic risk score (PRS). RESULTS:During a median follow-up of 13.63 years, 6754 participants (2.03%) developed AMD. Shorter LTL was not associated with incident AMD risk (HR=1.042, 95% CI: 0.992 to 1.094; p=0.10) after adjusting for multiple confounders. Sex showed an interactive effect with LTL (p=0.01 for interaction) on incident AMD risk, while age and PRS did not modify these associations. We identified a significant association between shorter LTL and incident AMD risk in females (HR=1.093, 95% CI: 1.025 to 1.166; p=0.007), but not in males. Moreover, shorter LTL was associated with thinner photoreceptor segments only in females at both baseline and repeated assessments (β=-0.141 µm, 95% CI: -0.267 to -0.016; β=-0.345 µm, 95% CI: -0.649 to -0.041, p<0.05). CONCLUSIONS:Shorter LTL increased the risk of incident AMD in females, suggesting LTL as a potential biomarker for AMD development with sex-specific function.

PURPOSE. To investigate the associations of omics-based biological aging with diabetic retinopathy (DR) and life expectancy among individuals with DR. METHODS. We included 68,672 UK Biobank participants with prediabetes or diabetes in the metabolomic cohort and 8716 in the proteomic cohort, from which biological age was estimated using a metabolomic aging score and proteomic age (ProtAgeGap), respectively. Associations with prevalent and incident DR were assessed using logistic regression and Cox proportional hazards models, respectively. Life expectancy was estimated from survival curves. RESULTS. Cross-sectionally, both the higher metabolomic aging score and ProtAgeGap were associated with a higher risk of prevalent DR. Prospectively, during a median follow-up of 13.40 years, 2491 participants (3.7%) developed DR among those free of DR at baseline in the metabolomic cohort and 358 (4.14%) in the proteomic cohort. Higher biological aging was associated with increased DR risk, with hazard ratios of 1.73 (95% confidence interval [CI], 1.59-1.88) for the metabolomic aging score and 1.12 (95% CI, 1.07-1.17) for ProtAgeGap. These associations were independent of and additive to glycated hemoglobin levels and diabetes duration. At age 45 years, individuals with DR had reduced life expectancy compared with those without DR. Among those with DR, the highest quartile of metabolomic aging was associated with a reduced life expectancy compared with the lowest quartile. CONCLUSIONS. Advanced metabolomic and proteomic aging were associated with a higher risk of DR, particularly in individuals with poor glycemic control or longer diabetes duration, while advanced metabolomic aging was associated with reduced life expectancy among those with DR.

PURPOSE. To identify plasma proteins associated with glaucoma and assess the translational potential of key proteins as both biomarkers and therapeutic targets. METHODS. Genome-wide association study data were obtained from the UK Biobank Pharma Proteomics Project, FinnGen, and the Million Veteran Program. We used a four-stage analytical framework: Stage 1 applied Mendelian randomization and Bayesian colocalization to evaluate associations between 2923 plasma proteins and glaucoma; Stage 2 used summary-based Mendelian randomization to explore transcriptomic and epigenomic associations of the identified proteins with glaucoma risk; Stage 3 involved a prospective association analysis of protein levels and incident glaucoma in the UK Biobank cohort, including 40,170 glaucoma-free participants; and Stage 4 systematically evaluated the druggability of the prioritized protein targets. RESULTS. We identified 26 plasma proteins with putative causal associations with glaucoma, six of which were novel: COL24A1, KAZALD1, EBAG9, CSNK1D, AZI2, and AXIN1. COL24A1 (odds ratio [OR] = 0.85; 95% confidence interval [CI], 0.80-0.90; PFDR < 0.001; PP.H4 = 0.95) and EFEMP1 (OR = 0.88; 95% CI, 0.83-0.92; PFDR <0.001; PP.H4 = 0.98) emerged as the most compelling candidates. To further elucidate the regulatory mechanisms, multiomics analyses indicated that epigenetic modifications and alternative splicing events affecting these genes were associated with elevated glaucoma risk. Notably, EFEMP1 was significantly associated with glaucoma incidence in the prospective cohort analysis (fully adjusted Cox model: hazard ratio = 1.61; 95% CI, 1.29-2.00; PFDR = 0.002), demonstrating strong predictive performance (C-index = 0.811, area under the curve = 0.806) and representing a promising therapeutic target. CONCLUSIONS. Our findings provide new insights into the proteomic basis of glaucoma and highlight promising opportunities for developing targeted therapies.

Age-related macular degeneration (AMD) imposes a substantial burden of disability. Metabolic disturbances are associated with increased AMD risk. Here we evaluate the metabolic vulnerability index (MVX), derived from inflammation- and malnutrition-related markers, and MetaboHealth score, developed from metabolomics-based biological aging, as biomarkers for AMD incidence. UK Biobank participants with metabolomic data and no AMD at baseline were included. Cox proportional hazards models were used to estimate the associations of MVX and MetaboHealth with incident AMD, adjusting for demographic, socioeconomic, lifestyle, and comorbidity factors. Interactions between AMD polygenic risk score (PRS, field 26,204) and both scores were evaluated on both multiplicative and additive scales using the relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (SI). Cross-sectional linear models were adopted to assess the associations of both scores with AMD-related retinal traits, including photoreceptor segment (PS) and retinal pigment epithelium–Bruch’s membrane thicknesses. Over a median follow-up of 13.66 years, AMD occurred in 5509 of 265,133 participants for MVX analysis and in 5498 of 264,352 participants for MetaboHealth analysis. Higher quintiles of MVX and the MetaboHealth score demonstrated a dose-dependent association with increased AMD risk (P for trends < 0.001), with hazard ratios (HRs) of 1.17 (95

Objective:To systematically identify plasma proteins associated with cataract development and explore their potential causal relationships. Design: Prospective population-based cohort study with integrated Mendelian randomization (MR) and colocalization analyses. Participants: Forty-nine thousand, five hundred and eighty-one UK Biobank participants free of cataract at baseline. Methods:Cox proportional hazards models were used to assess associations between 2920 plasma proteins and cataract risk, followed by MR to evaluate causal relationships. Colocalization analysis was conducted to examine whether identified protein-cataract associations shared causal genetic variants. Main Outcome Measures: Incident cataract. Results:Of the 2920 plasma proteins analyzed, 58 demonstrated significant associations with cataract risk (P < 1.71×10-5, Bonferroni-corrected threshold). Beta-crystallin B2 (CRYBB2) showed the most robust association (hazard ratio: 1.60; 95% confidence interval: 1.55-1.66, P = 5.28×10-164). Mendelian randomization analysis provided evidence supporting causal relationships for 4 proteins (CRYBB2, V-set and immunoglobulin domain-containing protein 4, mevalonate kinase, and metalloproteinase inhibitor 1) with cataract, with genetically predicted CRYBB2 levels showing a significant association with cataract risk, which is strongly supported by colocalization evidence. Functional enrichment analyses revealed involvement of biological pathways related to immune activation, cell fate decision, and structural remodeling in cataract development. Conclusions:This study identified distinct plasma proteomic signatures associated with incident cataract, offering novel insights into cataract pathogenesis and highlighting potential targets for early detection and therapeutic development. Financial Disclosures:The author has no/the authors have no proprietary or commercial interest in any materials discussed in this article.

Purpose:To investigate the role of tumour necrosis factor receptor superfamily member 10A (TNFRSF10A ) in chronic central serous chorioretinopathy (cCSCR), polypoidal choroidal vasculopathy (PCV), and neovascular age-related macular degeneration (nAMD). Design:Case-control genetic association study. Participants:A total of 1478 Chinese participants were recruited, including 217 patients with cCSCR (174 without and 43 with macular neovascularization [MNV]), 288 patients with PCV, 341 patients with nAMD, and 632 healthy controls. Methods:Thirteen single-nucleotide polymorphisms (SNPs) in TNFRSF10A that covered both the promoter and coding regions were genotyped, including 12 haplotype-tagging SNPs and a manually selected reference SNP, rs13278062. Two variants showing significant deviation from Hardy-Weinberg equilibrium were excluded, leaving 11 SNPs for the final analysis. Logistic regression, adjusted for age and sex, was applied to assess both allelic and haplotype associations. Conditional analyses were conducted to evaluate independent effects. Single-nucleotide polymorphisms were annotated based on TNFRSF10A domains defined by UniProtKB. Main Outcome Measures:Associations between individual SNPs and haplotypes in the TNFRSF10A with nAMD, PCV, and cCSCR (with or without MNV), respectively. Results:For cCSCR without MNV, 4 tagging SNPs showed significant associations: rs59693001 (odds ratio [OR] = 1.65, 95% confidence interval [CI]: 1.12 - 2.33; P = 0.0043), rs3808530 (OR = 1.91, 95% CI: 1.22 - 2.83; P = 0.0013), rs2235126 (OR = 1.74, 95% CI: 1.22 - 2.41; P = 7.50 × 10-4), and rs7814465 (OR = 1.66, 95% CI: 1.22 - 2.28; P = 0.0016). The reference SNP, rs13278062, also showed a significant association (OR = 1.81, 95% CI: 1.31 - 2.51; P = 3.64 × 10-4). In addition, 4 haplotypes within 2 blocks from a continuous region also showed significant associations. For PCV, only rs36005462 in an independent domain showed a marginally significant association (OR = 0.58; P = 0.0050). No significant association was identified for nAMD or cCSCR with MNV. Conclusions:This study identified multiple TNFRSF10A variants associated with cCSCR without MNV, while a distinct protective SNP was linked to PCV. These findings provide preliminary evidence for varying TNFRSF10A association patterns across the pachychoroid disease spectrum. Financial Disclosures:The authors have no proprietary or commercial interest in any materials discussed in this article.

Objective:To investigate the associations of plasma metabolites with incident rhegmatogenous retinal detachment (RRD). Design:A prospective cohort study. Subjects:A total of 213 173 UK Biobank participants. Methods:Plasma metabolomics were quantified using the Nightingale Health platform based on proton nuclear magnetic resonance spectroscopy, covering 251 metabolites. Associations with incident RRD were assessed using Cox proportional hazard models and restricted cubic splines. Two-sample Mendelian randomization analyses were conducted to assess whether genetically predicted metabolite levels showed patterns consistent with the observational associations. A metabolomic risk score (MRS) was constructed based on significant metabolites to evaluate their combined effects on RRD. Principal component analysis was used to test whether the metabolite profiles improved RRD risk prediction. Main Outcome Measures:Incident RRD, defined as the first recorded diagnosis during follow-up. Results:Over a median follow-up of 11.10 years, 1111 participants developed RRD. Seventeen metabolites were significantly associated with RRD after false discovery rate correction (P FDR < 0.05), including 11 high-density lipoprotein (HDL)-associated metabolites, 4 fatty acids, 1 very low-density lipoprotein (VLDL)-associated metabolite, and creatinine. Among them, omega-3, docosahexaenoic acid (DHA), and 11 HDL-associated metabolites were inversely associated with RRD, whereas monounsaturated fatty acids to total fatty acids, creatinine, and free cholesterol to total lipids in large VLDL showed positive associations. Mendelian randomization analyses provided supportive genetic evidence consistent with the inverse associations for omega-3, DHA, phospholipids in very large HDL, and total lipids in large HDL. Compared with participants in the low MRS group, those with high MRS had a significantly higher risk (hazard ratio = 1.608, 95% confidence interval: 1.187-2.178, P = 0.002). However, the RRD-associated metabolites did not materially improve model discrimination (C-index 0.694-0.697 across models). Conclusions:This study identified 17 plasma metabolites associated with RRD risk, particularly omega-3 and HDL-related lipids. Although metabolomics did not improve risk prediction, these findings provide exploratory evidence of systemic metabolic patterns associated with RRD risk. Financial Disclosures:The authors have no proprietary or commercial interest in any materials discussed in this article.

Purpose:This study aimed to characterize the shared genetic architecture and modifiable correlates between myopia and retinal-optic nerve diseases (RONDs). Design:Genetic pleiotropy analysis and population-based cohort study. Participants:A total of 81 491 UK Biobank participants and summary statistics from large-scale genome-wide association studies were included. Methods:We examined associations between myopia and 5 common RONDs using population-based analyses of prevalent and incident outcomes, followed by cross-trait genetic analyses, locus-level annotation, colocalization, and enrichment analyses. Among myopic individuals, modifiable correlates and gene-environment interactions were evaluated, and Mendelian randomization was used as complementary evidence for selected associations. Main Outcome Measures:Myopia and RONDs. Results:The primary findings were that, in baseline prevalent analyses, myopia was associated with higher risks of retinal detachment (RD) and primary open-angle glaucoma (POAG), but a lower risk of primary angle-closure glaucoma (PACG), with evident risk gradients across myopia severity, especially for RD. Diabetic retinopathy (DR) risk estimates were <1.0 across myopia severity categories but were not statistically significant. A U-shaped association was observed between refractive status and age-related macular degeneration, with elevated risk in both high myopia and hyperopia. Incident analyses during follow-up showed broadly consistent patterns. As supportive genetic evidence, cross-trait analyses revealed significant genetic correlations and overlaps between myopia and RONDs, identifying 66 pleiotropic loci and 115 candidate genes, with enrichment in immune-inflammatory, receptor-mediated signaling, and retinal developmental pathways. Among myopic individuals, exploratory analyses further showed that prevalent myopia-ROND comorbidity was associated with various modifiable correlates spanning health status, lifestyle, diet, mental health, sleep patterns, and medication use, and that 7 environmental factors interacted with 5 pleiotropic variants. Mendelian randomization analyses provided complementary and hypothesis-supporting evidence consistent with a positive association of myopia with RD and an inverse association with PACG, whereas findings for DR and POAG required more cautious interpretation because of pleiotropy or heterogeneity. Conclusions:This study reveals a shared genetic architecture and identifies modifiable correlates linking myopia to five common RONDs. These findings provide new insights into shared susceptibility patterns and offer a framework for future mechanistic, validation, and prevention-oriented research in myopic populations. Financial Disclosures:The author has no/the authors have no proprietary or commercial interest in any materials discussed in this article.

Abstract Background The gut–eye axis (GEA) has been proposed as a framework for understanding comorbidity between gastrointestinal and ocular diseases. This study aimed to investigate their shared genetic architecture, pleiotropy, and putative biological pathways potentially influenced by environmental exposures and gut microbiota. Methods This study integrated large-scale genome-wide association study summary data on five gastrointestinal and eight ocular diseases to assess genetic correlations and genetic overlap. Pleiotropic variants were identified, followed by functional and tissue-specific analyses. Gene–environment (G×E) interactions were evaluated using UK Biobank data. Mendelian randomization (MR) and mediation analyses were adopted to assess statistically inferred associations and potential mediating relationships involving gut microbiota. Results Extensive genetic correlations were identified between 40 trait pairs. In total, 366 pleiotropic loci were identified, with 21 loci showing evidence of colocalized shared signals. Notably, 2p21, 4q24, 19q13.32 and 5p15.31 were colocalized across 2 trait pairs, highlighting them as recurrent pleiotropic loci of potential interest. Of the 603 genes associated with pleiotropic variants, 261 recurred across two or more trait pairs. These genes were enriched in immune and inflammatory pathways and included well-known loci such as HLA-B and RBFOX1. Twenty-six pleiotropic variants interacted with 16 modifiable exposures (e.g., diet, mental health, BMI, smoking, physical activity), suggesting that G×E interactions may contribute to gut–eye comorbidity risk. Bidirectional MR identified 11 genetically predicted associations, while mediation analysis suggested a potential statistical association involving the polyamine biosynthesis pathway in the relationship between gastroesophageal reflux disease and diabetic retinopathy. Conclusions This study characterizes shared genetic and environmental architecture across GEA-related disorders and highlights putative contributions from immune-related pathways and gut microbiota to disease comorbidity. Our findings provide a hypothesis-generating framework for future replication and experimental validation.

OBJECTIVES:To evaluate the associations of baseline brain care score (BCS) with the incidence of age-related eye diseases (AREDs), and to examine the modifying effects of age and genetic susceptibility. METHODS:We included 382,221 UK Biobank participants without cataract, glaucoma, or age-related macular degeneration (AMD) at baseline. Baseline BCS (0-19 point) encompassed physical, lifestyle and social-emotional factors. Higher BCS scores indicated better brain care. Multivariable Cox regression was used to estimate associations between baseline BCS and incident cataract, glaucoma, and AMD. Polygenic risk scores (PRSs) were used to test gene-BCS interactions. RESULTS:Over a median follow-up of 14.28 (interquartile range: 13.34-15.11) years, 44,033 cataract cases, 9280 glaucoma cases, and 6754 AMD cases were identified. Compared with the lowest baseline BCS quintile, the highest baseline BCS quintile was associated with lower risk of cataract (adjusted hazard ratios [HR]: 0.89, 95% confidence interval [CI]: 0.86-0.92), glaucoma (0.92, 0.86-0.98), and AMD (0.90, 0.83-0.97). Stronger associations of per 5-unit increase in baseline BCS with incident cataract (0.78, 0.71-0.85) and glaucoma (0.72, 0.64-0.83) were observed in participants aged 40-50 years than in older groups, with significant interactions with age (P-interaction < 0.001). A significant interaction between baseline BCS and PRS was observed for cataract (P-interaction < 0.001), but not for glaucoma or AMD. CONCLUSIONS:Higher baseline BCS is associated with lower long-term risk of AREDs, especially in middle-aged individuals. These findings underscore BCS as a novel and potentially modifiable factor for AREDs.

To evaluate the associations of systemic diseases with AMD incidence and explore whether polygenic risk score (PRS) for AMD influences these associations. To assess the impacts of polymorbidities and serum biomarkers on AMD risk. This prospective study of 471156 AMD-free UK Biobank participants assessed systemic diseases (hypertension, diabetes, cardiovascular disease [CVD], dyslipidemia, chronic kidney disease [CKD], and dementia) and AMD incidence using multivariable Cox proportional hazard models. Five systemic diseases were associated with an increased risk of AMD incidence, including hypertension (fully adjusted HR = 1.13, 95% CI: 1.09–1.18; false discovery rate [FDR]-corrected p  = 3.41 × 10 −8 ), diabetes (HR = 1.48, 95% CI: 1.38–1.58; p  = 3.79 × 10 −27 ), CVD (HR = 1.13, 95% CI: 1.08–1.18; p  = 7.60 × 10 −8 ), dyslipidemia (HR = 1.11, 95% CI: 1.05–1.16; p  = 1.28 × 10 −4 ), and CKD (HR = 1.22, 95% CI: 1.07–1.39; p  = 0.006), whereas dementia showed no association ( p  = 0.74). AMD PRS modified the association with diabetes, but not with the other diseases. The risk of AMD incidence increased in participants with one to five comorbidities ( p for trends < 0.001), compared to those without. Serum biomarkers related to lipid regulation, inflammation, glycemic control, renal function, and nutrition were associated with AMD incidence. Major systemic diseases elevate AMD risk, compounded by comorbidities. Serum biomarkers further implicate systemic health in AMD. Holistic health management and regular ocular screenings are crucial for AMD patients and those with systemic diseases.

Purpose:To evaluate the effects of haplotype-tagging single nucleotide polymorphisms (SNPs) in the complement factor H-complement factor H related 5 (CFH-CFHR5) locus on neovascular age-related macular degeneration (nAMD), polypoidal choroidal vasculopathy (PCV), and chronic central serous chorioretinopathy (cCSCR) in Chinese patients. Design:Case-control genetic association study. Participants:A total of 846 patients (341 nAMD, 288 PCV, and 217 cCSCR including 43 with secondary macular neovascularization [MNV]) and 632 healthy Chinese controls. Methods:A total of 17 candidate SNPs were initially selected from the CFH-CFHR5 region; after excluding 5 SNPs that deviated from Hardy-Weinberg equilibrium, 12 SNPs were retained for the final analysis. Association analyses included logistic regression adjusted for age and sex and haplotype-based analysis using Haploview. Study-wide significance threshold was set at P < 0.0042 for allelic tests (Bonferroni-corrected for 12 SNPs) and at P < 0.05 for haplotype tests (adjusted using 10 000 permutations). Main Outcome Measures:Associations between individual SNPs and haplotypes in the CFH-CFHR5 locus with nAMD, PCV, and cCSCR (with or without MNV), respectively. Results:The tagging SNP, rs12144939, for the CFHR3/1 deletion was significantly associated with nAMD (odds ratio [OR] = 0.37, P = 0.0031). Notably, we identified 3 candidate variants showing novel associations with PCV, including rs12144939 (OR = 0.29, P = 6.29 × 10-4), rs423641 in CFHR1 (OR = 0.74, P = 0.0038), and rs10922152 in CFHR5 (OR = 1.55, P = 0.0031). No SNP in this locus was associated with cCSCR without MNV, whereas CFH rs529825 was nominally associated with cCSCR with MNV (OR = 0.47, P = 0.0047). Similar patterns of haplotype associations were observed across the 3 maculopathies. Notably, the haplotype A-T-C-G spanning CFHR4, CFHR2, and CFHR5 (OR = 1.81, permutation P = 0.0099) and haplotype G-A-G within CFHR5 (OR = 1.56, permutation P = 0.025) were specifically associated with PCV. Conclusions:This study validates the association of the CFHR3/1 deletion (tagged by rs12144939) with nAMD. Furthermore, we reveal a novel genetic architecture for PCV within the CFH-CFHR5 locus, characterized by associations at rs12144939, rs423641 (CFHR1), and rs10922152 (CFHR5), as well as risk haplotypes unique to PCV. These findings underscore the critical role of CFH-related genes in PCV and provide new insights into its genetic mechanisms. Financial Disclosures:The author has no/the authors have no proprietary or commercial interest in any materials discussed in this article.

BACKGROUND:Leukocyte telomere length (LTL) has been associated with various diseases, including age-related eye diseases such as cataract and age-related macular degeneration. However, the role of LTL in the longitudinal development of glaucoma is still unknown. Here we prospectively evaluate the association of LTL with glaucoma incidence and related traits, in the UK Biobank cohort. METHODS:The study cohort included 419,603 participants with complete baseline data for glaucoma analyses. Multivariable Cox proportional hazards models were used to evaluate the association between LTL and the risk of glaucoma incidence, and multivariable linear regression was employed to test the association between LTL and glaucoma-related traits. RESULTS:During a 13.58-year follow-up period, 7385 (1.76%) participants developed glaucoma. No association between LTL and incident glaucoma was found in either Model 1 (adjusted for age, sex, ethnicity and the ancestry components; HR = 1.011, 95% CI: 0.990-1.033; P = 0.311), or Model 2 (additionally adjusted for smoking status, alcohol consumption, body mass index, systolic blood pressure, education level, Townsend Deprivation Index, polygenic risk score for glaucoma, and history of diabetes and cardiovascular diseases; HR = 1.010, 95% CI: 0.988-1.032; P = 0.367). Non-significant associations were also observed for glaucoma-related traits, including the retinal nerve fibre layer, ganglion cell-inner plexiform layer, and intraocular pressure with LTL (all P-values > 0.05), but LTL was associated with a slightly increased vertical cup-to-disc ratio (P = 0.009). CONCLUSIONS:This study suggested that LTL is not a major biomarker for incident glaucoma in the UK Biobank population. Further studies in different populations are warranted.

PURPOSE:To evaluate the associations between omega-3 polyunsaturated fatty acids (ω-3 PUFAs) and other dietary factors with myopia. METHODS:A total of 1005 Chinese children, aged from 6 to 8 years, from a population-based Hong Kong Children Eye Study, were included in the analysis. Diet was assessed using a validated food-frequency questionnaire. Cycloplegic spherical equivalent (SE) refraction was assessed with an autorefractometer, and axial length (AL) by an IOL Master. RESULTS:AL was longest in the lowest quartile group of ω-3 PUFAs intake, compared with the highest (adjusted mean (95% CI), 23.29 (23.17 to 23.40) mm vs 23.08 (22.96 to 23.19) mm, p=0.01; p-trend=0.02) after adjusting for age, sex, body mass index, near-work time, outdoor time, and parental myopia history. The corresponding trends were observed in SE (-0.13 (-0.32 to 0.07) D in the lowest and 0.23 (0.03 to 0.42) D in the highest quartile groups, p=0.01; p-trend=0.01). In contrast, AL was longest in the highest quartile group of saturated fatty acids (SFA) intake, compared with the lowest (23.30 (23.17 to 23.42) mm vs 23.13 (23.01 to 23.24) mm, p=0.05; p-trend=0.04). The corresponding trends were observed in SE (-0.12 (-0.33 to 0.09) D in the highest and 0.13 (-0.04 to 0.31) D in the lowest quartile group, p=0.06; p-trend=0.04). A lower intake of ω-3 PUFAs was associated with myopia (p-trend=0.006). None of the other nutrients were associated with SE or AL or myopia. CONCLUSIONS:Intake of ω-3 PUFAs is a protective factor against myopia, while higher SFA intake is a risk factor. Our findings indicated a possible effect of diet on myopia, of which ω-3 PUFAs intake may play a protective role against myopia development in children.

Purpose:To investigate the associations of lung function with glaucoma and related traits, explore the interactions between glaucoma genetic risk and lung function, and assess the causal relationships using Mendelian randomization (MR). Methods:This cross-sectional study involved 85,369 participants with lung function measurements at baseline from the UK Biobank. Associations between lung function parameters and glaucoma and related traits were tested by multivariable logistic and linear regression. Two-sample MR analyses were conducted using summary statistics from large genetic datasets. Results:Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and FEV1/FVC ratio were inversely associated with glaucoma, with the lowest quartiles conferring odds ratios (ORs) of 1.51 (95% confidence interval [CI], 1.31-1.74; P = 7.6 × 10-8), 1.58 (95% CI, 1.37-1.81; P = 4.7 × 10-10) and 1.20 (95% CI, 1.08-1.34; P = 0.002), respectively, compared with the highest quartiles (P trends < 0.001 observed for each). Similar associations were found for impaired lung function (FEV1 <80% Global Lung Initiative predicted FEV1: OR, 1.22, 95% CI, 1.11-1.33; P = 1.2 × 10-5; FEV1/FVC <0.7: OR, 1.13, 95% CI, 1.03-1.24; P = 0.01). Lower lung function was associated with lower intraocular pressure (IOP), thinner macular retinal nerve fiber layer thickness, and thinner ganglion cell-inner plexiform layer thickness. No interactions were observed between glaucoma genetic risk and lung function. MR analyses did not suggest causal relationships. Conclusions:Lower FVC, FEV1, FEV1/FVC, and impaired lung function are potential biomarkers for glaucoma risk. These findings may facilitate clinical strategies for glaucoma management, particularly for individuals with impaired lung function.

PURPOSE. Age-related eye diseases (AREDs) are major causes of vision loss worldwide. Biological age acceleration (BAA) reflects systemic aging, but its relationship with AREDs and underlying genetic mechanisms remains unclear. This study investigated the combined effects of BAA and genetic risk on AREDs and blindness, and explored shared genetic pathways and potential anti-aging targets. METHODS. Biological age was measured using the Klemera-Doubal method for estimating biological age (KDM-BA) and PhenoAge algorithms. We assessed the cross-sectional and prospective associations between BAA and AREDs in 297,375 participants from the UK Biobank, followed by genetic pleiotropy analysis. RESULTS. Participants with higher BAA were more likely to experience AREDs at baseline and had an increased risk of incident AREDs during follow-up. In participants with high genetic susceptibility to AREDs, accelerated biological aging was associated with an increased risk of disease onset. Notably, we observed a significant additive interaction between BAA and genetic risk. The multi-omics integrative analysis identified 115 genetic variants with pleiotropic effects and 512 candidate genes. Notably, we identified APOE, APOC1, TOMM40, PVRL2, and BCAM as shared genes between BAA and the three AREDs. Among ARED patients, accelerated biological aging was associated with a reduction in vision-healthy life expectancy, compared to those without accelerated biological aging. CONCLUSIONS. Accelerated biological aging significantly increases ARED risk, especially in those with high genetic risk, and is linked to shorter vision-healthy life expectancy. Identifying individuals with accelerated aging may help reduce ARED risk and improve vision-healthy life expectancy. APOE, APOC1, TOMM40, PVRL2, and BCAM could be potential targets for ocular anti-aging interventions.

PurposeTo evaluate the associations of the TIE2 gene with diabetic retinopathy (DR) and diabetic macular edema (DME).MethodsThis study included a Chinese cohort of 285 non-proliferative DR patients and 433 healthy controls. The DR patients were classified further into those with or without DME. Thirty haplotype-tagging single-nucleotide polymorphisms (SNPs) in TIE2 were genotyped using TaqMan technology. Associations of DR and subtypes were analyzed by logistic regression adjusted for age and sex. Stratification association analysis by sex was performed.ResultsTIE2 rs625767 showed a nominal but consistent association with DR [odds ratio (OR) = 0.71, P = 0.005] and subtypes (DR without DME: OR = 0.69, P = 0.016; DME: OR = 0.73, P = 0.045). SNP rs652010 was consistently associated with overall DR (OR = 0.74, P = 0.011) and DR without DME (OR = 0.70, P = 0.016), but not with DME. Moreover, SNPs rs669441, rs10967760, rs549099 and rs639225 showed associations with overall DR, whilst rs17761403, rs664461 and rs1413825 with DR without DME. In stratification analysis, three SNPs, rs625767 (OR = 0.62, P = 0.005), rs669441 (OR = 0.63, P = 0.006) and rs652010 (OR = 0.64, P = 0.007), were associated with DR in females, but not in males. Moreover, one haplotype T-T defined by rs625767 and rs669441 was significantly associated with DR in females only.ConclusionsThis study revealed TIE2 as a susceptibility gene for DR and DME in Chinese, with a sex-specific association in females. Further validation should be warranted.

Purpose:The purpose of this study was to identify serum metabolites associated with age-related macular degeneration (AMD) incidence and investigate whether metabolite profiles enhance AMD risk prediction. Methods:In a prospective cohort study involving 240,317 UK Biobank participants, we assessed the associations of 168 metabolites with AMD incidence using Cox hazards models. Principal component analysis (PCA) captured 90% of the variance in metabolites. These principal components (PCs) were added to the Cox models, with the first PC selected to evaluate model performance using receiver operating characteristic (ROC) curves. Results:During a median follow-up of 13.69 years, 5199 (2.16%) participants developed AMD. After accounting for demographic, lifestyle, multimorbidity, socioeconomic factors, and genetic predispositions to AMD, 42 metabolites were associated with AMD incidence. Very-low-density lipoprotein (VLDL)-related particles, low-density lipoprotein (LDL)-related particles, three additional lipids particles, and albumin were associated with decreased AMD incidence, whereas glucose increased the risk of AMD incidence. Compared to those in the lowest quartile, individuals in the highest quartile of protective metabolite scores exhibited lower risk of AMD incidence (hazard ratio [HR] = 0.869, 95% confidence interval [CI] = 0.803-0.940, false discovery rate [FDR]-adjusted P = 1.44 × 10-3). However, the AMD-associated metabolites did not enhance predictive performance (both areas under the curve [AUC] = 0.776). Conclusions:Our findings reveal significant associations between specific metabolites and AMD incidence, highlighting the roles of lipoprotein subclasses, cholesterol subtypes, apolipoproteins, glucose, and albumin. Although metabolomics did not improve risk prediction, certain biomarkers may serve as promising therapeutic targets.