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Published on: July 14, 2016
Association and Age Heterogeneity of Systemic Metabolomic Signatures With Age-Related Cataract: A Mendelian
Zhangluxi Liu1, Ao Lu1, Siyuan He1
1Ophthalmology Medical Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Eye Diseases, Chongqing Branch (Municipality Division) of National Clinical Research Centre for Ocular Diseases, Chongqing, China.
Purpose:
To evaluate systemic metabolomic signatures associated with age-related cataract and prioritize signals with age-stable or age-heterogeneous patterns.
Methods:
We performed two-sample Mendelian randomization (MR) analyses of 249 Nightingale Health metabolomic traits against age-related cataract in FinnGen 12. Higher-confidence MR candidates were defined by inverse-variance weighted (IVW) false discovery rate (FDR) < 0.05, complete directional concordance across seven complementary MR and sensitivity analyses, and nominal support in at least five analyses. MR-prioritized candidates were then triangulated against UK Biobank incident cataract associations. Age-stratum heterogeneity was assessed using tertile-specific UK Biobank estimates and Cochran Q statistics.
Results:
Among 249 metabolites, 71 met the IVW FDR threshold, and 22 remained after higher-confidence MR filtering. Of these, 13 showed MR-concordant associations with incident cataract in the UK Biobank 500,000 summary layer. Age-stratum assessment prioritized eight metabolites, comprised of five age-stable fatty-acid/lipoprotein-related signals and three age-heterogeneous signals involving glycoprotein acetyls, phenylalanine, and total fatty acids.
Conclusions:
Using an MR-guided triangulation framework, we prioritized eight systemic metabolomic signals associated with age-related cataract. These signals were comprised of an age-stable fatty-acid/lipoprotein axis and age-heterogeneous inflammatory, amino-acid, and fatty-acid traits, highlighting distinct systemic metabolic patterns that may inform future cataract biomarker and mechanistic studies.
Translational Relevance:
This study provides a focused set of systemic metabolic candidates for future cataract biomarker validation and prospective risk-stratification research. The integration of MR prioritization, UK Biobank triangulation, and age-stratum heterogeneity assessment offers a transferable framework for studying metabolic signatures in age-related ocular disease.