Contributions of lipid-related metabolites and complement proteins to early and intermediate AMD

Simon Nusinovici*, Lei Zhou, Xinyue Wang, Yih Chung Tham, Xiaomeng Wang, Tien Yin Wong, Usha Chakravarthy, Ching-Yu Cheng

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Objective
Our objective was to determine the effects of lipids and complement proteins on early and intermediate age-related macular degeneration (AMD) stages using machine learning models by integrating metabolomics and proteomic data.

Design
Nested case-control study.

Subjects, Participants, and/or Controls
The analyses were performed in a subset of the Singapore Indian Chinese Cohort (SICC) Eye Study. Among the 6,753 participants, we randomly selected 155 AMD Indian and 155 Chinese cases and matched them with 310 controls on age, sex and ethnicity.

Methods
We measured 35 complement proteins and 56 lipid-related metabolites using Mass Spectrometry and Nuclear Magnetic Resonance, respectively. We first selected the most contributing lipids and complement proteins to early and intermediate AMD using random forest models. Then we estimated their effects using a multinomial model adjusted for potential confounders.

Main Outcome Measures
AMD was classified using the Beckman classification system.

Results
Among the 310 individuals with AMD, 166 (53.5%) had early and 144 (46.5%) intermediate AMD. Firstly, high-density lipoprotein (HDL) particle diameter was positively associated with both early and intermediate AMD (ORearly=1.69 [1.11, 2.55] and ORintermediate=1.72 [1.11, 2.66] per 1-SD increase in HDL diameter). Secondly, five complement proteins: complement protein 2 (C2), complement C1 inhibitor (ICI1), complement protein 6 (C6), complement protein 1QC (C1QC) and complement factor H-related protein 1 (FHR1), were associated with AMD. C2 was positively associated with both early and intermediate AMD (ORearly=1.58 [1.08, 2.30] and ORintermediate=1.56 [1.04, 2.34]). C6 was positively (ORearly=1.41 [1.03, 1.93]) associated with early AMD. However, IC1 was negatively associated with early AMD (ORearly=0.62 [0.38, 0.99]), while C1QC (ORintermediate=0.63 [0.42, 0.93]) and FHR1 (ORintermediate=0.73 [0.54, 0.98) were both negatively associated with intermediate AMD.

Conclusions
While both HDL diameter and C2 levels show associations with both early and intermediate AMD, dysregulations of IC1, C6, C1QC, and FHR1 are only observed at specific stages of AMD. These findings underscore the complexity of complement system dysregulation in AMD, which appears to vary depending on the disease severity.
Original languageEnglish
Article number100538
JournalOphthalmology Science
Early online date26 Apr 2024
DOIs
Publication statusEarly online date - 26 Apr 2024

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