N-Glycosylation Patterns across the Age-Related Macular Degeneration Spectrum.

Ivona Bućan,Iris Jerončić Tomić,Ozren Polašek,Olga Gornik,Kajo Bućan,Jelena Škunca Herman,Gordan Lauc,Zoran Vatavuk

doi:10.3390/molecules27061774

Abstract

The pathogenesis of age-related macular degeneration (AMD) remains elusive, despite numerous research studies. Therefore, we aimed to investigate the changes of plasma and IgG-specific N-glycosylation across the disease severity spectrum. We examined 2835 subjects from the 10.001 Dalmatians project, originating from the isolated Croatian islands of Vis and Korčula. All subjects were classified into four groups, namely (i) bilateral AMD, (ii) unilateral AMD, (iii) early-onset drusen, and (iv) controls. We analysed plasma and IgG N-glycans measured by HPLC and their association with retinal fundus photographs. There were 106 (3.7%) detected cases of AMD; 66 of them were bilateral. In addition, 45 (0.9%) subjects were recorded as having early-onset retinal drusen. We detected several interesting differences across the analysed groups, suggesting that N-glycans can be used as a biomarker for AMD. Multivariate analysis suggested a significant decrease in the immunomodulatory bi-antennary glycan structures in unilateral AMD (adjusted odds ratio 0.43 (95% confidence interval 0.22–0.79)). We also detected a substantial increase in the pro-inflammatory tetra-antennary plasma glycans in bilateral AMD (7.90 (2.94–20.95)). Notably, some of these associations were not identified in the aggregated analysis, where all three disease stages were collapsed into a single category, suggesting the need for better-refined phenotypes and the use of disease severity stages in the analysis of more complex diseases. Age-related macular degeneration progression is characterised by the complex interplay of various mechanisms, some of which can be detected by measuring plasma and IgG N-glycans. As opposed to a simple case-control study, more advanced and refined study designs are needed to understand the pathogenesis of complex diseases.

Highlights

These results show a complex nature of age-related macular degeneration progression
We detected activation of the anti-inflammatory mechanisms in early-onset drusen and dysregulation of immune regulation in unilateral and strong pro-inflammatory signals in bilateral disease. Collapsing all these stages into a single category, age-related macular degeneration (AMD), yielded only one significant result. This finding clearly shows that the biomarker discovery studies should aim towards more refined phenotypes as possible to avoid missing the possible differences across the disease severity or progression spectrum
The early-onset disease is denoted by the occurrence of drusen, which presents a collection of protein and lipids which are assumed not to be causal for AMD, but may serve as the early-stage disease marker [37]

Summary

Introduction

About 40% of all human proteins are glycosylated, meaning that glycans have an essential role in many biological and pathological mechanisms [1,2]. Previous studies have well established the role of glycans in ageing [3,4], suggesting that their composition may be used as the marker of biological vs chronological ageing [5]. Most of our understanding of their role as potential biomarkers for diseases originates from oncology [6–8], especially the field of colorectal cancer [9]. In most instances, they do not seem to have the sufficient ability for causal disease occurrence prediction, but in some cases, they can be a valuable biomarker of disease progression [10]

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