A Proteogenomic Signature of Age-related Macular Degeneration in Blood

Abstract

Age-related macular degeneration (AMD) is one of the most frequent causes of visual impairment in the elderly population. The overall etiology of AMD is complex and still poorly understood, though age, obesity, smoking, and high-density lipoprotein are known risk factors. In one of the first successful reported genome-wide association studies (GWAS), common genetic variants were strongly associated with AMD, including variants within the complement factor H (CFH) gene. To date, 34 genomic regions have been linked to AMD; however, the genes that mediate the risk remain largely unknown, indicating that novel approaches to identifying causal candidates are needed. Recent advances in proteomic technology have exposed the serum proteome's depth and complexity. In the Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS), a broad population-based study of the elderly (N = 5764), levels of 4137 human serum proteins and associated networks were integrated with established genetic risk loci for AMD, revealing many predicted as well as novel proteins and pathways, linked to the disease. Serum proteins were also found to reflect AMD severity independent of genetics and predict progression from early to advanced AMD after five years in this population. A two-sample Mendelian randomization study of five proteins associated with AMD found CFHR1, CFHR5, and FUT5 to be causally related to the disease, all of which were directionally consistent with the observational estimates. This study provides a robust and unique framework for elucidating the pathobiology of AMD.

Patterns of gene expression and allele-specific expression vary among macular tissues and clinical stages of Age-related Macular Degeneration

“…This suggests that variants in the gene regions showing heritable differences in AMD risk may influence the expression of tissue. A recent proteomic study on serums from patients with and without all types of late AMD (both neovascular and GA), found that ZBPB, KREMEN2, and LINGO1A were upregulated in diseased patients [64]. We found the expression of these genes to be significantly upregulated MicroRNAs may play an important role in AMD and represent a potential therapeutic target for treatment [79,80].…”

Zinc supplementation induced transcriptional changes in primary human retinal pigment epithelium: a single-cell RNA sequencing study to understand age-related macular degeneration

“…Based on literature searches we generated gene lists that have been shown to contribute to the pathological changes associated with AMD and we examined the effects of cell maturation and zinc supplementation on these genes (Figure 5, Supplementary Table 11). Specific attention was paid to the activation complement system and lipid metabolism related genes as these were the genetically most significantly associated pathways with AMD [17, 67]. We also scrutinized genes associated with pigmentary changes and mineralization associated genes due to their potential link with RPE function and/or sub-RPE deposit formation in AMD [2a, 20d].…”

Recent Advances in Proteomic-based Approaches to Study Age-related Macular Degeneration: A Systematic Review

“…ROC and multivariate regression analysis indicated an excellent diagnostic accuracy, especially for PLTP. Using the same technology, the proteogenomic signature of AMD in blood has been recently investigated [115] in the "Age, Gene/Environment Susceptibility Reykjavik Study" (AGES-RS) cohort [116]. The authors defined a set of 28 AMD-associated serum proteins.…”