Associations of Host Genetics and Plasma Proteomics with Incident Age-related Macular Degeneration in Persons with AIDS

Objective
To evaluate whether common plasma proteomic pathways connect host genetic risk factors to incident age-related macular degeneration (AMD) in persons with the acquired immunodeficiency syndrome (AIDS).
Design
Nested case-control study.
Participants
Subset of persons enrolled in the Longitudinal Study of Ocular Complications of AIDS (LSOCA).
Methods
Baseline cryopreserved plasma specimens were assayed for inflammatory and cardiovascular proteins using the Olink Inflammation Explore Panels 1-2 and the Cardiometabolic Explore Panels 1-2. AMD-associated genetic variants were assessed using ABI Taqman probes. Baseline proteomic profiles for 26 persons who subsequently developed incident intermediate-stage AMD after 5-10 years of follow-up and 49 controls without AMD matched for age, sex, race/ethnicity, and follow-up duration were compared. False discovery rate (FDR) correction was performed with the Storey Q method, and both unsupervised gene ontology pathway enrichment and dedicated pathway analyses were performed. AMD-associated plasma protein levels were compared between AMD-high and AMD-low risk genotypes.
Main Outcome Measure
Incident intermediate-stage AMD.
Results
371 (26%) of 1448 evaluable plasma proteins were associated with incident AMD at the FDR Q<0.05 threshold. Hallmark pathways significantly enriched in incident AMD included inflammation, complement, and fatty acid metabolism pathways. Complement factor H (CFH), a complement activation regulating protein with a genetic association with AMD, levels appeared to be associated with AMD (aOR 0.12 per 2-fold increase, P=0.055). Several related proteins in the Hallmark complement pathway were strongly associated with AMD including CD46, platelet-derived growth factor (PDGFβ), CXCL1, and CCL5 (all Q<0.05), which have been linked to AMD risk in genetic studies. Among cholesterol homeostasis-related genes, lipoprotein lipase (LPL) was associated with a decreased risk of AMD (aOR 0.18 per 2-fold increase, Q=0.008). Participants with AMD-high risk genotypes had elevated levels of shared proteins in inflammatory, complement, and fatty acid metabolism pathways.ConclusionsLevels of several plasma proteins linked to the complement pathway and cholesterol homeostasis, which have been linked to AMD risk in genetic studies, are associated with incident AMD in people with AIDS. Plasma levels of shared inflammatory proteins linked to several different genetic AMD risk factors predicted AMD risk, suggesting common immunologic mechanisms linking genetic risk factors for AMD.