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A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
Associations of Host Genetics and Plasma Proteomics with Incident Age-Related Macular Degeneration in Persons with
Peter W Hunt1, Efe Sezgin2, Adam B Olshen1
1Department of Medicine, the University of California, San Francisco, School of Medicine, San Francisco, California.
Objective:
To evaluate whether common plasma proteomic pathways connect host genetic risk factors to incident age-related macular degeneration (AMD) in persons with AIDS.
Design:
Nested case-control study.
Participants:
Subset of persons enrolled in the Longitudinal Study of Ocular Complications of AIDS.
Methods:
Baseline cryopreserved plasma specimens were assayed for inflammatory and cardiovascular proteins using the Olink Inflammation Explore Panels 1 to 2 and the Cardiometabolic Explore Panels 1 to 2. Age-related macular degeneration‑associated genetic variants were assessed using Applied Biosystems Taqman probes. Baseline proteomic profiles for 26 persons who subsequently developed incident intermediate-stage AMD after 5 to 10 years of follow-up and 49 controls without AMD matched for age, natal sex, race/ethnicity, and follow-up duration were compared. False discovery rate correction was performed with the Storey Q method, and both unsupervised gene ontology pathway enrichment and dedicated pathway analyses were performed. Age-related macular degeneration‑associated plasma protein levels were compared between AMD high-risk and AMD low-risk genotypes.
Main Outcome Measures:
Incident intermediate-stage AMD.
Results:
371 (26%) of 1448 evaluable plasma proteins were associated with incident AMD at the false discovery rate Q < 0.05 threshold. Hallmark pathways significantly enriched in incident AMD included inflammation, complement, and fatty acid metabolism pathways. Complement factor H, a complement activation regulating protein with a genetic association with AMD, levels appeared to be associated with AMD (adjusted odds ratio: 0.12 per 2-fold increase, P = 0.055). Several related proteins in the Hallmark complement pathway were strongly associated with AMD, 16 including CD46, platelet-derived growth factor β, chemokine ligand 1, and CCL5 (all Q < 0.05), which have been linked to AMD risk in genetic studies. Among cholesterol homeostasis-related genes, lipoprotein lipase was associated with a decreased risk of AMD (adjusted odds ratio: 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.
Conclusions:
Levels 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.
Financial Disclosures:
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
