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Kameran Lashkari, Gianna C Teague, Ursula Beattie, Megan McLaughlin, Francisco J. Lopez; Identification of Novel Biomarkers in Geographic Atrophy using Wide Spectrum Multiplexing. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2417.
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Local inflammation is associated with development and progression of geographic atrophy (GA) associated with age-related macular degeneration (AMD). Despite recent studies targeting the alternative complement pathway for treatment of GA, the biomarker profile of GA has not been fully studied. In this study, we used a wide spectrum approach (multiplex immunoassays) to identify factors that were associated with GA, and distinct from intermediate dry AMD.
Levels of 320 factors were analyzed by multiplex immunoassays in a cohort of 91 subjects (63F:31M; mean age 77 years). Subjects were divided into 3 groups based on clinical diagnostic criteria: Controls (AREDS 0), intermediate dry AMD (AREDS stage III) and Geographic Atrophy (AREDS 4/5 from a GSK-sponsored study, NCT01342926). Results were evaluated for quality control and then analyzed by Kruskal-Wallis, Principal Component Analysis, partial least squares, MANOVA, and univariate ANCOVAs. Of 320 factors, 40 were identified as highly significant. These factors were then re-evaluated using individual ELISAs in a second cohort of 86 subjects (56F:30M, mean age 77 years). Results were analyzed using similar methodology.
In the first Cohort, 40 factors including amyloid-β (Aβ)(1-40) were significantly elevated in GA (P=0.013). There was a statistically significant linear trend among the three diagnostic groups (P<0.05). The levels of Aβ(1-42) were not significantly elevated. In the second Cohort, ELISA analysis of the 40 factors identified 12 factors including Aβ(1-40) that were elevated (P=0.01); Aβ(1-42) levels were not elevated. Analysis of protein clustering versus enriched pathways showed that many of factors identified were functionally connected to the Aβ pathways (Fisher’s exact test, P<0.01).
Using wide spectrum approaches for biomarker analysis, we initially identified 40 and subsequently confirmed 12 factors that were significantly associated with GA in 2 clinical cohorts. Among these factors, Aβ(1-40) was significantly elevated while Aβ(1-42) was not elevated. The remaining factors that were elevated in both cohorts with GA interact with Aβ. Targeting these factors may have therapeutic applications in treatment of GA.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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