June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Evidence for Sub-Types of Geographic Atrophy based on circulating biomarkers
Author Affiliations & Notes
  • Brandie Wagner
    University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • Jennifer Patnaik
    University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • Alan G Palestine
    University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • Naresh Mandava
    University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • Marc Mathias
    University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • Niranjan Manoharan
    University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • Talisa E de Carlo Forest
    University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • Anne M Lynch
    University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • Footnotes
    Commercial Relationships   Brandie Wagner None; Jennifer Patnaik None; Alan Palestine None; Naresh Mandava None; Marc Mathias None; Niranjan Manoharan None; Talisa de Carlo Forest None; Anne Lynch None
  • Footnotes
    Support  Research to Prevent Blindness grant to the Department of Ophthalmology, University of Colorado, the Frederic C. Hamilton Macular Degeneration Center, Sue Anschutz-Rogers Eye Center Research Fund, by NIH/NCATS Colorado CTSA Grant Number UL1 TR002535 and the Greenwald Family research fund.
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 2260. doi:
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    • Get Citation

      Brandie Wagner, Jennifer Patnaik, Alan G Palestine, Naresh Mandava, Marc Mathias, Niranjan Manoharan, Talisa E de Carlo Forest, Anne M Lynch; Evidence for Sub-Types of Geographic Atrophy based on circulating biomarkers. Invest. Ophthalmol. Vis. Sci. 2023;64(8):2260.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : There is currently no effective treatment for Geographic Atrophy (GA). Genetic studies have implicated the complement system in the development and progression of GA. However, results from clinical trials targeting the complement pathway, including inhibitors for different complement factors, have been inconsistent. One possible explanation for the varying results, may be the existence of different sub-types of GA, in which the anti-complement treatments may be helpful in certain sub-types. The purpose of this study was to evaluate whether there may be multiple sub-types of GA that could shed light on outcome heterogeneity in clinical trials.

Methods : Circulating levels of 25 complement, cytokines, chemokines and systemic inflammatory markers were examined in a cohort of 96 patients with GA recruited into the University of Colorado AMD registry from August 2014 to June 2021. Biomarker levels were measured by multiplex immunoassay. An unsupervised random forest was used to generate a distance metric, the resulting proximity matrix was clustered using PAM to define sub-types. All analyses were performed using R Statistical Software (v3.4.1; R Core Team 2021).

Results : Three clusters (sub-types) were identified that were distinguished by differences mainly in complement factors C1q, C3, C4, C4b, C5, Factor B, Factor H, Factor I, C4b/C4 as well as, TNFα, CRP, RANTES and VEGF (Figure 1). The largest sub-type (sub-type 2) contained 40 (42%) of the GA patients. This group displayed the highest median values for most of the biomarkers, most notably C5, CRP and VEGF, this sub-type had lower C1q and C4 levels. The smallest sub-type (sub-type 1; n = 21 (22%)) had lower levels for most biomarkers compared to the largest sub-type but notably high C4 levels and low C4b/C4 ratios. Sub-type 3 (n = 35 (36%)) had low median levels for all biomarkers except C4b and the C4b/C4 ratio. There were no differences in age, sex or BMI across the sub-types.

Conclusions : This analysis provides preliminary evidence of GA sub-types, that could provide additional insights into disease heterogeneity, potentially leading to a personalized approach to treatment or better selection for clinical trials with different drug targets.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

 

Figure 1. Heatmap displaying the centered and normalized circulating biomarker levels (rows) for each subject (columns). The three sub-types and subject demographics are indicated at the top of the figure.

Figure 1. Heatmap displaying the centered and normalized circulating biomarker levels (rows) for each subject (columns). The three sub-types and subject demographics are indicated at the top of the figure.

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