Large-scale genetic analysis of AMD drug targets highlights precision therapy opportunities for patients with high polygenic risk

Abstract

Abstract Background: In the past two decades, genetic studies have elucidated the contributions of key biological pathways to the pathogenesis of age-related macular degeneration (AMD), including complement activation, lipoprotein metabolism, angiogenesis, and extracellular matrix maintenance. Of these pathways, complement in particular has been observed to dominate the genetic architecture of AMD. Yet, clinical treatment of AMD with complement inhibitors has met with limited success. Methods: Using data from four large-scale cohorts spanning 30,251 AMD cases and 438,016 AMD controls, we identified functional genetic variants to serve as proxies for complement inhibitor drug effects, and assessed their interaction with a pathway-specific AMD polygenic risk score (PRS). In each cohort, subjects were divided into low, medium, and high AMD risk groups based on quantiles of the PRS, such that each risk group included one-third of the cohort's AMD cases. Drug target variant associations with AMD were evaluated in each risk group, as well as in all-comers. Quantitative biomarker analysis leveraging retinal phenotypes derived from optical coherence tomography (OCT) data was also performed. Results: Genetic proxies for C3 and CFB inhibition had an effect on AMD risk that was 1.6 to 2.3 times higher in the high PRS group compared to all-comers. Interactions between genetic drug proxies and the PRS was statistically significant, with replication across cohorts. Examining a retinal thickness phenotype (ISOS-RPE), genetic drug proxy by PRS interaction was nominally significant for CFB, and directionally consistent for C3. Our results point to a continuous relationship between genetic complement activation / inhibition and AMD risk, across disease stages, without threshold effects. Conclusion: Our findings suggest that patient heterogeneity due to genetically-influenced complement activation may explain the limited efficacy of AMD treatment with complement inhibitors to date. Prospective studies are warranted to assess whether precision therapy with complement inhibitors may be achieved by enrichment of patients with high PRS in future trials.

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