Functional genomics of systemic complement activation in AMD

Abstract

Abstract Purpose To describe the current status of genetic variants associated with age‐related macular degeneration (AMD) and present functional genomic association studies demonstrating that systemic complement activation is inlfuenced by haplotypes in AMD risk loci and increases the risk of having age‐related macular degeneration. Methods A genome wide association study using the Illumina 370 Beadchip on over 3000 subjects was performed. Focused genetic association and haplotype studies investigating the genetic mechanisms increasing AMD risk in complement and non‐complement AMD risk loci were performed using standard methods. Functional genomic association studies relating genetic risks for AMD to plasma complement levels measured using ELISA assays were performed. Results The collaborative genome‐wide association study revealed novel pathways increasing the risk of AMD and will be discussed. The established genetic variants in the CFH, CFHR, FI, ARMS2 (10q26), and ApoE loci will be reviewed with a focus on insights from genetic studies on functional consequences. The proteogenomic association study showed that haplotypes in complement genes associated with AMD altered plasma levels of complement substrates, regulators, and activation by‐products. The majority of the difference between case and control levels of complement proteins in plasma was explained by the genetic variants associated with AMD. Conclusion Multiple independent pathways leading to AMD have been identified using the genetic approach. Detailed genetic studies and functional genomic studies are beginning to suggest mechanisms through which AMD risk is increased. Commercial interest