Decoding the Factor H‐Related Proteins: Gatekeepers of Complement Dysregulation in AMD

Age-related macular degeneration (AMD) is the third most common form of blindness in the Western world, with a predicted 288 million individuals affected worldwide by the year 2040. Both genetic and biochemical evidence point toward complement overactivation, through a diminished regulatory capacity, at the back of the eye, causing inflammation and tissue damage that helps drive this devastating disease. While much historic effort has gone into understanding the loss of regulatory control by complement factor H and factor H-like protein 1, recent studies have uncovered an emerging role of the factor H-related proteins and their capacity for driving forward complement amplification. FHR gene deletions have been shown to be protective against AMD, and increased circulating levels of FHR proteins have been found to associate with their deposition in the back of the eye at the site of disease pathogenesis. Here, we will explore the current understanding of FHR and their association with AMD risk, possible mechanisms by which they promote inflammation and extracellular matrix remodeling, and the potential effectiveness of their targeting as a novel therapeutic strategy for reducing the risk of AMD.