Rare Genetic Variants May Drive Risk of Age-Related Macular Degeneration

Published on: 

In families carrying very rare AMD-causing variants, the analysis found two proteins that may be the driving force behind AMD pathology in affected patients.

A recent study from the National Eye Institute (NEI) identified extremely rare genetic variants that may point to one of the general mechanisms causing age-related macular degeneration (AMD) in older adults.1

The identified variants generate malformed proteins that alter the stability of the membrane attack complex (MAC) and could drive a chronic inflammatory response in the retina. These new findings suggest individuals with AMD have mutations in one of two proteins that form one end of MAC: complement Factor 8-alpha (C8A) and C8-beta (C8B).

“By looking at large families with ultra-rare variants that track closely with disease across generations, we found two proteins that may directly be the driving force behind AMD pathology in affected patients,” said Anand Swaroop, PhD, lead author of the study and chief of the NEI Neurobiology, Neurodegeneration and Repair Laboratory.1 “These proteins could be targets for future drugs.”

Genome-wide association studies have revealed 52 independent common and rare variants across 34 genetic loci, which can influence AMD susceptibility. The complement system emerged as a major contributor involved in the disease, alongside chronic inflammation and disruption of the extracellular matrix. However, the pathophysiological mechanisms of AMD remaining mostly unclear has hindered effective diagnosis and the development of therapies, according to investigators.

The investigative team had collected information for hundreds of patients and families with a high number of individuals with AMD. Together, Swaroop and colleagues searched for families carrying very rare AMD-causing variants and where the variant directly affects protein structure and function. A rare variant like this may reveal the root cause of disease, they added.

In four identified families, the analysis showed individuals with AMD had mutations in C8-alpha and C8-beta. Variants from all 4 families affected the ability of the C8 protein to stick to each other, altering how MAC behaves in the retina. MAC forms a circular pore closed by C8 proteins and the pore permits the flow of ions through the outer membrane of cells, the final step in the complement cascade.

Despite initial beliefs that the only function of MAC was to insert into bacterial cell membranes, recent research has shown the complex role of MAC in regulating inflammatory processes in tissues, including in the retina. Other data from the Age-Related Eye Disease Studies (AREDS) suggest the role of C8 proteins and others higher up in the complement cascade in AMD.

Being the final step in the complement cascade, variants affecting any of the complement proteins may ultimately alter AMC function. Investigators noted that the level of MAC stability in the retina may lead to destructive inflammation and in turn, drive progression of AMD. Thus, the results suggest that MAC might be a more effective target than the early steps of the complement pathway in developing treatments for AMD.

“Given that MAC is the end of the immune system’s complement pathway, and because there’s such a strong link between these rare variants and disease, we think that targeting it may be a more effective strategy to control AMD,” Swaroop said.1 “With a small molecule drug, we might be able to control how strongly MAC drives inflammation, and from there slow down progression of AMD.”


  1. Nateyeinstitute. (2023, April 1). Extremely rare gene variants point to a potential cause of age-related macular degeneration. EurekAlert! Retrieved April 4, 2023, from