Researchers at the National Eye Institute have identified two genetic variants linked to age-related macular degeneration (AMD) that could potentially play a pivotal role in the disease development and progression.
Give me some background on genetic variants.
A number of genetic variants are known to have a small, insignificant impact in lowering or raising the risk of AMD development.
These variants create malformed proteins that then alter the membrane attack complex (MAC) stability notably within the complement pathway, potentially triggering a chronic inflammatory response within the retina that leads to AMD progression.
And in this research?
Investigators sought to identify genetic variants that directly and significantly impact AMD and protein function/structure by assessing clinical data from patients and families—previously analyzed using population and genome-wide association study [GWAS] data based on fundus photographs and relevant medical history—including a high incidence of AMD in at least one eye.
What did they find?
Among four families (39 patients total; ages 52-89), two ultra-rare variants were identified that form one end of the MAC: complement factor 8A (C8A) and 8B (C8B).
These variants affect C8 proteins’ ability to bind with each other—potentially modulating how MAC behaves within the retina.
What else?
The researchers then used genotyping data from two large AMD cohorts that participated in the Age-Related Eye Disease (AREDS) 1 (NCT00000145) and 2 (NCT00345176) studies—which previously determined that variants such as C8 may affect MAC function—to investigate the role of C8 variants on a population level.
They determined that the role of C8 variants could contribute to a genetic risk for AMD development, even in non-familial AMD cases.
Limitations?
The authors noted that the genetic analysis of the study is based on an exome capture, which limits the coverage of the genome to the coding regions covered by the provided probes.
Note: an exome sequencing capture can be equated to casting a “fishing rod or net” —the coding regions are the “fish” while the respective probes act as “bait."
They recommended further investigations with relevant target tissues or cells as well as the use of in vivo model systems to assess the roles of C8 and MAC in AMD.
Take home.
The results suggest that MAC, instead of the early steps of the complement pathway, may be a more effective target for AMD treatment designs.
“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,” stated Anand Swaroop, PhD, lead author of the study. “With a small-molecule drug, we might be able to control how strongly MAC drives inflammation, and from there slow down progression of AMD.”