A study funded in part by the National Institutes of Health (NIH) has revealed important insights into the genetics of deposits in the eye, known as reticular pseudodrusen (RPD), that are linked to greater risk of vision loss among people with age-related macular degeneration (AMD). The study underscores that AMD is not one disease and highlights the need for novel treatment approaches.
"This study could help explain why drugs that target just the complement pathway have shown a minimal effect in slowing geographic atrophy," said Anand Swaroop, Ph.D., chief of the Neurobiology Neurodegeneration and Repair Laboratory at NIH's National Eye Institute (NEI) and a coauthor of the study report. "It's clear that AMD involves multiple pathways that differentially synergize to generate distinct phenotypes."
Drusen are lipid-rich deposits that develop in the eye's light-sensing retina and are a hallmark feature of AMD, one of the most common causes of irreversible vision loss in older Americans. The development of a few small drusen is normal with age, but AMD risk increases as drusen deposits increase. Typical drusen are located beneath a layer of cells that supports the health and function of the photoreceptors essential for vision, known as the retina's pigmented epithelium (RPE). In contrast, reticular pseudodrusen appear above the RPE in clusters that have a distinct ribbon- or dot-like appearance. Presence of pseudodrusen is linked to greater risk of progression to late-stage disease condition called geographic atrophy in which retinal cells die off.
The researchers looked at DNA from three groups of people: one with AMD and reticular pseudodrusen (AMD+RPD); one with AMD but no reticular pseudodrusen (AMD-RPD); and a third group with no AMD or reticular pseudodrusen (control). When combined, the two groups with AMD had a greater frequency of AMD-related gene variants, compared to the control group. As with prior studies, there was a disproportionately high prevalence of previously identified AMD risk variants on chromosomes 1 and 10, in both AMD groups, compared to control participants.
The picture was different when comparing the two AMD groups to each other. There was no difference between the AMD groups with and without RPD in AMD-associated variations on chromosome 1 Chromosome 1 bears the gene for complement H factor (CFH), a part of the immune system that helps tamp down inflammation. In 2005, scientists first revealed a link between CFH gene variants and AMD and have since vigorously explored how the gene and other components of the immune system's complement cascade influence AMD. In 2023, the FDA approved two new AMD drugs that target the complement cascade . While the drugs slowed geographic atrophy, their effects were modest.
In contrast, the frequency of chromosome 10 variations was greater in the AMD+RPD group, compared with the AMD-RPD group, especially with increasing reticular pseudodrusen number. The study found that the reticular pseudodrusen association on chromosome 10 was in a location comprising the genes ARMS2 and HTRA1. In this region, they found an association with variants of HTRA1-AS1 (also known as BX842242.1)-a stretch of DNA corresponding to a long non-coding RNA. Such molecules affect the function of other genes without first being translated into proteins.
"Our data show that these deposits of reticular pseudodrusen, present in some but not all AMD cases, are driven by pathways associated with chromosome 10 and not by genetic risk in other AMD-related genes such as those on chromosome 1," said Robyn Guymer, Ph.D., Centre for Eye Research Australia, Melbourne, who together with Melanie Bahlo, Ph.D., The Walter and Eliza Hall Institute of Medical Research, Melbourne, authored a report on the study with an international group of researchers representing the Reticular Pseudodrusen Consortium.
The researchers explored how the chromosome 10 risk variants might exert their effects by evaluating eye scans, finding that these variants were associated with thinner retina, compared with controls. While more research is needed, the chromosome 10 variants appear likely to affect retinal structure.
"This study reinforces that AMD is not one disease," said Emily Chew, M.D., who leads the NEI Division of Epidemiology and Clinical Applications and a co-author of the study report. "Our findings highlight that different treatment approaches will be needed for different AMD subtypes."
The study was funded in part by NEI. Principal funding was provided by a Synergy Grant through Australia's National Health and Medical Research Council .
