In recent decades, scientists have made significant advances in understanding age-related macular degeneration (AMD). Genetics is now known to play a major role in the risk and onset of AMD, with around 50% of cases believed to be inherited and passed through family lines.
Common Risk Factors for Macular Degeneration
Today, a number of specific genes are known to be associated with AMD. These findings not only help scientists better understand the mechanism of the disease, but open the door to the development of precision drugs that may one day help prevent or treat AMD.
Characteristics of AMD
Age-related macular degeneration is the most common cause of blindness in the developed world, affecting around 5% of the world’s population, including an estimated 11 million Americans. It typically develops after the age of 60.
AMD manifests with gradual changes in pigmentation of the retina and development of fatty deposits (drusen) in the central retina, called the macula. Central vision loss can occur as the result of the progressive deterioration of the retina (geographic atrophy) and/or the bleeding or excretion of fluid from the vascular layer deep in the retina, called the choroid.
There are numerous risk factors for AMD, many of which are environmental or health-associated. These include:
- Older age
- High blood pressure
- High cholesterol
- Cardiovascular disease
- Excessive sun exposure
- History of heavy alcohol use
- Being female
Other risk factors for AMD are clearly related to a person’s genetics. These include light eye color—something that you inherit from your parents—and a family history of the disease.
Scientists have known for many years that genetics played in part in the development of AMD. Research conducted among families has shown that having a first-degree relative with AMD, such as a parent or sibling, doubles your risk of the disease compared to families with no history of AMD (23.7% versus 11.6% respectively).
Among twins, the risk of AMD in both siblings ranges between 46% to 71%, according to a landmark study from the Harvard School of Public Health. Not surprisingly, monozygotic (identical) twins were more likely to both have AMD due to their shared genetics than dizygotic (fraternal) twins.
Patterns are also seen among people of different races. While AMD has long been considered a disease that affects whites more the Blacks, recent research suggests the association is not as straightforward with other racial or ethnic groups.
According to a 2011 analysis published in the American Journal of Ophthalmology, Latinos are at higher risk of nonexudative AMD (dry AMD) than whites, but at lesser risk of exudative AMD (wet AMD), a more advanced stage of the disease associated with profound central vision loss and blindness.
The same pattern has emerged with Asian-Americans, who are more likely to get AMD than whites but less likely to progress to severe disease.
How ancestry plays into these dynamics as is of yet unknown, but scientists have begun to make strides in understanding how certain specific genes contribute.
Gene Variants Linked to AMD
The advent of genome-wide association studies in the 1990s enabled scientists to identify common and rare genetic variants associated with specific traits and genetic diseases. Interestingly, AMD was one of the first diseases in which a specific causal variant was found through genomic research.
Scientists investigating the genetic causes of AMD made their first major discovery in 2005 with the identification of a specific variant of the so-called CFH gene. The variant, referred to as the Y402H risk allele, was shown to increase the risk of AMD by nearly fivefold if one parent contributes the gene. If both parents contribute the gene, the likelihood of AMD increases more than seven-fold.
The CFH gene is located on chromosome 1, the largest human chromosome, and provides the body with instructions on how to make a protein known as complement factor H (CFH). This protein regulates a part of the immune system, called the complement system, that helps immune cells destroy foreign invaders (such as bacteria and viruses), trigger inflammation, and remove debris from the body.
Scientists are still unsure how the Y402H risk allele causes retinal damage, but it is theorized that local disruption of the complement system has damaging effects on the eyes.
Although CHF is produced mainly by the liver, the retina also produces some CHF. When produced at normal levels, CHF helps retinal cells regenerate and remain healthy due to the continual clearance of dead cells (a process known as efferocytosis). When CHF levels are low, this process is impaired and may help explain why fatty deposits are able to collect in the macula of people with AMD.
The Y402H risk allele is also linked to a rare disorder called C3 glomerulonephritis in which the failure of CHF to clear debris from the filters of the kidney can cause serious kidney impairment and damage. Drusen are also common features of C3 glomerulonephritis.
Other Possible Variants
Even though the Y402H risk allele is the strongest genetic risk factor for AMD, having the variant doesn’t necessarily mean you will get AMD. Many scientists, in fact, believe that multiple risk alleles may be needed for AMD to occur (referred to as an additive genetic effect).
If so, it may explain why some people only get dry AMD while others progress to wet AMD. The combination of risk alleles and other risk factors (such as smoking and high blood pressure) may ultimately determine whether you get AMD and how badly.
Other genes linked to AMD include the ARMS2 and HTRA1 genes. both located on chromosome 10. Other rare variants involve the VEGF and KCTD genes. How these variants contribute to the development of AMD is still unknown.
The Way Forward
As the list of AMD-associated genetic variants grows, so, too, will interest in developing predictive risk models by which to develop genetic tests for AMD. While there are genetic tests for CHF, ARMS2, and HTRA1, their ability to accurately predict who will or will not get AMD is at best limited. Moreover, the identification of these variants really does little, if anything, to alter how AMD is treated.
If scientists are one day able to unlock how the genetic variants actually cause AMD, they may be able to develop precision drugs able to prevent or treat the disease. We saw this in the past when BRCA tests used to predict a woman’s genetic predisposition for breast cancer led to the development of precision drugs like Lynparza (olaparib) that directly targets BRCA mutations in women with metastatic breast cancer.
It is wholly conceivable that similar therapies can one day be developed that are able to correct abnormalities in the complement system cause by errant gene mutations.