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Defining the genomic architecture of Age-related Macular Degeneration (AMD)

to improve diagnosis, prevention, and treatment.

Guidance regarding genetic testing for age-related macular degeneration

Multiple studies have provided compelling evidence that common variants can account for about 70% of the hereditary component for AMD. Highly penetrant rare risk alleles have also been identified which carry a very high likelihood of the development of AMD and have been particularly valuable in understanding the biology of the condition.

The development of genetic risk models (some of which include nongenetic factors such as smoking exposure and nutritional data) has caused both patients and clinicians to wonder if genetic testing and genetic risk scores (GRS), which are a composite of multiple variants would be useful. In particular, there has been considerable controversy as to whether modifiable exposures and behaviors such as smoking and nutrient supplements should be selectively applied to individuals with varying genetic risk profiles. To date, the best evidence indicates that, regardless of an individual’s genetic risk level for AMD, the avoidance of smoking, a healthy Mediterranean-style diet, and the use of the AREDS2 supplements are able to lower the overall risk of incidence and/or progression.

We now recognize that for complex genetic conditions such as AMD, population-based genetic risk models (particularly those that have been established with limited population diversity), while useful for clinical trials (to stratify risk groups and for randomization) have limited applicability to individuals since there is no guarantee that an individual with a low AMD GRS will not develop AMD, nor that a person with a high GRS will inevitably develop vision-threatening AMD (perhaps because of one or more unrecognized protective alleles).

There are several scenarios for which one might consider performing molecular genetic testing. It is perhaps easiest to consider each representative case.

1) A young individual who has been diagnosed with AMD (either early or advanced disease)

For these individuals, the primary question is not whether or not they have AMD unless they are relatively young and one suspects that they may have a “late” onset macular dystrophy (a Mendelian inherited condition – either autosomal dominant, autosomal recessive, X-linked or mitochondrial).

If the onset of clinical findings of retinal disease is below the age of 50, then one should consider looking for associated systemic manifestations (particularly renal disease), as well as pentosan, plaquenil, and/or phenothiazine exposure. These individuals should be clinically characterized (using blue light autofluorescence) to determine if the drusen or drusenoid-deposits are hyperautofluorescent (contain lipofuscin). One may consider obtaining a full field ERG if there are symptoms of nyctalopia, light sensitivity, color vision difficulties, and/ or poor dark adaptation).

Genetic testing can be considered using a panel of genes that includes the macular dystrophies, cone dystrophies, the mitochondrial variant and rare variants associated with AMD. AMD genetic screening with a common variant AMD panel is not advised as a first line of molecular genetic testing.

2) An individual with early or intermediate AMD who is concerned about the risk of disease progression to geographic atrophy or exudative AMD.

Genetic testing might provide some insight into the probability of progression but would not have sufficient discrimination on an individual level to guide surveillance frequency or alter potential treatments. Genetic studies have shown that avoiding smoking and a Mediterranean diet can lower risk of incident and progressive AMD over the entire spectrum of genetic risk levels. At this time, genetic testing doesn’t play a role in guiding the treatment for AMD progression.

3) An individual who has one or both parents with AMD and who is concerned that they are at risk for the condition.

Generally, the best advice is to optimize modifiable risk factors (smoking, diet, activity (including treatment for possible sleep apnea) and not have genetic testing since it would not modify the recommendations. If the person is 45 or older, one can do clinical testing with OCT to see if drusen are present and consider testing for delays in dark adaptation kinetics.

If the person is insistent that they need genetic testing because of their concerns regarding their family members, it is preferable to do AMD genetic testing first in the affected family members so that one knows which genetic variants are potentially attributable to that person’s disease and then test the proband. If one finds that the affected parent lacks the major (or multiple) high-risk AMD alleles, then genetic testing in the proband will be of limited utility, since exogenous factors and/or undetected AMD risk alleles will confound the interpretation of the proband’s test results. Ideally both parents would be tested before the proband is tested.

4) An individual with exudative AMD who wants to know if genetic testing will alter their recommended treatment (intravitreal agent and/or frequency of injections, supplements).

Genetic testing yields no discernable benefits at this time. While some have advocated modified anti-VEGF therapy with PDT for AMD-related patients with polypoidal choroidopathy, this distinction is best determined by clinical diagnostics (OCT, OCTA and/or retinal angiography). Genetic testing is not useful in this circumstance.

What about genetic testing for individuals with AMD who are unsure if they should take nutrient supplements (AREDS II formulation)? Some investigators have reported that their analyses have indicated that some genetic subtypes of AMD can benefit from taking nutrient supplements while others may experience no benefit and possibly some detrimental effects. This has been contrasted with the findings of the AREDS study group who found no correlation of AMD genetic variants with potential benefits from the AREDS II supplements. Many clinicians are unaware that this dispute has been resolved by having three independent groups of statisticians reanalyze the same data from which the opposing claims have been made.

Their findings were published and clearly sided with the lack of genetic associations with the effectiveness or risks of the nutrient supplements. There is no indication for genetic testing for AMD to guide nutrient supplementation use. This is in conflict with the assertions made by Arctic Dx at their website, which continues to cite the original studies that have been in dispute.

5) An individual who is going to enter a clinical trial for either prevention, progression and/or treatment of AMD.

Given that many of these therapeutic modalities are targeting specific biological pathways (e.g. complement activation pathway, lipid metabolism, inflammatory cycle), it is useful to know the underlying genetic architecture of the patient’s AMD.

Genetic testing for AMD-related risk variants could provide insights into whether or not the intervention is beneficial (or not) for genetically-defined subgroups of AMD patients. Since this has no direct benefit for the patient, the costs of such testing should be part of the clinical research protocol and not charged to the patient.

These clinical trials, regardless of the efficacy of the therapeutic agent under study, provide detailed phenotyping and progression-related measures that can further aid our understanding the differences between the biology responsible for the incidence of AMD and the factors that affect disease progression.

Contact us:

Susan Halloran Blanton, PhD

Project Manager, IAMDGC

Email:  SBlanton@med.miami.edu