meyerle

We asked Catherine Meyerle, MD, a recent MVRF International Scientific Conference participant, to answer some of your frequently asked questions about the genetics of AMD and what it means for you and your family.

Do genetics play a big role in age-related macular degeneration (AMD)? What should I tell my children?

Yes, genetics play a role. Genome wide association studies have identified multiple genetic loci that convey susceptibility to AMD. Theses genetic loci are estimated to account for up to 65% of AMD heritability1. But the key word is susceptibility. The susceptibility genes of age-related macular degeneration differ from the Mendelian inheritance pattern of blue eyes for example. If both parents have blue eyes, then the children will have blue eyes as they have inherited two recessive alleles. But the development of AMD is complex with aging and environmental factors, in addition to genetics, affecting the ultimate development or lack of development of AMD.

While one cannot halt the aging process, there are controllable environmental factors that play a role in the form of epigenetic changes. While we inherit our parents’ genes, environmental factors can affect expression of those genes. Children of AMD patients should know that they may have inherited AMD susceptibility genes, but they can still control environmental factors that may increase their risk. For example, smoking is a known modifiable risk factor2. And it is important to have annual dilated eye examinations, particularly after age 50 years, to detect retinal changes that may indicate the need to begin anti-oxidant supplements to reduce risk of progression to advanced AMD.

In summary, children of age-related macular degeneration patients may have an increased chance of developing age-related macular degeneration but their family history is not necessarily their “destiny.” They have control of behavioral factors that may reduce their risk of developing this multifactorial retinal disease.

How will AMD genetics play a role as a resource for future treatment options?

Identification of genetic susceptibility loci has promoted greater understanding of the pathogenesis of age-related macular degeneration that is translating into treatment strategies. For example, genome wide association studies have implicated the complement pathway in the development of age-related macular degeneration. Multiple clinical trials now exist exploring modulation of the complement pathway. This is particularly important for geographic atrophy, the less common form of advanced disease for which there is currently no treatment. Investigation of lampalizumab, a Factor D inhibitor that affects the alternative complement pathway, has shown promise in slowing the growth of geographic atrophy3.

The role of genetic testing may change in the future as well. At this time, I do not recommend genetic testing as the genes only predict susceptibility and 35% of the heritability of AMD remains unknown. My advice regarding not smoking and routine eye examinations would remain unchanged for family members with either a positive or negative genetic test. Additionally, there are currently no prophylactic treatments for individuals with specific susceptibility genetic loci. However, as understanding of AMD pathogenesis continues to evolve, treatments targeting the altered biochemical pathways conferred by a specific gene may be discovered and this would change the implications of routine genetic testing and prevention strategies.

Is AMD more prevalent in women? Is it gender or genetics?

While there have been reports suggesting more women have AMD, worldwide population-based studies have not found an increased prevalence in women. A global meta-analysis of 129,664 individuals found no significant gender predilection4. Advanced age, however, is a strong risk factor. Since women typically live longer, there may be an impression that more women have AMD. While prevalence rates may vary by geographic location, worldwide studies with a macroscopic epidemiological view have not shown significant difference in prevalence among women. Therefore, a family history of AMD is more important than female gender.

In your opinion, name the most recent significant scientific breakthrough in the field of genetics that will have an impact on advancing vision research from “bench to bedside?”

Genome wide association studies have promoted greater understanding of disease pathogenesis and have provided the rationale for many current clinical trials. Yet 35% of the heritability of AMD remains unknown. There may be rare genetic variants that genome wide association studies have not been able to detect1 and more advanced DNA sequencing techniques may be required. Further studies in epigenetics may also explain the gap in known heritability and elucidate how interactions between genetics and the environment can trigger the expression of genes leading to AMD development. Genome wide association studies have created the foundation for future studies to identify additional heritability factors that may guide treatment strategies to block the cascade of molecular and cellular events promoting the development of AMD.

Content contributed by
Catherine Meyerle, MD

Assistant Professor of Ophthalmology
Wilmer Eye Institute, Johns Hopkins School of Medicine

November 2015

References 1. Fritsche LG, Chen W, Schu M et al. AMD Gene Consortium Seven New Loci associated with age-related macular degeneration. Nat Genet 2013; 45:433-9. 2. Evans JR. Risk Factors for Age Related Macular Degeneration. Prog Retin Eye Res 2001; 20(2):227-253 3. Jack LS, Sadiq MA, Do DV et al. Emixustat and Lampalizumab: Potential therapeutic options for geographic atrophy. Dev Ophthalmol. 2016; 55;302-309. 4. Wong WL, Xinyi S, Xiang L et al. Global prevalence of agerelated macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Global Health 2014; (2)e106-116.