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Genotype–Phenotype Analysis of Atrophic Age-Related Macular Degeneration

What Does It Mean When You Don’t Find What You Were Expecting?
      In this issue, the article entitled, “Cluster Analysis and Genotype–Phenotype Assessment of Geographic Atrophy in Age-Related Macular Degeneration: AREDS2 Report 25,”
      • Keenan T.D.L.
      • Oden N.L.
      • Agrón E.
      • et al.
      Cluster analysis and genotype–phenotype assessment of geographic atrophy in age-related macular degeneration: Age-Related Eye Disease Study 2 report 25.
      addresses several critical areas related to our understanding of the clinical features of age-related macular degeneration (AMD) and the potential contributions of specific biochemical pathways and genetic risk variants to how AMD is manifested and progresses in the eye (see pg. 1061). As clinicians, we appreciate how each individual affected with AMD demonstrates a variety of retinal, retinal pigment epithelial, and choroidal alterations: hard drusen; soft drusen; reticular pseudodrusen (also known as subretinal drusenoid deposits); pigment migration; pigment epithelial detachments, tears, or both; geographic atrophy (GA); and different forms of choroidal neovascular membrane. As AMD progresses, the distribution of these clinical findings changes, in part from progression or regression of specific lesions as well as the obscuring of some features by more advanced features of the condition. For a complex genetic disorder such as AMD, a key question is why some features dominate in one individual and are less apparent in others. Are these differences meaningful for understanding the pathogenesis of the condition and the risk of progression? Can the genetic risk factors be more predictive of specific forms of AMD pathologic features as well as the likelihood, rate, and clinical pathway by which AMD progresses in a specific individual? Can we then use that knowledge to guide therapies to slow progression and mitigate the advanced, vision-losing stages of AMD?
      The work by Keenan et al
      • Keenan T.D.L.
      • Oden N.L.
      • Agrón E.
      • et al.
      Cluster analysis and genotype–phenotype assessment of geographic atrophy in age-related macular degeneration: Age-Related Eye Disease Study 2 report 25.
      attempts to tackle these important issues by bypassing our preconceptions regarding how different features of AMD are related to the development and progression of GA. They used both the total AMD genetic risk score as well as subscores representing risk factors within specific metabolic pathways to evaluate associations. Using 2 different methods of cluster analysis, they observed clustering of GA-related phenotypes in cross-sectional analyses that were not reflective of the results of clustering using the longitudinal data. Just as importantly, they did not find distinct subtypes of GA phenotypes with specific biochemical pathways defined by genetic risk variants. The results of this analysis are in contrast to the cluster analysis reported by Biarnes et al
      • Biarnes M.
      • Colijn J.M.
      • Sousa J.
      • et al.
      Genotype- and phenotype-based subgroups in geographic atrophy Secondary to age-related macular degeneration: the EYE-RISK Consortium.
      with the EYE-RISK Consortium in Europe. The differences between these 2 studies with respect to populations and study design are addressed carefully in the discussion by Keenan et al.
      • Keenan T.D.L.
      • Oden N.L.
      • Agrón E.
      • et al.
      Cluster analysis and genotype–phenotype assessment of geographic atrophy in age-related macular degeneration: Age-Related Eye Disease Study 2 report 25.
      Even with those differences, it is clear that the failure of this study to replicate the cluster analysis especially with respect to the genotype data in the European study was unexpected, because a number of AMD investigators have proposed phenotype distinctions for AMD that are driven by different risk alleles and genes. Neither group carried out a flawed analysis, and both have used cluster analysis appropriately as an exploratory process that can infer (but not prove) relationships. Perhaps a key distinction is the emphasis on longitudinal data in this article, which addresses the potential of changing AMD features over time.
      It is tempting to read the abstract of this article and quietly say, “They did a lot of great and sophisticated analyses, but didn’t really find anything new.” However, not finding the associations that many people have taken for granted and having done so with sufficient rigor and power that those fundamental assumptions need to be challenged really does represent a scientific breakthrough. This is not the first time when research results regarding atrophic AMD have upended our expectations. The failure of the lampalizumab clinical trials
      • Holz F.G.
      • Sadda S.R.
      • Busbee B.
      • et al.
      Efficacy and safety of lampalizumab for geographic atrophy due to age-related macular degeneration: Chroma and Spectri phase 3 randomized clinical trials.
      and the work of Grassman et al
      • Grassmann F.
      • Harsch S.
      • Brandl C.
      • et al.
      Assessment of novel genome-wide significant gene loci and lesion growth in geographic atrophy secondary to age-related macular degeneration.
      on the genetics of GA progression in AMD also are indications that our understanding of the progression of GA is incomplete. The absence of replication of the cluster analysis study by Biarnes et al
      • Biarnes M.
      • Colijn J.M.
      • Sousa J.
      • et al.
      Genotype- and phenotype-based subgroups in geographic atrophy Secondary to age-related macular degeneration: the EYE-RISK Consortium.
      is not a repudiation of that work, but rather is a challenge to our sense of certainty and a call to further investigation.
      If the observations and conclusions of Keenan et al
      • Keenan T.D.L.
      • Oden N.L.
      • Agrón E.
      • et al.
      Cluster analysis and genotype–phenotype assessment of geographic atrophy in age-related macular degeneration: Age-Related Eye Disease Study 2 report 25.
      are correct, they have important implications for the use of molecular genetic risk factors to predict AMD features and progression as well as to suggest that other factors, as yet unknown either genetic or environmental factors, can impact AMD and therapies that target specific biochemical or metabolic pathways of AMD may have impact regardless of the genetic makeup of the individual. The use of personalized (or precision) medical therapy for AMD may be beyond the capacity of our current knowledge of the genetics of AMD, but also may not be dependent solely on those genetic markers. Prior studies
      • Assel M.J.
      • Li F.
      • Wang Y.
      • et al.
      Genetic polymorphisms of CFH and ARMS2 do not predict response to antioxidants and zinc in patients with age-related macular degeneration: independent statistical evaluations of data from the Age-Related Eye Disease Study.
      have shown that the benefits of the Age-Related Eye Disease Study supplements are not contingent on the genetic risk factors that underlie an individual’s specific type of AMD. These findings challenge the notion that the phenotype of AMD and disease progression are not directly reflective of specific genetic risk factors that primarily contribute to an individual’s risk. We accept that in a cohort analysis, those with higher AMD genetic risk scores are both more likely to demonstrate AMD and more likely to do so at an earlier age. We also accept that those with more severe pre-GA phenotypic features of AMD are more likely to demonstrate GA (or choroidal neovascular membrane, or both) complications. The molecular genetics of AMD and the phenotypes of AMD cannot serve as proxies of each other, yet both inform our understanding of the risk of disease progression. As-yet unknown additional factors remain, such as environmental exposures (including smoking), behavioral factors (such as exercise, stress, sleep behavior), comorbidities, diet and gut microbiome, and epigenetic changes, that both may influence AMD and may serve as potential targets for interventions to lessen the potential for AMD-related vision loss. Finally, the possibility exists that new retinal imaging technologies, such as fluorescent lifetime retinal imaging
      • Dysli C.
      • Wolf S.
      • Zinkernagel M.S.
      Autofluorescence lifetimes in geographic atrophy in patients with age-related macular degeneration.
      and retinal features such as diffuse trickling GA
      • Fleckenstein M.
      • Grassmann F.
      • Lindner M.
      • et al.
      Distinct genetic risk profile of the rapidly progressing diffuse-trickling subtype of geographic atrophy in age-related macular degeneration (AMD).
      and basal laminar deposits, which are not easily visualized from fundus photographs,
      • Curcio C.A.
      Soft drusen in age-related macular degeneration: biology and targeting via the oil spill strategies.
      may yield new insights regarding phenotype–genotype associations that will change our perspectives again.
      The conclusions of this work challenge us to forsake at least some of our prior assumptions of this disease and guide us to a new space for our understanding and future management of AMD. In the context of the rising calls for precision or personalized medicine to address disease, we have to rethink both the genetic and phenotypic tools at our disposal to understand the variations of AMD manifestations and progression, as well as how that information can be used to guide therapeutics. Like any good piece of research, this work pushes us to do more and to ask more critical questions.

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        Cluster analysis and genotype–phenotype assessment of geographic atrophy in age-related macular degeneration: Age-Related Eye Disease Study 2 report 25.
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        Genotype- and phenotype-based subgroups in geographic atrophy Secondary to age-related macular degeneration: the EYE-RISK Consortium.
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        • Sadda S.R.
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        Efficacy and safety of lampalizumab for geographic atrophy due to age-related macular degeneration: Chroma and Spectri phase 3 randomized clinical trials.
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        Assessment of novel genome-wide significant gene loci and lesion growth in geographic atrophy secondary to age-related macular degeneration.
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        • Assel M.J.
        • Li F.
        • Wang Y.
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        Genetic polymorphisms of CFH and ARMS2 do not predict response to antioxidants and zinc in patients with age-related macular degeneration: independent statistical evaluations of data from the Age-Related Eye Disease Study.
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        Distinct genetic risk profile of the rapidly progressing diffuse-trickling subtype of geographic atrophy in age-related macular degeneration (AMD).
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