An assessment of prevalence of Type 1 CFI rare variants in European AMD, and why lack of broader genetic data hinders development of new treatments and healthcare access

PurposeAdvanced age-related macular degeneration (AAMD) risk is associated with rare complement Factor I (FI) genetic variants associated with low FI protein levels (termed 'Type 1'), but it is unclear how variant prevalences differ between AMD patients from different ethnicities.MethodsCollective prevalence of Type 1 CFI rare variant genotypes were examined in four European AAMD datasets. Collective minor allele frequencies (MAFs) were sourced from the natural history study SCOPE, the UK Biobank, the International AMD Genomics Consortium (IAMDGC), and the Finnish Biobank Cooperative (FINBB), and compared to paired control MAFs or background population prevalence rates from the Genome Aggregation Database (gnomAD). Due to a lack of available genetic data in non-European AAMD, power calculations were undertaken to estimate the AAMD population sizes required to identify statistically significant association between Type 1 CFI rare variants and disease risk in different ethnicities, using gnomAD populations as controls.ResultsType 1 CFI rare variants were enriched in all European AAMD cohorts, with odds ratios (ORs) ranging between 3.1 and 7.8, and a greater enrichment was observed in dry AMD from FINBB (OR 8.9, 95% CI 1.49-53.31). The lack of available non-European AAMD datasets prevented us exploring this relationship more globally, however a statistical association may be detectable by future sequencing studies that sample approximately 2,000 AAMD individuals from Ashkenazi Jewish and Latino/Admixed American ethnicities.ConclusionsThe relationship between Type 1 CFI rare variants increasing odds of AAMD are well established in Europeans, however the lack of broader genetic data in AAMD has adverse implications for clinical development and future commercialisation strategies of targeted FI therapies in AAMD. These findings emphasise the importance of generating more diverse genetic data in AAMD to improve equity of access to new treatments and address the bias in health care.Peer reviewe

An assessment of prevalence of Type 1 CFI rare variants in European AMD, and why lack of broader genetic data hinders development of new treatments and healthcare access

PurposeAdvanced age-related macular degeneration (AAMD) risk is associated with rare complement Factor I (FI) genetic variants associated with low FI protein levels (termed ‘Type 1’), but it is unclear how variant prevalences differ between AMD patients from different ethnicities.MethodsCollective prevalence of Type 1 CFI rare variant genotypes were examined in four European AAMD datasets. Collective minor allele frequencies (MAFs) were sourced from the natural history study SCOPE, the UK Biobank, the International AMD Genomics Consortium (IAMDGC), and the Finnish Biobank Cooperative (FINBB), and compared to paired control MAFs or background population prevalence rates from the Genome Aggregation Database (gnomAD). Due to a lack of available genetic data in non-European AAMD, power calculations were undertaken to estimate the AAMD population sizes required to identify statistically significant association between Type 1 CFI rare variants and disease risk in different ethnicities, using gnomAD populations as controls.ResultsType 1 CFI rare variants were enriched in all European AAMD cohorts, with odds ratios (ORs) ranging between 3.1 and 7.8, and a greater enrichment was observed in dry AMD from FINBB (OR 8.9, 95% CI 1.49–53.31). The lack of available non-European AAMD datasets prevented us exploring this relationship more globally, however a statistical association may be detectable by future sequencing studies that sample approximately 2,000 AAMD individuals from Ashkenazi Jewish and Latino/Admixed American ethnicities.ConclusionsThe relationship between Type 1 CFI rare variants increasing odds of AAMD are well established in Europeans, however the lack of broader genetic data in AAMD has adverse implications for clinical development and future commercialisation strategies of targeted FI therapies in AAMD. These findings emphasise the importance of generating more diverse genetic data in AAMD to improve equity of access to new treatments and address the bias in health care.</p

The Past, Present, and Future of Exudative Age-Related Macular Degeneration Treatment

Treatment of exudative age-related macular degeneration has been revolutionized within the last 6 years with the introduction of vascular endothelial growth factor neutralizing agents. Previously popular “destructive treatments,” such as laser photocoagulation and photodynamic treatment have either been abandoned or used as an adjunct to pharmacotherapy. Despite the increase in vision after antivascular endothelial growth factor (VEGF) agents, they require repetitive and costly intravitreal injections that also carry the inherit risks of infection, retinal tears, and detachment. Several new and more potent VEGF inhibitors are at different stages of development. The goal of evolving pharmacotherapy is to preserve the therapeutic effect while reducing or eliminating the discomfort of intravitreal drug delivery, as well as identify new therapeutic targets. Complement inhibitors, immunomodulators, integrin inhibitors are a few of the new class of drugs that are expected to be in our armamentarium soon. Current medications act to decrease leakage through abnormal subretinal choroidal vasculature and promote involution. However, these medications are only effective in treating the active stage of the choroidal neovascular membrane. Restoration of vision of a large number of patients with involuted choroidal neovascular membranes is warranted. For this purpose, tissue engineering techniques have been employed to reconstruct the subretinal anatomy. Discovery of biomarkers, pharmacogenetics, and very specific targeting holds the promise of increased potency and safety in the future

Increased intraretinal radial reflectance ("retinal flare") as an optical coherance tomographic biomarker for the diagnosis of retinal angiomatous proliferation

Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO) -- APR 29-MAY 03, 2018 -- Honolulu, HIWOS: 000442932800093…The Association for Research in Vision and OphthalmologyResearch to Prevent Blindness, Inc, New York, NY, Slomo; Cindy Silvian Foundation, New York, NY. New York StateSupport Supported by an unrestricted grant from Research to Prevent Blindness, Inc, New York, NY, Slomo and Cindy Silvian Foundation, New York, NY. New York Stat