Genomic Architecture of Progression and Treatment Response in AMD

Numerous studies have identified common and rare genetic variation associated with risk of advanced age-related macular degeneration (AMD). However, risk is just one facet of AMD disease architecture. Both disease progression and response to treatment are two critical elements that may also be influenced by genetic variation. The primary aim of this study was to identify genetic variation influencing progression and response to treatment for AMD, with a secondary aim of further elucidating the genetic etiology of AMD risk. We ascertained AMD cases and controls of European ancestry from Vanderbilt Eye Institute (VEI) and the Bascom Palmer Eye Institute (BPEI) and obtained blood samples from all participants. Eyes were examined using standard ophthalmological methods, and graded according the modified Age-Related Eye Disease Study scale (AREDS grades 1-5) using fundus photography. Individuals were re-examined in follow-up exams at regular intervals to assess any change in AMD grade. Eyes with advanced neovascular AMD that were examined using ocular coherence tomography imaging (OCT), treated with anti-angiogenesis therapy and monitored for response to treatment. All individuals ascertained for the study were exome-chipped for genome-wide single nucleotide variation coverage. To target rare genetic variation, whole exome sequencing was performed on individuals at the phenotypic extremes based on 1) AMD grade, 2) rate of progression from intermediate to advanced AMD and 3) response to anti-VEGF treatment for eyes with advanced neovascular AMD. ]]> Whole exome sequencing: 3 sets of phenotypically extreme individuals of European ancestry were whole exome sequenced. 1. Risk extremes To target novel AMD risk and protective variants we sequenced 99 phenotypically extreme individuals; 49 cases and 50 controls. Inclusion/exclusion criteria: Extreme cases Inclusion: individuals with bilateral advanced choroidal neovascular (AREDS grade 5) AMD. Extreme controls Inclusion: unaffected controls (bilateral AREDS grade 1) with no (or very few) small drusen. 2. Progression extremes To target variants associated with progression of AMD we whole exome sequenced 35 individuals that progressed quickly to advanced AMD (fast-progressors) and 30 individuals that did not progress quickly (maintainers): Inclusion/exclusion criteria: Fast-progressors Inclusion: individuals with at least 1 eye that progressed from AREDS grade 2, 3 or 4 to grade 5 in a year or less. Maintainers Inclusion: individuals with at least 1 eye that remained at grade 3 for at least 4 years. 3. Treatment response To target variants associated with the response to anti-angiogenesis treatment of advanced neovascular AMD (AREDS grade 5), we whole exome sequenced 43 grade 5 individuals with a baseline exam and a follow-up exam at one year. Treatment response was defined using gain/loss of lines of vision, change in intraretinal or subretinal fluid and central retinal thickness. Treatment response was characterized qualitatively as: 1. GOOD RESPONSE - three lines of vision gain, prolonged or persistent (at least 6 months) absence of SRF on OCT, absence of intraretinal fluid on OCT, presence of unchanged small intraretinal cysts with no recurrence of SRF; 2. PARTIAL RESPONSE - decrease in SRF and intraretinal fluid, but not complete absence; 3. RESPONSE WITH RECURRENCE - Recurrence of SRF and or intraretinal fluid after good response for at least 6 months; 4. POOR RESPONSE - three lines of vision loss, persistent SRF and IRF, formation of disciform scar. Inclusion/exclusion criteria: Inclusion: Individuals with at least one follow-up exam one year (7-17 months) after baseline exam were included. Exome-chip genotyping: We exome-chip genotyped all individuals ascertained for this study that had not been genotyped at CIDR by the International AMD Genomics Consortium. These were done on 2 Illumina chips, 384 on the first and 356 on the second, 740 in total. We have 627 cases and 56 controls. We will provide updated phenotype files for the exome chip genotyped individuals as we continue in our analyses.]]>