Deficiency in the metabolite receptor SUCNR1 (GPR91) leads to outer retinal lesions.

Age-related macular degeneration (AMD) is a prominent cause of blindness in the Western world. To date, its molecular pathogenesis as well as the sequence of events leading to retinal degeneration remain largely ill-defined. While the invasion of choroidal neovessels in the retina is the primary mechanism that precipitates loss of sight, an earlier dry form precedes it. Here we provide the first evidence for the protective role of the Retinal Pigment Epithelium (RPE)-resident metabolite receptor, succinate receptor 1 (SUCNR1; G-Protein coupled Receptor-91 (GPR91), in preventing dry AMD-like lesions of the outer retina. Genetic analysis of 925 patients with geographic atrophy and 1199 AMD-free peers revealed an increased risk of developing geographic atrophy associated with intronic variants in theSUCNR1 gene. In mice, outer retinal expression of SUCNR1 is observed in the RPE as well as microglial cells and decreases progressively with age. Accordingly, Sucnr1-/- mice show signs of premature sub-retinal dystrophy with accumulation of oxidized-LDL, abnormal thickening of Bruch's membrane and a buildup of subretinal microglia. The accumulation of microglia in Sucnr1-deficient mice is likely triggered by the inefficient clearance of oxidized lipids by the RPE as bone marrow transfer of wild-type microglia into Sucnr1-/- mice did not salvage the patho-phenotype and systemic lipolysis was equivalent between wild-type and control mice. Our findings suggest that deficiency in SUCNR1 is a possible contributing factor to the pathogenesis of dry AMD and thus broaden our understanding of this clinically unmet need.

NEI-AMD is a collaborative of researchers from the University of Michigan, Mayo Clinic, University of Pennsylvania, and the AREDS group including National Eye Institute intramural investigators. Institutional review boards at each NEI-AMD study site reviewed and approved the study protocols. Each participant provided written informed consent in accordance with the Declaration of Helsinki.

Subjects and Study Design
NEI-AREDS Cohort. Details on AREDS and the demographics NEI-AREDS participants involved in the NEI-AREDS genome-wide association study design exist at the link cited above. In brief, AREDS was a 12 year multi-center natural history study (with a 5-year phase III clinical trial) on 4757 elderly U.S. residents designed to assess the clinical course of, and risk factors for, the development and progression of AMD by collecting data on possible risk factors, measuring changes in visual acuity, photographically documenting changes in macula status, and assessing self-reported visual function. Eleven retinal specialty clinics enrolled participants aged 55 to 80 years from November 1992 through January 1998, and followed them until April 2001. A natural history study extending to December 2005 was implemented in April 2001. Our analytic sample contained 391 people with GA or GA+NV AMD and 189 of their AMD-free peers.
NEI-AMD Cohort. Details on the NEI-AMD genomewide association (GWA) study exist at the link in the first paragraph of this section.
In brief, three independent cohorts from the University of Michigan in Ann Arbor, the University of Pennsylvania in Philadelphia, and the Mayo Clinic in Rochester, Minnesota contributed data to this genome-wide association study. Our analytic sample contained respectively 329, 110, and 95 people with GA or GA+NV AMD from the University of Michigan, University of Pennsylvania, and The Mayo Clinic. There were 508, 194, and 308 AMD-free people, aged > 65 years from these respective sites.

Outcome Ascertainment
We restricted our AMD-free comparison cohort to people aged > 65 years. The likelihood of having AMD increases 2-to-6 fold after age 75 and it was therefore essential to select our oldest AMD-free participants to reduce the chances of including false negatives in analyses (that would otherwise result from non-random misclassification in the youngest members of the control group).
AREDS Cohort. AREDS Report 1 contains information on outcome ascertainment in the NEI-AREDS cohort.
Specifics on the classification of GA exist at https://web.emmes.com/study/areds/mopfiles/chp15_mo p.pdf Geographic atrophy was classified as one or more sharply defined, usually more or less circular patches of partial or complete depigmentation of the retinal pigment epithelium (RPE), typically with exposure of underlying large choroidal blood vessels --either at baseline or during the course of the study. To be classified as geographic atrophy in AREDS, a patch had to be at least as large in area as Circle I-1 (see link directly above). In general, at least two of the characteristics mentioned (sharp edges, more or less circular shape, and visibility of underlying choroidal vessels) were required for a patch to be classified as geographic atrophy --if much of the RPE appeared to be preserved and large choroidal vessels were not visible, a roundish patch of RPE depigmentation with sharp edges may still have been classified as geographic atrophy. "Edge sharpness" was defined in either of two ways: (1) when the depigmentation within the patch was subtle, a "sharp" edge needed to be abrupt and smooth, like one made with a cookie-cutter, but (2) when contrast between depigmentation within a patch and the normal pigmentation around it was substantial, the edge of the patch may still have been considered "sharp", even if the transition occurred gradually or irregularly over a zone 125 to 250 μm in width. Increased visibility of large choroidal vessels was the single most important criterion and, when present, it was not necessary for all the edges of the patch to be classified as sharp.
Our NEI-AREDS controls have three distinguishing characteristics: • Phenotype was determined annually over a 12year period (AREDS) or across an 8-year period with a standardized protocol by multiple professional graders who were masked to phenotypic information from previous years. Adjudication with a standardized protocol occurred when discrepancies emerged.

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The criteria for AMD-free classification (< 5 drusen of < 63 μm in both eyes for the entire follow-up period) is stringent relative to those applied in previous association studies for AMD.

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The age of the AREDS AMD-free group is in the range in which AMD prevalence increases ~3 times (from ~4% in those age 74-to-79 to ~12% in those > 80year-of-age) in population-based studies.
NEI-AMD Cohorts. Experienced graders (ophthalmologists) classified outcomes according to AMD diagnosis in the worse eye. Our AMD-free comparison group was composed of people > 65-years-of-age who had no large www.impactaging.com