Age-related macular degeneration (AMD) is the most frequent cause of irreversible blindness in the elderly in developed countries. Our previous studies implicated activation of complement in the formation of drusen, the hallmark lesion of AMD. Here, we show that factor H (HF1), the major inhibitor of the alternative complement pathway, accumulates within drusen and is synthesized by the retinal pigmented epithelium. Because previous linkage analyses identified chromosome 1q25-32, which harbors the factor H gene (HF1͞CFH), as an AMD susceptibility locus, we analyzed HF1 for genetic variation in two independent cohorts comprised of Ϸ900 AMD cases and 400 matched controls. We found association of eight common HF1 SNPs with AMD; two common missense variants exhibit highly significant associations (I62V, 2 ‫؍‬ 26.1 and P ‫؍‬ 3.2 ؋ 10 ؊7 and Y402H, 2 ‫؍‬ 54.4 and P ‫؍‬ 1.6 ؋ 10 ؊13 ). Haplotype analysis reveals that multiple HF1 variants confer elevated or reduced risk of AMD. One common at-risk haplotype is present at a frequency of 50% in AMD cases and 29% in controls [odds ratio (OR) ‫؍‬ 2.46, 95% confidence interval (1.95-3.11)]. Homozygotes for this haplotype account for 24% of cases and 8% of controls [OR ‫؍‬ 3.51, 95% confidence interval (2.13-5.78)]. Several protective haplotypes are also identified (OR ‫؍‬ 0.44 -0.55), further implicating HF1 function in the pathogenetic mechanisms underlying AMD. We propose that genetic variation in a regulator of the alternative complement pathway, when combined with a triggering event, such as infection, underlie a major proportion of AMD in the human population.A ge-related macular degeneration (AMD) is the leading cause of irreversible vision loss (1, 2), affecting Ϸ50 million individuals worldwide. AMD is characterized by a progressive loss of central vision attributable to degenerative and neovascular changes that occur at the interface between the neural retina and the underlying choroid. At this location are the retinal photoreceptors, the retinal pigmented epithelium (RPE), a basement membrane complex known as Bruch's membrane (BM) and a network of choroidal capillaries.The prevailing view is that AMD is a complex disorder stemming from the interaction of multiple genetic and environmental risk factors (3,4). Familial aggregation studies indicate that a genetic contribution can be identified in up to 25% of the cases (5). Thus, AMD appears to be a product of the interaction between multiple susceptibility loci rather than a collection of single-gene disorders. The number of loci involved, the attributable risk conferred, and the interactions between various loci remain obscure.

IMPORTANCE With the advent of more sophisticated imaging systems, such as spectral domain optical coherence tomography (SD-OCT), disruption of the inner segment/outer segment (IS/OS) band, and thinning of the outer nuclear layer (ONL) have been identified in association with acute macular neuroretinopathy (AMN). OBJECTIVES To characterize a new SD-OCT presentation of AMN as a paracentral acute middle maculopathy and to describe multimodal imaging findings that implicate an underlying pathogenesis related to retinal capillary ischemia. DESIGN, SETTING, AND PARTICIPANTS Retrospective observational case series (January 1, 2012, to January 1, 2013) reviewing clinical and imaging data from 9 patients (11 eyes) with AMN at 6 tertiary referral centers. Lesions were classified as type 1 or 2 in relation to the SD-OCT location of the lesion above (type 1) or below (type 2) the outer plexiform layer (OPL) at 6 tertiary referral centers. RESULTS Of the 9 patients, 5 were female and 4 were male (mean age, 47.6 years; range, 21-65 years). All patients presented with an acute paracentral scotoma and demonstrated a classic dark gray paracentral lesion with near-infrared imaging. Visual acuity ranged from 20/15 to 20/30. Six eyes (5 patients) had type 1 SD-OCT lesions, also referred to as paracentral acute middle maculopathy, and 5 eyes (4 patients) had type 2 SD-OCT lesions. Although type 1 lesions lead to inner nuclear layer (INL) thinning, type 2 lesions resulted in ONL thinning. Type 2 lesions were always associated with significant outer macular defects, including disruption of the inner segment/outer segment and outer segment/retinal pigment epithelium bands, whereas type 1 lesions spared the outer macula. CONCLUSIONS AND RELEVANCE Paracentral acute middle maculopathy may represent a novel variant of AMN that affects the middle layers of the macula above the OPL as diagnosed with SD-OCT imaging. Two types of AMN lesions may be seen with SD-OCT occurring above and below the OPL. Type 1 refers to hyperreflective bands in the OPL/INL region with subsequent INL thinning. Type 2 is hyperreflective bands in the OPL/ONL region with subsequent ONL thinning. Type 2 lesions may be associated with concomitant defects of the inner segment/outer segment layer. We propose that each of these lesions may be explained by occlusion of either the superficial capillary plexus (type 1) or deep capillary plexus (type 2) located in the innermost and outermost portion of the INL, respectively, immediately adjacent to each corresponding lesion type.

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Analyses of AREDS2 data on natural history of GA provide representative data on GA evolution and enlargement. GA enlargement, which was influenced by lesion features, was relentless, resulting in rapid central vision loss. The genetic variants associated with faster enlargement were partially distinct from those associated with risk of incident GA. These findings are relevant to further investigations of GA pathogenesis and clinical trial planning.

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Central serous chorioretinopathy (CSC) is characterized by leakage of fluid from the choroid into the subretinal space and, consequently, loss of central vision. The disease is triggered by endogenous and exogenous corticosteroid imbalance and psychosocial stress and is much more prevalent in men. We studied the association of genetic variation in 44 genes from stress response and corticosteroid metabolism pathways with the CSC phenotype in two independent cohorts of 400 CSC cases and 1,400 matched controls. The expression of cadherin 5 (CDH5), the major cell–cell adhesion molecule in vascular endothelium, was downregulated by corticosteroids which may increase permeability of choroidal vasculature, leading to fluid leakage under the retina. We found a significant association of four common CDH5 SNPs with CSC in male patients in both cohorts. Two common intronic variants, rs7499886:A>G and rs1073584:C>T, exhibit strongly significant associations with CSC; P = 0.00012; odds ratio (OR) = 1.5; 95%CI [1.2;1.8], and P = 0.0014; OR = 0.70; 95%CI [0.57;0.87], respectively. A common haplotype was present in 25.4% male CSC cases and in 35.8% controls (P = 0.0002; OR = 0.61, 95% CI [0.47–0.79]). We propose that genetically predetermined variation in CDH5, when combined with triggering events such as corticosteroid treatment or severe hormonal imbalance, underlie a substantial proportion of CSC in the male population.