Age-related macular degeneration is the leading cause of irreversible blindness in people 50 years of age or older in the developed world. This article reviews the clinical and histopathological features of age-related macular degeneration and its genetics and epidemiology and discusses current management options and research advances.

Research from JAMA Ophthalmology — Inhibition of Vascular Endothelial Growth Factor Prevents Retinal Ischemia—Associated Iris Neovascularization in a Nonhuman Primate

CHOROIDAL neovascularization (CNV) is the major cause of severe visual loss in patients with age-related macular degeneration (AMD). New blood vessels grow from the choroid and penetrate through the Bruch membrane into the subretinal pigment epithelial and subretinal space. These vessels can leak and bleed, leading to exudative retinal detachment and hemorrhage. Eventually, this process progresses to a fibrovascular scar with destruction of photoreceptors and vision loss.

We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH ( P < 10 ⁻⁷⁵ ), ARMS2 ( P < 10 ⁻⁵⁹ ), C2/CFB ( P < 10 ⁻²⁰ ), C3 ( P < 10 ⁻⁹ ), and CFI ( P < 10 ⁻⁶ ). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 × 10 ⁻¹¹ ), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci ( LIPC , P = 1.3 × 10 ⁻⁷ ; CETP , P = 7.4 × 10 ⁻⁷ ) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c—associated alleles near LPL ( P = 3.0 × 10 ⁻³ ) and ABCA1 ( P = 5.6 × 10 ⁻⁴ ). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.

Glaucoma is a widespread ocular disease characterized by a progressive loss of retinal ganglion cells (RGCs). Previous studies suggest that the cytokine tumor necrosis factor-α (TNF-α) may contribute to the disease process, although its rolein vivoand its mechanism of action are unclear. To investigate pathophysiological mechanisms in glaucoma, we induced ocular hypertension (OH) in mice by angle closure via laser irradiation. This treatment resulted in a rapid upregulation of TNF-α, followed sequentially by microglial activation, loss of optic nerve oligodendrocytes, and delayed loss of RGCs. Intravitreal TNF-α injections in normal mice mimicked these effects. Conversely, an anti-TNF-α-neutralizing antibody or deleting the genes encoding TNF-α or its receptor, TNFR2, blocked the deleterious effects of OH. Deleting the CD11b/CD18 gene prevented microglial activation and also blocked the pathophysiological effects of OH. Thus TNF-α provides an essential, although indirect, link between OH and RGC lossin vivo. Blocking TNF-α signaling or inflammation, therefore, may be helpful in treating glaucoma.