A genetic approach to stratification of risk for age-related macular degeneration

The genetic determinants of age-related macular degeneration (AMD) are reviewed and a novel approach to risk determination based upon inherited genetic polymorphisms and smoking history is presented. Although AMD was long thought to have primarily an environmental etiology, genetic variation is now known to account for the majority of the disease risk, with variations in the genes of the complement pathways playing a prominent role. Independent and validated clinical studies have implicated the C3 gene and its regulator, complement factor H (1q31.1), complement component 2 (6q21.33), and complement factor B (6q21.33). Subtle variations in complement activity increase the risk of symptomatic macular inflammation with age. A second group of AMD-associated genetic markers may aggravate complement-mediated inflammation by permitting retinal oxidative damage. Variation within the chromosomal site (10q26) coding a mitochondrial-associated protein (age-related maculopathy susceptibility 2) and an independent variation within the mitochondrial genome itself (A4917G) suggest a contributing pathophysiological role of retinal oxidative stress. A genetic panel of disease-susceptibility markers and smoking history can identify a group of individuals with greater than 65% lifetime risk of AMD. The introduction of genetic marker testing into clinical practice may identify patients with early disease who may be aided by presymptomatic monitoring or inclusion into trials of newer prophylactic agents.