Genetics of Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the most common form of legal blindness in the USA as well as other developed countries. The Eye Disease Prevalence Group estimated that 1.75 million US citizens in 2004 had advanced AMD in at least one eye [1]. As the population lives longer this number is expected to increase to 22 million individuals having some form of AMD by 2050; unless the disease can be prevented, progression to advanced disease can be slowed or treated effectively at any stage [2]. Approximately 10% of the population aged 43 and older is affected with some form of the disease and 30% of the population aged 75 and older is affected with AMD [3]. For further information on the prevalence and epidemiology of AMD, please see other chapters in this book. Most current therapies are anti-VEGF based, and are focused on an advanced stage of the disease, neovascular AMD. Although these treatments offer some chance of visual improvement, they require invasive delivery methods and have limited ability to prevent or reverse vision loss. Assessments of an individual's risk of developing advanced AMD are still based on ocular findings in those who already have the early stages [4]. Methods in biomarker development continue to be refined that determine which individuals are at highest risk of vision loss due to AMD prior to the development of any signs of the disease. Men and women can both be affected with AMD, though some reports show that woman are 1.3 times at greater risk for AMD [5]. Age and a positive family history of AMD are the two strongest risk factors for AMD. Studies of some genetic and epidemiologic factors have not been in agreement as to predictors of AMD. Cigarette smoking appears to be a consistent epidemiologic risk factor associated with an increased risk for AMD [6], while allelic variants in the complement factor H gene (CFH) located on chromosome 1 and the ARMS2/HTRA1 gene on chromosome 10 are the strongest genetic risk factors. AMD-associated variants in these two loci have been identified consistently, whether the analysis is a candidate gene study or a genome-wide association studies (GWAS). In fact, 50% of the heritability of AMD can be explained by variants at these two loci (CFH and ARMS2/HTRA1). Several independent reports have shown the functional polymorphism Y402H in CFH (rs1061170), where a tyrosine is substituted by a histidine, to be associated with increased risk of both early [7-11] and late stages of AMD (both neovascular and geographic atrophy) [7, 8, 11-18]. Although having these factors may increase one's risk of disease, there are still many individuals who both smoke and have the CFH-associated disease variants but have no signs of AMD. For this reason, the magnitude of risk for AMD probably depends on exposure to other environmental and genetic risk factors in combination with smoking and CFH variation. Similarly, there are several variants at the age-related maculopathy susceptibility 2/HtrA serine peptidase 1 (ARMS2/HTRA1) locus, including the single nucleotide polymorphism, A69S (rs10490924), that while associated with all AMD subtypes, risk alleles are still found at a high frequency in the normal population at a high frequency (> 30%) in age-matched normals [15, 19-22]. Discovering precisely which genes and environmental factors, and their interactions, contribute to the pathophysiology of AMD could provide targets that could be modifiable through therapeutic or behavioral intervention, thereby reducing or preventing the incidence of this disease. Knowing which common and/or rare variants in a handful of genes may predict which individuals in the population are at greatest risk for converting to the more advanced stages of AMD, these genes in turn could serve as biomarkers and/or hence pharmacological targets in preventing or slowing down progression of diseases. This chapter focuses on genetic contributions to the etiology of AMD.