Key Points

•Age-related Macular Degeneration (AMD) is a multifactorial disease involving genetic and environmental influences.

•Complement Factor H (CFH) and HTRA1/ LOC387715 are the two main loci associated with AMD.

•A genetic understanding of AMD may allow for early diagnosis and treatment.

Introduction

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed world. In the United States alone, over 10 million people are affected, with over 1.75 million people exhibiting advanced forms of the disease. By 2020, nearly 3 million people in the United States will suffer from advanced AMD [1]. AMD is a complex disease, with multiple genetic and environmental factors playing a role in its pathogenesis [2]. With an improved understanding of disease-causing genes, genetic testing of individuals has become increasingly commonplace for early diagnosis of various

D.T. Kasuga ( )

Department of Ophthalmology, University of California at San Diego, Skaggs (SSPPS) Rm. 4186, 9500 Gilman Dr., La Jolla, San Diego, CA, USA

e-mail: dankasuga@gmail.com

diseases and conditions. Due to the increasing number of individuals affected by this disease, identification of genetic factors and early genetic screening will be needed to determine populations at risk and allow for early intervention. In this chapter, we will review our current understanding of the genetics associated with AMD.

Etiology

AMD can be classified into early and late phases. The early phase is characterized by large yellow subretinal deposits called drusen and retinal pigmented epithelium (RPE) changes (Fig. 1.1). The disease can progress to either choroidal neovascularization (CNV), a rapidly deteriorating late form of AMD characterized by new blood vessels that invade the macula (Fig. 1.1c), or to geographic atrophy (GA), a slower late form causing degeneration of the macula’s retinal pigmented epithelium (Fig. 1.1d).

Although extensive research has investigated the underlying etiology of AMD, the exact mechanism remains unknown. Researchers have investigated inflammatory dysregulation, lipid metabolism defects, oxidative stress, and structural defects, to name a few. Many have looked for a genetic answer to the question. Coupled with an age-related time course and two distinct late-stage phenotypes, the possibility of a single genetic cause seems unlikely. However, researchers have identified unique polymorphisms, which harbor impressive associations to AMD.