Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in older adults in the western hemisphere.1 It is estimated that 30% of Americans ≥ 75 years of age have AMD2 and that by the year 2020, approximately 3 million Americans will be affected by advanced AMD.3 The etiology of the disease is multifactorial, involving a complex interaction of inflammatory, oxidative, degenerative, and genetic components. Recent developments in the field of human genomics have fostered advancements in our knowledge of the genetic basis of AMD.
Prior to 2005, understanding of the heritability of AMD was limited and based largely on familial aggregation studies. These studies confirmed that a family history of AMD increases one’s risk for the development of the disease, and first degree relatives of affected patients have a four-fold increased risk of developing the condition. In addition, monozygotic twins are known to have a high level of concordance for AMD compared to dizygotic twins.4-7 Underlying genes of multiple heritable dystrophies including TIMP3, EFEMP1, ABCA4, RDS, ELVOL4, and VMD28 have been investigated as possible candidate genes associated with AMD, but to date, a pathogenic role has only been proven for TIMP39and ABCA4.8
In 2005, a new era dawned with the completion of the International Haplotype Map Project which compiled a collection of millions of single nucleotide polymorphisms (SNP), which are normal variations in gene structure that may protect against or predispose to various conditions. Genome-wide association studies in large cohorts have identified several susceptibility loci associated with increased AMD risk.
Complement factor H (CFH), complement factor B (CFB)/complement component 2 (C2), LOC387715/ARMS2 and HTRA1 are believed to be responsible for the majority of heritable AMD risk, with other genes playing a significant but smaller role.10-12 Complement factor H SNP Y402H (rs1061170) on chromosome 1q32 was the first major susceptibility gene discovered for AMD and could be responsible for 50% of AMD risk. The CFH gene codes for a glycoprotein that regulates the alternative complement pathway and binds to Bruch’s membrane. The Y402H SNP can result in abnormal complement activation and host cell destruction secondary to ineffective binding to Bruch’s membrane. CFH Y402H promotes the development of early AMD (drusen formation) and progression to advanced AMD, and can act synergistically with smoking history to increase one’s risk of wet AMD.13,14
Various SNPs in the complement factor I (CFI),15 CFB/C2,11 and complement component 3 (C3) genes also promote complement activation and increase AMD risk. Complement component 3, the convergence point of the complement pathways, plays a critical role in the formation of the membrane attack complex (MAC) and consequential cell lysis. Nine SNPs in the C3 gene are associated with AMD, with SNP R102G being specifically related to wet AMD.16
Affecting every step in AMD pathogenesis, the consequences of uncontrolled complement include promoting leukocyte accumulation, reactive oxygen species, drusen formation, retinal pigment epithelial cell damage (MAC-induced cell lysis), and elevation of vascular endothelial growth factor (VEGF) which leads to development of choroidal neovascularization (CNV).15
LOC387715/ARMS2 A69S and HTRA1 was the second major susceptibility locus identified for AMD. These genes occupy several kilobases on a segment of chromosome 10q26. ARMS2 is thought to mediate oxidative stress, and HTRA1 is a serine protease found in drusen. Homozygosity for the high risk polymorphism confers increased risk for AMD progression and earlier onset of wet AMD.12
AMD susceptibility is also associated with polymorphisms in the LIPC, CETP, LPL, ABCA1 and APOE genes that are involved with cholesterol metabolism.9 Other genetic variants with weak or questionable AMD association include HMCN1, VEGF, TLR3, TLR4, and Serping1.17,18
During the past few years we have made great strides to elevate our level of understanding of the complex and polygenic basis of AMD. This knowledge has provided the foundation for genetic testing, and the potential for gene-guided treatment and gene therapy.
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About our author(s):
Jaclyn L. Kovach, MD
Assistant Professor of Clinical Ophthalmology
Bascom Palmer Eye Institute
University of Miami Miller School of Medicine