Genetics of Age-Related Macular Degeneration

Anna Gabrielian, MD
Rama D. Jager, MD, FACS

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss and blindness in older adults in the developed world.¹ AMD has been implicated to be an inherited disease in a number of epidemiologic, functional, and genetic studies.

Familial aggregation studies have found the prevalence of AMD to be significantly higher among first-degree relatives of cases than in controls, in both siblings and offspring.^2-4 Twin studies have provided an even stronger evidence of AMD heritability, explaining 46-71% of AMD variation.²

To date, a large number of both negative and positive candidate genes involved in the pathogenesis of AMD have been described. Negative candidate genes include TIMP3, VMD2, RDS, and several others examined recently in multi-candidate gene studies.^5,6 Positive candidate genes include ABCA4, VEGF, MMP9, APOE, HLA, and several others.^5,6 A number of linkage analysis studies have attempted to identify the genomic regions containing the susceptibility loci for AMD. An association with nearly every chromosome in the human genome has been implicated in the development AMD by linkage analysis.⁵ The most replicated linkage findings have been on chromosomes 1q25-31 and 10q26, with genetic variants at these loci conferring major disease risks, and together accounting for more than 50% of AMD pathology.^7,8,9

Perhaps the most important discovery as a result of both linkage and association studies thus far is the consistent association of AMD pathogenesis and the complement factor H gene (CFH) located on chromosome 1q.⁸ CFH is a component of the immune system that helps to regulate inflammatory responses by preventing uncontrolled complement activation.¹⁰ Abnormal regulation of the complement cascade in AMD patients occurs at the level of Bruch's membrane and the adjacent retinal pigment epithelium, leading to drusen formation.¹¹ Recent studies have shown the existence of a risk variant within the CFH gene - the Y402H variant - which puts patients expressing it at significantly higher risk of developing AMD.⁹ Several other factors involved in the complement cascade have also been studied (factor B [BF], complement component 2 [C2]) and appear to be protective of AMD.¹²

Most recently, investigations into the 10q26 locus have shown polymorphisms in the ARMS2 gene, localized to the ellipsoid region of the photoreceptors. Absence of this gene is a major risk factor for AMD, conferring disease through mitochondrial-related pathways.¹³ Polymorphisms in a promoter gene HTRA1, also localized to 10q26,¹³ have also shown a significant association with wet AMD in a co-dominant model of action. The genetic effect seemed to be stronger in older and Caucasians subjects versus younger and Asian subjects.¹⁴

Despite the many difficulties in deciphering the genetic code of AMD (the polygenic complexity of the disease, variable heritability and expression patterns, and the impact of lifestyle and environmental factors such as cigarette smoking and diet), recent research in AMD genetics has the potential of uncovering the genetic basis of this potentially devastating disease, in order to promote the development of newer and more effective therapies.

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