The Genetics of AMD

The complement system and oxidative stress are genetically implicated in the pathogenesis of AMD

Five genes that alter the risk of AMD (Click to enlarge)

Overwhelming data suggest that AMD has a complex etiology resulting from the interplay of multiple risk factors, both genetic and environmental. A genetic contribution is supported by epidemiologic studies and twin studies. Given the late age at onset of AMD, standard family-based approaches toward gene discovery, including genetic linkage analysis, are hampered in their ability to localize these genes. Thus, the numerous genetic linkage studies performed over the last 10 years were not able to generate sufficient support and localization to identify any single AMD-related gene

Detailed investigations of the 1q32 chromosome identified a common variation within the complement factor H (CFH) gene. Further investigation demonstrated that the genetic role of CFH is complicated because the risk effect of this variation is not seen in Asian populations The identification of variation in CFH as a major risk factor implicated the alternative complement inflammatory pathway in the etiology of AMD. Testing genes coding for other proteins in this pathway has revealed additional protective effects of variants in the complement factor B (CFB) gene complex on chromosome 6 and a risk effect for variation in the complement component 3 (C3) gene on chromosome 19. Thus, the complement system clearly plays a critical role in the development of AMD.

The region on chromosome 10q26 has also been subjected to intense scrutiny and has elicited substantially more controversy. The linkage signal was quickly localized through allelic association analysis to a small chromosomal region containing three genes, PLEKHA1, HTRA1, and a DNA sequence (LOC387715) coding for a hypothetical protein of unknown function. Recent research has conclusively found LOC387715 and not HTRA1 as the chromosome 10q26 AMD gene. LOC387715 codes for a functional protein that is abundantly expressed in human placental tissue and moderately expressed in human retina. Furthermore, this protein has been localized to the mitochondria, the structures within cells that are responsible for energy generation. Given the high energy requirement of the retina, it is interesting to speculate that the retina may be especially sensitive to oxidative damage resulting from altered mitochondrial function. This may help explain the statistical gene-environment interaction between rs10490924 and a history of smoking, a known cause of oxidative stress.

The gene coding for apolipoprotein E (APOE) has also been convincingly associated with AMD. APOE is involved in transport and metabolism of lipid and cholesterol and in the response to neuronal injury. APOE has three common alleles, or gene variants, known as epsilon2, epsilon3, and epsilon4. Initially, two studies reported a reduction in the frequency of the epsilon4 allele in patients with AMD compared to controls, suggesting a protective effect. In addition, epsilon2 allele frequency was increased in AMD patients compared to controls. The association between APOE and AMD has now been replicated by several independent reports. The role of apolipoprotein E seems to be real, but the nature of its role is still unclear.

AMD has been a tremendous success story for the application of the latest tools of human genetics. Linkage analysis and locational cloning, genome-wide association, and pathway candidate gene approaches have all yielded genes involved in AMD. These latest findings, combined with other functional data, now implicate oxidative stress as a second major pathway, in addition to the complement system, that contributes to the pathogenesis of macular degeneration (Figure).

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