Mendelian linkage and association studies In addition to ARMD, several Mendelian forms of macular degenerations have been described. The age of onset, pattern of inheritance, and clinical characteristics of these diseases vary widely. To date, about 17 human Mendelian macular degeneration genes have been mapped (Tuo, Bojanowski, and Chan, 2004). So far genes for nine different forms of human Mendelian macular degenerations have been identified using a positional cloning approach. These genes can be broadly classified into two groups: genes that are expressed in photorecep-tors (ELOVL4, RDS/peripherin, RPGR, and ABCA4) and genes expressed in RPE (Bestrophin, EFEMP1, TIMP3, Hemicentin-1, and CTRP5). The genes ELOVL4, RDS, RPGR, and ABCA4 are expressed in both rod and cone photoreceptors. Except for the ELOVL4 gene, mutations in the remaining three genes were shown to be associated with retinitis pigmentosa (RP) in addition to macular degeneration. Mutations in TIMP3, EFEMP1, Hemicentin-1, CTRP5, and Bestrophin have not been implicated in RP. Of the genes involved in causing macular degeneration, all four photoreceptor-expressed genes are associated with an atrophic phenotype, whereas the RPE-expressed genes are associated with subretinal deposits and drusen in the early stages of the disease, which then progresses to neovascularization at later stages. The genes EFEMP1, TIMP3, Hemicentin-1, and CTRP5 share structural homology and are components of the extracellular matrix, and Bestrophin was reported to be a membrane channel. Recently, Fibulin-5, which also belongs to the fibulin family of extracellular proteins and shares homology with the EFEMP1 and CTRP5 proteins, was shown to be associated with AMD.
Linkage and association studies of AMD Although some families show Mendelian inheritance of AMD, the disease in the general population is inherited in a complex or multifactorial fashion. In attempts to identify the genes that contribute to AMD risk in the population at large, investigators have looked at inheritance of AMD in small families or even pairs of affected siblings. A number of studies have examined families in which more than one member is affected with AMD, to determine whether polymorphic genetic markers at known positions in the human genome are co-inherited with the disease. These genome-wide scans have identified at least 21 linked regions on multiple chromosomes, including most consistently regions on chromosomes 1q, 9q, 10q, 12q, and 16q. However, AMD has not been associated with mutations in genes in any of these regions except complement factor H.
Three genes, ATP binding cassette subfamily A member 4 (ABCA4), apolipoprotein E (APOE), and complement factor H (HF1), have been reported to be associated with susceptibility to AMD in the general population (Tuo, Bojanowski, and Chan, 2004). However, the role of ABCA4 is somewhat controversial, and it probably is responsible for a few percent of AMD cases at most. Involvement of APOE in AMD seems to be more solid, with most studies showing a risk ratio of individuals carrying at least one APOE-e4 allele reduced to about 40 to 50% of control values, although some studies could not replicate this finding. Recently, a Y402H polymorphism in the complement factor H protein has been shown to be associated with a two- to seven-fold increase in risk for AMD in two studies of unrelated individuals.
The gene encoding complement factor H lies in the chromosome 1q25-31 region implicated in linkage studies of both a large single family and of multiple small families and sibling pairs. One study suggested that this gene might account for as much as 50% of the hereditary tendency of AMD in the general population (Edwards et al., 2005). In addition, the biochemical activities of both APOE and HF1 are consistent with the proposed atherosclerotic and inflammatory associations of AMD and the histological and biochemical analysis of the subretinal deposits. Thus, significant progress is being made in understanding the biological nature of the genes associated with macular degenerations and their roles in the disease. However, despite these advances little is understood about the overall mechanism underlying the disease process.
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