Age-Related Macular Degeneration

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Retinal and Corneal Disease

Age-related macular degeneration

  • Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss among the elderly, accounting for 8.7% of blindness worldwide. Globally, the total number of patients with any type of AMD is expected to increase over the next 25 years to 288 million affected individuals (Wong et al., 2014). 

  • The disease is characterized by a gradual loss of central vision due to photoreceptor cell degeneration in the center of the retina at the back of the eye, known as the macula. 

  •  Photoreceptors are in close contact with a layer of cells called the retinal pigment epithelium (RPE). RPE cells support the function of the photoreceptors and play an important role in maintaining retinal homeostasis.

  •  In AMD, this natural function of the RPE is disturbed, resulting in the accumulation of retinal waste products called drusen underneath the RPE. 

  • Two forms of advanced AMD are distinguished. Neovascular AMD, is characterized by infiltration of abnormal blood vessels into the retina.

  •  These newly formed vessels are fragile and when they break, the leakage of blood constituents in the retina leads to sudden vision loss. 

  • The second form of advanced AMD, geographic atrophy, is the result of gradual degeneration of the RPE and photoreceptors cells.

  •  However, no treatment is available for the remaining majority of early, intermediate or geographic atrophy AMD cases, and furthermore there are no effective means of preventing progression of early to advanced stages (Chakravarthy et al., 2010a, Jager et al., 2008). 

  • The complement system plays a central role in the etiology of AMD2. it is known that AMD is the result of a complex interaction of environmental and genetic risk factors. 

  • Studies into the molecular constituents of drusen had already suggested that AMD may have an immunological component. This suggestion arose after proteins involved in inflammation and/or other immune-associated responses, including components of the complement system, were found within drusen. (Hageman et al., 2001, Johnson et al., 2001, Mullins et al., 2001).Evidence for a strong genetic component in AMD arose from twin and family studies. 

  • Twin studies showed high concordance between AMD between monozygotic pairs, even double compared to dizygotic pairs, and estimated that the heritability of AMD may be as high as 45 to 70% (Hammond et al., 2002, Meyers et al., 1995, Seddon et al., 2005). 

  • These findings were consistent with familial aggregation analyses that observed a higher prevalence of AMD characteristics and an earlier onset of disease symptoms among relatives of patients compared to control families (Klaver et al., 1998, Seddon et al., 1997). 

  • There is genetic evidence for a role of the complement system in AMD. (Abecasis et al., 2004, Iyengar et al., 2004, Majewski et al., 2003, Seddon et al., 2003, Weeks et al., 2004). 

  • When the first genome-wide association study (GWAS) for AMD was performed in 2005, it identified that same genomic region, which lead to the discovery of a highly associated genetic variant in complement factor H (CFH; Tyr402His) (Klein et al., 2005). 

  • These findings were corroborated by three additional studies (Edwards et al., 2005, Hageman et al., 2005, Haines et al., 2005).

  • Through genetic studies that followed over the next decade, the understanding of the genetic basis of AMD increased dramatically with the identification of disease-associated variants across several biological systems (Fritsche et al., 2013). 

  • The genetic link between AMD and the complement genetic variants in or near complement factor I (CFI), complement component 3 (C3), complement component 2 (C2), complement component 9 (C9), complement factor B (CFB) and vitronectin (VTN) were also found to be associated with the disease (Fagerness et al., 2009, Fritsche et al., 2013, Fritsche et al., 2016, Gold et al., 2006, Maller et al., 2007, Yates et al., 2007). 

  • In addition, a common haplotype carrying a deletion of complement factor H related genes CFHR1 and CFHR3 was found to be protective for AMD (Hughes et al., 2006).