2010
DOI: 10.1007/978-1-4419-5635-4_4
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Genetic Control of Complement Activation in Humans and Age Related Macular Degeneration

Abstract: The major focus of our research is to understand how age-related macular degeneration (AMD) develops. It is known that genetic variation can explain much of the risk of developing AMD. However, we do not know what controls the transition between a normal fundus and the extensive accumulation of subretinal inflammatory material that we recognize as drusen in AMD. We do know that the accumulation of this inflammatory material that characterizes the maculopathy underlying AMD is by far the most important predicto… Show more

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Cited by 13 publications
(9 citation statements)
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References 54 publications
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“…A number of the proteins detected in drusen are either complement components or related molecules. Importantly, variations in several complement-related genes have been shown to be highly significant risk factors for the development of AMD (20,21). Taken together, these findings are consistent with the general conclusion that chronic local inflammation at the RPE/ Bruch's membrane interface contributes to drusen formation and to AMD pathogenesis (12,14,22,23).…”
supporting
confidence: 78%
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“…A number of the proteins detected in drusen are either complement components or related molecules. Importantly, variations in several complement-related genes have been shown to be highly significant risk factors for the development of AMD (20,21). Taken together, these findings are consistent with the general conclusion that chronic local inflammation at the RPE/ Bruch's membrane interface contributes to drusen formation and to AMD pathogenesis (12,14,22,23).…”
supporting
confidence: 78%
“…Although the primary biosynthetic source for most of these circulating molecules is the liver, a number of them are also known to be synthesized locally by RPE cells (15)(16)(17)(18)(19). The respective contributions of RPE-derived and plasma-derived molecules to the process of drusen biogenesis, as well as the relevant molecular interactions leading to drusen deposition, have not yet been fully elucidated.During the past decade, compelling evidence has emerged implicating the immune system-and the complement system in particular-in drusen biogenesis and AMD (15,20,21). A number of the proteins detected in drusen are either complement components or related molecules.…”
mentioning
confidence: 99%
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“…An extension of the excellent studies by Newman and colleagues would be comparing the transcriptome of anatomically healthy eyes at genetically low- or high-risk for developing AMD. Identifying altered patterns of complement proteins has been explored in human tissues with known AMD-associated genotypes [25,26]. Systems based analysis of tissues with different genotypes may uncover the initial molecular events in eyes predisposed to disease, even before the genesis of any overt pathology.…”
Section: Discussionmentioning
confidence: 99%
“…[16][17][18][19] Presuming an analogous role in AMD pathogenesis, multiple groups are exploring the possibility that complement inhibition may be effective for preventing or slowing AMD progression. 12,[20][21][22] Several findings, however, argue against this strategy. For example, mice lacking C3a and/or C5a signaling have abnormal susceptibility to neuroexcitotoxicity, 23 abnormal neurogenesis, 24 abnormal differentiation and migration of neural progenitor cells, 25 abnormal liver cell survival/regeneration, 26 and abnormal remyelination.…”
mentioning
confidence: 99%