The AMD patients had increased activation of the alternative complement pathway (P = 0.003) and elevated levels of complement activation components C3d (P<0.0001) and C5a (P<0.0001), CFB (P<0.0001), and an increased C3d/C3 ratio (P<0.0001) calculated as a measure of C3 activation.
PPARGC1A influences activation of the AMD-associated complement component 3 (C3) promoter fragment and CFB influences activation and proteolysis of C3.
Transgenic zebrafish overexpressing human HTRA1 in rod PRCs showed morphologic changes of the RPE, including PRC death and lipofuscin accumulation, features similar to those of early AMD. htra1 expression was also increased in a retinitis pigmentosa zebrafish model compared with wild type.
These data implicate increased HTRA1 expression in the pathogenesis of AMD and highlight the importance of exploring multiple functional consequences of alleles in haplotypes that confer susceptibility to complex traits.
Increased expression of TIMP-3 is also observed in other degenerative retinal diseases, including the more severe forms of age-related macular degeneration, the most common cause of blindness in the elderly in developed countries.
Association of rare variants in the CFH, CFI, C9, and C3 genes with AMD, serum levels of corresponding proteins, and C3b degradation ability of CFH and CFI variant carriers.
A promoter variant of the gene encoding HTRA1 is part of a mutant allele that causes increased HTRA1 expression and contributed to age-related macular degeneration (AMD) in genomewide association studies.
Among different genotype combinations ARMS2-CFH and CFH-C3 combinations have the most significant levels of synergism and C3-CFI combination has the most significant level of antagonism in AMD patients.
Our results were supported by significant accumulation and expression overlap of both TIMP-3 and EFEMP1 between the retinal pigment epithelia and Bruch membrane in the eyes of ML and AMD patients.
Our data thus reveal a novel role of IL-27 in regulating complement activation through up-regulation of CFH and suggest that defects in IL-27 signaling or expression may contribute to the reduction of CFH expression in the retina of patients with AMD.
This result is at least as important at the population level as ApoE4 and Alzheimer's disease, playing a role in almost 60% of AMD at the population level.
Expression of human complement factor H prevents age-related macular degeneration-like retina damage and kidney abnormalities in aged Cfh knockout mice.