Complement Factor B Polymorphism and the Phenotype of Early Age-related Macular Degeneration

Mantel, Irmela; Ambresin, Aude; Moetteli, Leila; Droz, Ivaine; Roduit, Raphaël; Munier, Francis L.

doi:10.3109/13816810.2013.766217

Cited by 16 publications

(15 citation statements)

References 44 publications

(69 reference statements)

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“…Bora et al in 2005, reported C3 and MAC complex depositions in neovessels in mice model of laser-induced choroidal neovascularization (CNV), while the C3 knock out (C3 −/− ) CNV mice showed an absence of neovascularization, with a reduced level of angiogenic factors, thereby suggesting complement component C3 as a pro-angiogenic factor (15). This was further supported by genetic association studies of complement proteins in AMD pathogenesis, where a strong association of CFB and CFH polymorphism was observed along with a strong deposition of complement components in the RPE-Bruch layer (16)(17)(18). Further, the deposition of C3 in the retinal microglia and macrophage population in the outer retinal layers was shown to induce retinal degeneration in a mouse model of AMD (19).…”

Section: Introductionmentioning

confidence: 86%

A Systematic Investigation on Complement Pathway Activation in Diabetic Retinopathy

et al. 2020

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The complement system plays a crucial role in retinal homeostasis. While the proteomic analysis of ocular tissues in diabetic retinopathy (DR) has shown the deposition of complement proteins, their exact role in the pathogenesis of DR is yet unclear. We performed a detailed investigation of the role of the complement system by evaluating the levels of major complement proteins including C3, C1q, C4b, Complement Factor B (CFB), and Complement Factor H (CFH) and their activated fragments from both the classical and alternative pathways in vitreous humor and serum samples from proliferative DR (PDR) patients and controls. Further, the expressions of complements and several other key pro-and anti-angiogenic genes in the serum and vitreous humor were analyzed in the blood samples of PDR and non-PDR (NPDR) patients along with controls without diabetes. We also assessed the pro-inflammatory cytokines and matrix metalloproteinases in the vitreous humor samples. There was a significant increase in C3 and its activated fragment C3bα' (110 kDa) along with a corresponding upregulation of CFH in the vitreous of PDR patients, which confirmed the increased activation of the alternative complement pathway in PDR. Likewise, a significant upregulation of angiogenic genes and downregulation of anti-angiogenic genes was seen in PDR and NPDR cases. Increased MMP9 activity and upregulation of inflammatory markers IL8 and sPECAM with a downregulation of anti-inflammatory marker IL-10 in PDR vitreous indicated the possible involvement of microglia in DR pathogenesis. Further, a significantly high C3 deposition in the capillary wall along with thickening of basement membranes and co-localization of CFH expression with CD11b +ve activated microglial cells in diabetic retina suggested microglia as a source of CFH in diabetic retina. The increased CFH levels could be a feedback mechanism for arresting excessive complement activation in DR eyes. A gradual increase of CFH and CD11b expression in retina with early to late changes in epiretinal membranes of DR patients indicated a major role for the alternative complement pathway in disease progression.

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Section: Introductionmentioning

confidence: 86%

A Systematic Investigation on Complement Pathway Activation in Diabetic Retinopathy

et al. 2020

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“…The risk of developing AMD was decreased in half for patients carrying at least one of the rare alleles for any of the previously mentioned CFB SNPs (Sun et al, 2012). In another study, CFB SNP rs641153 (R32Q) was seen only in patients with drusen ≤250 μm and appeared to be protective against the formation of larger drusen >250 μm (Mantel et al, 2014). A meta-analysis found that patients with CFB SNPs rs4151667 and rs614153 carrying the minor A allele had a significantly smaller likelihood of having AMD (OR=0.54 and 0.41 respectively) (Thakkinstian et al, 2012).…”

Section: Biomarkers In Heritability and Geneticsmentioning

confidence: 98%

“…Complement factor B (CFB) polymorphisms have shown to be protective against the development of AMD (Gold et al, 2006b; Mantel et al, 2014; Spencer et al, 2007; Sun et al, 2012; Thakkinstian et al, 2012). In the first steps of the alternative pathway, CFB is bound to C3b.…”

Section: Biomarkers In Heritability and Geneticsmentioning

confidence: 99%

Risk factors and biomarkers of age-related macular degeneration

Lambert

Elshelmani

Singh

et al. 2016

Progress in Retinal and Eye Research

282

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A biomarker can be a substance or structure measured in body parts, fluids or products that can affect or predict disease incidence. As age-related macular degeneration (AMD) is the leading cause of blindness in the developed world, much research and effort has been invested in the identification of different biomarkers to predict disease incidence, identify at risk individuals, elucidate causative pathophysiological etiologies, guide screening, monitoring and treatment parameters, and predict disease outcomes. To date, a host of genetic, environmental, proteomic, and cellular targets have been identified as both risk factors and potential biomarkers for AMD. Despite this, their use has been confined to research settings and has not yet crossed into the clinical arena. A greater understanding of these factors and their use as potential biomarkers for AMD can guide future research and clinical practice. This article will discuss known risk factors and novel, potential biomarkers of AMD in addition to their application in both academic and clinical settings.

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“…pooled data from 19 studies which took place between 2006 and 2011 for 4 SNPs: rs9332739 and rs547154 for C2 gene and rs4151667 and rs641153 for CFB gene, suggesting that these alleles contribute to lowering the risk of AMD pathogenesis in Caucasian population by 2.0% to 6.0% [30]. Recently, it has been reported that complement factor B polymorphism (R32Q) correlates with early AMD but have protective effect on late AMD as seen in Caucasian population [31]. On the contrary, it has been reported in INDEYE study that polymorphisms in ARMS2/HTRA1 locus are significantly associated with early and late AMD but instead of this locus the complement factor components like C2, CFH and CFB have not been found to be associated with AMD [32].…”

Section: Genetics Of Amdmentioning

confidence: 99%

Using Current Data to Define New Approach in Age Related Macular Degeneration: Need to Accelerate Translational Research

Anand

Sharma

Chen

et al. 2014

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Age related macular degeneration (AMD) is one of the major retinal degenerative disease of ageing whose complex genetic basis remains undeciphered. The involvement of various other factors like mitochondrial genes, cytoskeletal proteins and the role of epigenetics has been described in this review. Several population based AMD genetic studies have been carried out worldwide. Despite the increased publication of reports, clinical translation still eludes this davastating disease. We suggest models to address roadblocks in clinical translation hoping that these would be beneficial to drive AMD research towards innovative biomarkers and therapeutics Therefore, addressing the need large autopsy studies and combining it with efficient use of bioinformatic tools, statistical modeling and probing SNP-biomarker association are key to time bound resolution of this disease.

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Complement Factor B Polymorphism and the Phenotype of Early Age-related Macular Degeneration

Cited by 16 publications

References 44 publications

A Systematic Investigation on Complement Pathway Activation in Diabetic Retinopathy

A Systematic Investigation on Complement Pathway Activation in Diabetic Retinopathy

Risk factors and biomarkers of age-related macular degeneration

Using Current Data to Define New Approach in Age Related Macular Degeneration: Need to Accelerate Translational Research

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