Regulation of age-related macular degeneration-like pathology by complement factor H

Toomey, Christopher B.; Kelly, Una; Saban, Daniel R.; Rickman, Catherine Bowes

doi:10.1073/pnas.1424391112

Cited by 126 publications

(172 citation statements)

References 99 publications

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“…CFH normally protects self tissues from complement-induced destruction by binding to a range of surface signals including glycoproteins and C-reactive protein. In addition to the binding of CFH to MDA noted above, it was also reported that CFH inhibits lipoprotein binding toward Bruch’s membrane [67]. The breach of Bruch’s membrane and the intrusion of blood vessels into the retina are the hallmarks of wet AMD [52], which are consistent with our finding of high association in Degradation of extracellular matrix and Common pathway of fibrin clot formation in Fig.…”

Section: Resultssupporting

confidence: 90%

Genotype distribution-based inference of collective effects in genome-wide association studies: insights to age-related macular degeneration disease mechanism

Woo

Kumar

et al. 2016

BMC Genomics

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BackgroundGenome-wide association studies provide important insights to the genetic component of disease risks. However, an existing challenge is how to incorporate collective effects of interactions beyond the level of independent single nucleotide polymorphism (SNP) tests. While methods considering each SNP pair separately have provided insights, a large portion of expected heritability may reside in higher-order interaction effects.ResultsWe describe an inference approach (discrete discriminant analysis; DDA) designed to probe collective interactions while treating both genotypes and phenotypes as random variables. The genotype distributions in case and control groups are modeled separately based on empirical allele frequency and covariance data, whose differences yield disease risk parameters. We compared pairwise tests and collective inference methods, the latter based both on DDA and logistic regression. Analyses using simulated data demonstrated that significantly higher sensitivity and specificity can be achieved with collective inference in comparison to pairwise tests, and with DDA in comparison to logistic regression. Using age-related macular degeneration (AMD) data, we demonstrated two possible applications of DDA. In the first application, a genome-wide SNP set is reduced into a small number (∼100) of variants via filtering and SNP pairs with significant interactions are identified. We found that interactions between SNPs with highest AMD association were epigenetically active in the liver, adipocytes, and mesenchymal stem cells. In the other application, multiple groups of SNPs were formed from the genome-wide data and their relative strengths of association were compared using cross-validation. This analysis allowed us to discover novel collections of loci for which interactions between SNPs play significant roles in their disease association. In particular, we considered pathway-based groups of SNPs containing up to ∼10, 000 variants in each group. In addition to pathways related to complement activation, our collective inference pointed to pathway groups involved in phospholipid synthesis, oxidative stress, and apoptosis, consistent with the AMD pathogenesis mechanism where the dysfunction of retinal pigment epithelium cells plays central roles.ConclusionsThe simultaneous inference of collective interaction effects within a set of SNPs has the potential to reveal novel aspects of disease association.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2871-3) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 90%

Genotype distribution-based inference of collective effects in genome-wide association studies: insights to age-related macular degeneration disease mechanism

Woo

Kumar

et al. 2016

BMC Genomics

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“…Our data also point to downstream lipid peroxidation-related products, specifically CEP and 4-HNE, in the etiology of AMDf (37,38). Interactions between mutated Complement factor H (CFH), a strong risk factor for human AMD, and high dietary lipids and cholesterol lead to an AMD phenotype that resembles the HG phenotype (15). Although we did not observe changes in Cfh in our mice, the underlying pathobiology may be similar.…”

Section: Discussionmentioning

confidence: 49%

“…Despite lacking a macula, the mouse retina shows many AMDf and has been useful for relating risk factors for AMD, including cigarette smoking, diet, and inflammation (10,(14)(15)(16)(17)(18). Here we tested the hypothesis that changing from an HG to an LG diet even during maturity can delay or arrest AMDf.…”

Section: Significancementioning

confidence: 99%

Involvement of a gut–retina axis in protection against dietary glycemia-induced age-related macular degeneration

Rowan

Jiang

Korem

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

190

192

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Age-related macular degeneration (AMD) is the major cause of blindness in developed nations. AMD is characterized by retinal pigmented epithelial (RPE) cell dysfunction and loss of photoreceptor cells. Epidemiologic studies indicate important contributions of dietary patterns to the risk for AMD, but the mechanisms relating diet to disease remain unclear. Here we investigate the effect on AMD of isocaloric diets that differ only in the type of dietary carbohydrate in a wild-type aged-mouse model. The consumption of a high-glycemia (HG) diet resulted in many AMD features (AMDf), including RPE hypopigmentation and atrophy, lipofuscin accumulation, and photoreceptor degeneration, whereas consumption of the lower-glycemia (LG) diet did not. Critically, switching from the HG to the LG diet late in life arrested or reversed AMDf.LG diets limited the accumulation of advanced glycation end products, long-chain polyunsaturated lipids, and their peroxidation end-products and increased C3-carnitine in retina, plasma, or urine. Untargeted metabolomics revealed microbial cometabolites, particularly serotonin, as protective against AMDf. Gut microbiota were responsive to diet, and we identified microbiota in the Clostridiales order as being associated with AMDf and the HG diet, whereas protection from AMDf was associated with the Bacteroidales order and the LG diet. Network analysis revealed a nexus of metabolites and microbiota that appear to act within a gut-retina axis to protect against diet-and age-induced AMDf. The findings indicate a functional interaction between dietary carbohydrates, the metabolome, including microbial cometabolites, and AMDf. Our studies suggest a simple dietary intervention that may be useful in patients to arrest AMD.age-related macular degeneration | glycemic index | advanced glycation end-product | gut microbiome | metabolomics A ge-related macular degeneration (AMD) is the leading cause of irremediable blindness in the industrialized world, with 200 million cases projected by 2020, at a cost of $300 billion (1, 2). Dry AMD accounts for the great majority of cases and is associated with photoreceptor cell loss, often preceded by compromise to the retina pigment epithelium (RPE) cells that nourish and remove waste from the photoreceptors. The etiology of AMD remains an enigma but is clearly multifactorial. Stresses associated with AMD include environment, age, and genetics (3). Frustratingly, there are no early biomarkers to anticipate AMD, and there are no therapies or cure.Recently, we and others observed in epidemiologic studies that, in addition to micronutrients (4-6), macronutrient quality [e.g., consuming a diet with a high glycemic index (GI)] is a significant risk factor for AMD onset and/or progress in nondiabetic humans (7)(8)(9). The GI appears to be an attractive dietary intervention target, because simple replacement of small amounts of high-index foods (such as white bread) with lower-index foods (such as wholegrain bread) can significantly reduce glycemic peaks without requiring ...

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“…Compelling mechanistic evidence of a role for complement dysregulation was lacking until the recent work by Toomey et al (Toomey et al, 2015). Using aged CFH +/− mice given a high fat diet, this group found that decreased CFH led to increased basal deposit formation and decreased vision, as quantified by ERG changes.…”

Section: The Role Of Inflammation On the Rpementioning

confidence: 99%

The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD

Datta

Cano

Ebrahimi

et al. 2017

Progress in Retinal and Eye Research

567

487

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The retinal pigment epithelium (RPE) is a highly specialized, unique epithelial cell that interacts with photoreceptors on its apical side and with Bruch’s membrane and the choriocapillaris on its basal side. Due to vital functions that keep photoreceptors healthy, the RPE is essential for maintaining vision. With aging and the accumulated effects of environmental stresses, the RPE can become dysfunctional and die. This degeneration plays a central role in age-related macular degeneration (AMD) pathobiology, the leading cause of blindness among the elderly in western societies. Oxidative stress and inflammation have both physiological and potentially pathological roles in RPE degeneration. Given the central role of the RPE, this review will focus on the impact of oxidative stress and inflammation on the RPE with AMD pathobiology. Physiological sources of oxidative stress as well as unique sources from photo-oxidative stress, the phagocytosis of photoreceptor outer segments, and modifiable factors such as cigarette smoking and high fat diet ingestion that can convert oxidative stress into a pathological role, and the negative impact of impairing the cytoprotective roles of mitochondrial dynamics and the Nrf2 signaling system on RPE health in AMD will be discussed. Likewise, the response by the innate immune system to an inciting trigger, and the potential role of local RPE production of inflammation, as well as a potential role for damage by inflammation with chronicity if the inciting trigger is not neutralized, will be debated.

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Regulation of age-related macular degeneration-like pathology by complement factor H

Cited by 126 publications

References 99 publications

Genotype distribution-based inference of collective effects in genome-wide association studies: insights to age-related macular degeneration disease mechanism

Genotype distribution-based inference of collective effects in genome-wide association studies: insights to age-related macular degeneration disease mechanism

Involvement of a gut–retina axis in protection against dietary glycemia-induced age-related macular degeneration

The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD

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