Genome-Wide Association Studies: Getting to Pathogenesis, the Role of Inflammation/Complement in Age-Related Macular Degeneration

Bailey, Jessica N. Cooke; Pericak‐Vance, Margaret A.; Haines, Jonathan L.

doi:10.1101/cshperspect.a017186

Cited by 14 publications

(11 citation statements)

References 76 publications

(143 reference statements)

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“… 33 , 34 Likewise, CR2-fH has been shown to reverse morphological changes in RPE and Bruch’s membrane in mouse seen after continuous smoke exposure. 17 These findings, together with genome-wide association study (GWAS) and other genetic data, 35 , 36 suggest AP activity as the common target in wet and dry AMD. Reducing AP activation would keep the classical and lectin pathways intact, which would still allow for production of C3a and C5a, anaphylatoxins necessary for normal homeostatic processes, as well as immune response and host defense.…”

Section: Discussionmentioning

confidence: 94%

Delivery of CR2-fH Using AAV Vector Therapy as Treatment Strategy in the Mouse Model of Choroidal Neovascularization

Schnabolk

Parsons

Obert

et al. 2018

Molecular Therapy - Methods & Clinical Development

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Complement activation plays a significant role in age-related macular degeneration (AMD) pathogenesis, and polymorphisms interfering with factor H (fH) function, a complement alternative pathway (AP) inhibitor, are associated with increased AMD risk. We have previously validated an AP inhibitor, a fusion protein consisting of a complement receptor 2 fragment linked to the inhibitory domain of fH (CR2-fH) as an efficacious treatment for choroidal neovascularization (CNV) when delivered intravenously. Here we tested an alternative approach of AAV-mediated delivery (AAV5-VMD2-CR2-fH or AAV5-VMD2-mCherry) using subretinal delivery in C57BL/6J mice. Secretion of CR2-fH was confirmed in polarized retinal pigment epithelium (RPE) cells. A safe concentration of AAV5-VMD2-CR2-fH was identified using electroretinography, optical coherence tomography (OCT), RPE morphology, and antibody profiling. One month after gene delivery, CNV was induced using argon laser photocoagulation. OCT assessment demonstrated reduced CNV with AAV5-VMD2-CR2-fH administration. Bioavailability studies revealed that gene-therapy delivered similar levels of CR2-fH to the RPE/choroid as treatment by intravenous injections, and C3a ELISA verified reduced CNV-associated ocular C3a production. These results contribute to existing data illustrating the importance of the AP of complement in CNV development and its potential role in AMD treatment. Demonstration of AAV-vector efficacy opens new avenues for the development of treatment strategies.

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Section: Discussionmentioning

confidence: 94%

Delivery of CR2-fH Using AAV Vector Therapy as Treatment Strategy in the Mouse Model of Choroidal Neovascularization

Schnabolk

Parsons

Obert

et al. 2018

Molecular Therapy - Methods & Clinical Development

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“…We speculated that PD may play a role in the development of AMD through a mechanism similar to the above. The pathogenesis of AMD is unclear, but the theory of inflammation and immunology has received increasing attention from researchers [ 13 – 15 ]. Aging causes a decrease in the ability of retinal pigmented epithelium (RPE) cells to clear metabolic products, aggravating oxidative damage to the retina, and synergistic effects of metabolic, functional, genetic, and environmental risk factors, resulting in the accumulation of retinal toxic elements.…”

Section: Discussionmentioning

confidence: 99%

“…Although the exact pathogenesis of AMD is still unclear, the theory of inflammation and immunology is gaining more and more attention, and the role of various inflammatory factors and immune factors has been confirmed by experiments and histopathological studies [ 13 – 15 ]. One possible mechanism for PD to affect systemic diseases is that periodontal bacteria and their metabolites (such as endotoxin) enter the systemic circulation, and when they reach other parts of the body, they activate monocytes/macrophages and produce a large number of inflammatory factors, which in turn causes inflammation in other organs [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Periodontal Disease and Age-Related Macular Degeneration: A Meta-Analysis of 112,240 Participants

Fang

et al. 2020

BioMed Research International

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Objective. Epidemiological studies have shown a correlation between periodontal disease (PD) and age-related macular degeneration (AMD). However, the results have been inconsistent, and no relevant meta-analysis has been performed on this topic. Hence, we performed a meta-analysis to evaluate whether the two diseases are related. Material and Methods. The PubMed, Embase, Cochrane Library, and Web of Science databases were searched up to April 20, 2020, for related articles. Two authors independently conducted literature screening and data extraction and then used the Stata 15.1 software to calculate the relative risk (RRs) and 95% confidence intervals (CIs) to assess the association between PD and AMD. Results. A total of 5 observational studies involving 112,240 participants and 5,005 AMD patients were included. The results of meta-analysis using the random-effects model showed that the incidence of AMD in PD patients was 1.35 times that of non-PD patients; the difference was statistically significant ( RR = 1.35 , 95 % CI = 1.07 – 1.70 , P = 0.011 ). Sensitivity analysis showed that the results were stable. Conclusions. PD patients have a higher risk of AMD, but the causal relationship between PD and AMD has not been confirmed. Further research should be carried out to verify the exact relationship between the two.

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“…As early as 1994, Van der Van der Schaft et al [ 3 ] proposed the hypothesis that cataract surgery may in some ways make the eye susceptible to AMD through inflammatory mechanisms. Acute or chronic postoperative inflammation [ 43 ], complement pathway, macrophage induction [ 21 ], and proinflammatory chemokines may act as an additional angiogenic stimulus [ 44 ]. When the blood–aqueous barrier is compromised, inflammation and oedema occur which can increase the vascular permeability [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Does Cataract Surgery Improve the Progression of Age-Related Macular Degeneration? A Meta-Analysis

Liu

Cai

2020

Journal of Ophthalmology

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Purpose. Cataract and age-related macular degeneration (AMD) are the common causes of blindness in the elderly. Although cataract surgery is the most effective treatment for cataract, some clinicians suspect that such interventions may accelerate the progression of AMD. Therefore, we carried out this meta-analysis to focus on demonstrating the effectiveness and safety of cataract surgery in eyes with AMD. Methods. We performed a systematic literature search in the PubMed, EMBASE, and Cochrane Library databases, and the electronic databases were last searched in January 2019. We planned to include cohort trials of eyes affected by both cataract and AMD in which cataract surgery would be compared to no surgery. Two reviewers independently evaluated the search results against the inclusion and exclusion criteria. 8 trials were included for this meta-analysis. Results. We used the Stata/12.0 to integrate the data that was extracted from the articles. Eight cohort trials with data from different study populations were included. In random effects model, the relative risk (RR) for the progression of AMD is 1.194 (95% CI 0.897–1.591). As for those grouped according to the follow-up year, the RR for longer than five years was 1.372 (95% CI 1.062–1.772). Conclusion. We could draw out such a conclusion that there is still a positive correlation between cataract surgery and the progression of AMD, especially for the Asians. However, based on the current results, it is not possible to draw conclusions from existing studies on the impact of cataract surgery on early AMD development.

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Genome-Wide Association Studies: Getting to Pathogenesis, the Role of Inflammation/Complement in Age-Related Macular Degeneration

Cited by 14 publications

References 76 publications

Delivery of CR2-fH Using AAV Vector Therapy as Treatment Strategy in the Mouse Model of Choroidal Neovascularization

Delivery of CR2-fH Using AAV Vector Therapy as Treatment Strategy in the Mouse Model of Choroidal Neovascularization

Periodontal Disease and Age-Related Macular Degeneration: A Meta-Analysis of 112,240 Participants

Does Cataract Surgery Improve the Progression of Age-Related Macular Degeneration? A Meta-Analysis

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