Selected Publications

Dr. Seddon has published several research findings about the associations between diet and nutrients and the impact on risk of AMD. These results have been applied to current dietary guidelines for people with AMD.

In a collaboration with AMDF, Dr. Seddon has published these 2 cookbooks, Eat Right for Your Sight, and Feast for the Eyes; which incorporate her research findings into healthy recipes, with the goal of reducing visual loss due to AMD.

 As noted in Dr. Seddon's 2014 Introduction of these books

“ YOU ARE WHAT YOU EAT”

was a book her father had when she was growing up, and now we know how true that is, especially for AMD.

Age-related macular degeneration (AMD) is a complex neurodegenerative eye disease with behavioral and genetic etiology and is the leading cause of irreversible vision loss among elderly Caucasians. Functionally significant genetic variants in the alternative pathway of complement have been strongly linked to disease. More recently, a rare variant in the terminal pathway of complement has been associated with increased risk, Complement component 9 (C9) P167S. To assess the functional consequence of this variant, C9 levels were measured in two independent cohorts of AMD patients. In both cohorts, it was demonstrated that the P167S variant was associated with low C9 plasma levels. Further analysis showed that patients with advanced AMD had elevated sC5b-9 compared to those with non-advanced AMD, although this was not associated with the P167S polymorphism. Electron microscopy of membrane attack complexes (MACs) generated using recombinantly produced wild type or P167S C9 demonstrated identical MAC ring structures. In functional assays, the P167S variant displayed a higher propensity to polymerize and a small increase in its ability to induce hemolysis of sheep erythrocytes when added to C9-depleted serum. The demonstration that this C9 P167S AMD risk polymorphism displays increased polymerization and functional activity provides a rationale for the gene therapy trials of sCD59 to inhibit the terminal pathway of complement in AMD that are underway.

Many of the risk factors for developing severe coronavirus disease 2019 (COVID-19) are also risk factors for eye diseases such as age-related macular degeneration (AMD). During the past decades, macrophages and the complement pathway (as a part of the innate immune system) have been identified as important contributors to the development of AMD, and we suggest that these mechanisms are of similar importance for the clinical course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Based on the experience with AMD, we discuss how behavioral factors such as diet, smoking and higher body mass index, as well as genetic determinants such as the complement and immune pathway genes may lead to the overactive inflammatory phenotypes seen in some patients with COVID-19, and may in part explain the heterogeneity of disease manifestations and outcomes. Based on this experience, we discuss potential genetic research projects and elaborate on preventive and treatment approaches related to COVID-19.

Rare variants in the complement pathway and a common risk allele in ARMS2/HTRA1, smoking, and higher BMI can lead to as much as 11.5 additional years of disease and treatment burden. Closer adherence to healthy lifestyles could reduce years of visual impairment.

The study demonstrated attenuation of submacular CC in early AMD subjects but no vascular pathology was observed outside the submacular region. While the affected area in some eyes was quite extensive histologically, these changes may not be detectable clinically using standard in vivo imaging.

Drusen deposits in the retina are hallmarks of AMD in the early and intermediate stages of AMD. A higher drusen burden increases risk of developing late or advanced stages of AMD with visual loss.

We found that a higher genetic susceptibility was related to drusen growth. A Mediterranean-style diet with healthful nutrient-rich foods (like fruits, vegetables, legumes and fish) reduced enlargement of drusen over time. These results highlight and underscore the benefits of the Mediterranean diet on progression of AMD as we first reported in 2015. (see article below).

Each type of advanced AMD is generally preceded by earlier stages that are characterized by the formation of drusen between the retinal pigment epithelium (RPE) and Bruch's membrane. The elevation of the RPE layer can be quantified by spectral domain–optical coherence tomography (SD-OCT) devices. Here, we used this feature from Zeiss Cirrus OCT to automatically measure the area and volume of drusen and found associations between these parameters and genes that are highly associated with advanced AMD. We found that risk variants in the CFH gene and in ARMS2/HTRA1 gene are independently associated with greater size of drusen.

Read more about this research on the IOVS journal (free access).

The American Ophthalmological Society (AOS) Thesis 2019.

We expanded our previous Age-related Macular Degeneration (AMD) prediction models by including 13 genes, (a polygenic risk score or GRS) plus demographic risk factors, and showed for the first time the ability of the model to predict visual acuity outcomes. We also validated the model in a large independent cohort. Identifying high-risk individuals at earlier stages could lead to more precise ways to prevent and treat AMD.

Check out the publication at the American Journal of Ophthalmology.

We evaluated morphologic features of the retina and choroid on optical coherence tomography (OCT) and found that OCT features of the retina and choroid could predict progression to advanced stages of AMD, including retinal hyper-reflective loci, nascent GA, and other inner and outer retinal irregularities.

Read more about this research on the Investigative Ophthalmology & Visual Science July 2017.

This article is a good summary of decades of research on AMD, including initial studies on diet, nutrition, smoking, and other modifiable factors, as well as common and rare genetic discoveries in the Seddon Lab, related to AMD onset and progression.

Checkout the publication at the IOVS journal.

We determined the association between genetic variants and transition to advanced AMD, and expanded our predictive model and updated our online application to assist in clinical decision making.

The complement factor H (CFH) R1210C rare variant confers the strongest genetic risk for age-related macular degeneration and earlier age at onset. Here, Dr. Seddon and Dr. Ferrara evaluated macular fundus features and disease staging among people with and without this rare variant. We found for the first time that the typical phenotype of the CFHR1210C rare variant is extensive drusen accumulation in the macula and throughout the fundus, as well as a high risk for advanced disease.

Together with our collaborators in Boston, other US and European labs, we discovered more novel genetic variants associated with risk of advanced AMD in genes in the complement immune pathway (CFI, C3, and C9 genes) with high impact on the development of this disease. We also showed the initial functional impact of the C3 rare variant.

Together with our collaborators in Boston, other US and European labs, we discovered a rare, high-penetrance variant in the complement factor H (CFH) gene associated with increased risk of age-related macular degeneration. This finding suggests that loss-of-function alleles at CFH are likely to drive AMD risk and represents one of the first instances in which a common complex disease variant has led to the discovery of a rare penetrant mutation. This rare variant is the strongest genetic risk factor for  macular degeneration to date.

The Clinical Age-Related Maculopathy Staging (CARMS) system for age-related maculopathy (ARM), uses a simple grading scale designed for clinical practice and clinical research protocols. It is a 5-level clinical scale, a valid and reliable staging system that can be used in both clinical practice and in clinical research protocols involving patients with all stages of ARM. Dr. Seddon evaluates and grades all ocular records and imaging data using this system.

Dr. Seddon conducted the first prospective study to detect the association between cigarette smoking and incidence of AMD. Her team led the analyses of data from the Nurses' Health Study between 1980-1992 in participants who did not report a diagnosis of cancer or AMD at the beginning of the study. We found that women who smoked 25 or more cigarettes per day had double the risk of AMD compared with women who never smoked. Past smokers also had higher risk.

Dr. Seddon led a team of collaborators to obtain diet data at 5 centers using her food frequency questionnaire, and this was the first study to evaluate the intake of specific nutrients and the risk of advanced AMD. Her analyses found that the carotenoids, lutein and zeaxanthin, primarily obtained from dark green, leafy vegetables like spinach and kale, were most strongly associated with a reduced risk for AMD. This was the first evidence leading to current management of patients with AMD to increase intake of dark green, leafy vegetables, and other food rich in lutein and zeaxanthin.

Search for Dr. Seddon's and her team's complete research publications at PubMed.