Using Genetic Variation and Environmental Risk Factor Data to Identify Individuals at High Risk for Age-Related Macular Degeneration

Abstract

A major goal of personalized medicine is to pre-symptomatically identify individuals at high risk for disease using knowledge of each individual's particular genetic profile and constellation of environmental risk factors. With the identification of several well-replicated risk factors for age-related macular degeneration (AMD), the leading cause of legal blindness in older adults, this previously unreachable goal is beginning to seem less elusive. However, recently developed algorithms have either been much less accurate than expected, given the strong effects of the identified risk factors, or have not been applied to independent datasets, leaving unknown how well they would perform in the population at large. We sought to increase accuracy by using novel modeling strategies, including multifactor dimensionality reduction (MDR) and grammatical evolution of neural networks (GENN), in addition to the traditional logistic regression approach. Furthermore, we rigorously designed and tested our models in three distinct datasets: a Vanderbilt-Miami (VM) clinic-based case-control dataset, a VM family dataset, and the population-based Age-related Maculopathy Ancillary (ARMA) Study cohort. Using a consensus approach to combine the results from logistic regression and GENN models, our algorithm was successful in differentiating between high- and low-risk groups (sensitivity 77.0%, specificity 74.1%). In the ARMA cohort, the positive and negative predictive values were 63.3% and 70.7%, respectively. We expect that future efforts to refine this algorithm by increasing the sample size available for model building, including novel susceptibility factors as they are discovered, and by calibrating the model for diverse populations will improve accuracy.

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

“…The most comprehensive case-control analysis in AMD in a recent report from the AMD Gene Consortium indicates that risk scores based on the now 19 known common SNPs mediating risk for AMD are able to distinguish fairly well between case and control individuals (Fritsche et al 2013), although it is not clear that the most recently identified variants contribute a great deal of information regarding disease risk beyond what prior known SNPs indicate. Other studies have evaluated the utility of categorized risk intervals based on genetic variation solely and in addition to known environmental contributors with generally positive results (e.g., Ho et al 2011;Spencer et al 2011;Grassmann et al 2012). Beyond simple genetic risk score analysis, the interaction of genetic risk with environmental factors is also valuable not only clinically but to further elucidate mechanisms of disease susceptibility and pathogenesis.…”

“…Beyond simple genetic risk score analysis, the interaction of genetic risk with environmental factors is also valuable not only clinically but to further elucidate mechanisms of disease susceptibility and pathogenesis. For example, Spencer and colleagues developed an algorithm using genetic profile and smoking history that was able to categorize individuals into high-and low-risk profiles for AMD (Spencer et al 2011). In addition, Buitendijk et al (2013) show that, although the difference is perhaps not clinically significant, the best statistical model for predicting AMD is attained when genetic as well as environmental factors are included.…”

LIPC rs10468017, rs493258 and LPL rs12678919 Role in Patients With Age- Related Macular Degeneration

“…This observation has led to the hypothesis that these lipid particles contribute to drusen formation during the development of AMD. It is thought that genetic predisposition accounts for 70% of the risk of the disease development [9]. Genetic variants in genes encoding components of lipid metabolism have been found to result in the deposit of lipid particles and the formation of drusen in the retina and BrM, thereby affecting retinal function [10].…”

Association of high-density lipoprotein and apolipoprotein E genetic variants with age-related macular degeneration

“…It can be classified as early, in termediate, or late, according to the presence of anomalies of the retinal pigmented epithelium (RPE), size of drusen (yellow pigments comprising cholesterol and apolipoproteins) (2) , area of atrophy of the RPE (geographic atrophy), and presence or absence of choroidal neovascularization (exudative and atrophic forms) (2)(3)(4) . In addition to genetic predisposition, which accounts for 70% of the risk of disease development (5) , advanced age is also considered a risk factor, which results in the deposition of lipid particles and for mation of drusen in the retina (Bruch's membrane, BM), thereby affecting retinal function (6) . Apolipoprotein E (APOE) acts in the metabolism of triglyceride-rich lipoproteins (TG) (7) and is also present in RPE and BM (4) .…”