Dataset Information

Bivariate Analysis of Age-Related Macular Degeneration Progression Using Genetic Risk Scores.

ABSTRACT: Age-related macular degeneration (AMD) is a leading cause of blindness in the developed world. While many AMD susceptibility variants have been identified, their influence on AMD progression has not been elucidated. Using data from two large clinical trials, Age-Related Eye Disease Study (AREDS) and AREDS2, we evaluated the effects of 34 known risk variants on disease progression. In doing so, we calculated the eye-level time-to-late AMD and modeled them using a bivariate survival analysis approach, appropriately accounting for between-eye correlation. We then derived a genetic risk score (GRS) based on these 34 risk variants, and analyzed its effect on AMD progression. Finally, we used the AREDS data to fit prediction models of progression based on demographic and environmental factors, eye-level AMD severity scores and the GRS and tested the models using the AREDS2 cohort. We observed that GRS was significantly associated with AMD progression in both cohorts, with a stronger effect in AREDS than in AREDS2 (AREDS: hazard ratio (HR) = 1.34, P = 1.6 × 10-22; AREDS2: HR = 1.11, P = 2.1 × 10-4). For prediction of AMD progression, addition of GRS to the demographic/environmental risk factors considerably improved the prediction performance. However, when the baseline eye-level severity scores were included as the predictors, any other risk factors including the GRS only provided small additional predictive power. Our model for predicting the disease progression risk demonstrated satisfactory performance in both cohorts, and we recommend its use with baseline AMD severity scores plus baseline age, education level, and smoking status, either with or without GRS.

SUBMITTER: Ding Y

PROVIDER: S-EPMC5419464 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Bivariate Analysis of Age-Related Macular Degeneration Progression Using Genetic Risk Scores.

Ding Ying Y Liu Yi Y Yan Qi Q Fritsche Lars G LG Cook Richard J RJ Clemons Traci T Ratnapriya Rinki R Klein Michael L ML Abecasis Gonçalo R GR Swaroop Anand A Chew Emily Y EY Weeks Daniel E DE Chen Wei W

Genetics 20170324 1

Age-related macular degeneration (AMD) is a leading cause of blindness in the developed world. While many AMD susceptibility variants have been identified, their influence on AMD progression has not been elucidated. Using data from two large clinical trials, Age-Related Eye Disease Study (AREDS) and AREDS2, we evaluated the effects of 34 known risk variants on disease progression. In doing so, we calculated the eye-level time-to-late AMD and modeled them using a bivariate survival analysis appro ...[more]

PMID: 28341650

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Project description:PURPOSE:Age-related macular degeneration (AMD) is a degenerative disease of the macula, often leading to progressive vision loss. The rate of disease progression can vary among individuals and has been associated with multiple risk factors. In this review, we provide an overview of the current literature investigating phenotypic, demographic, environmental, genetic, and molecular risk factors, and propose the most consistently identified risk factors for disease progression in AMD based on these studies. Finally, we describe the potential use of these risk factors for personalised healthcare. RECENT FINDINGS:While phenotypic risk factors such as drusen and pigment abnormalities become more important to predict disease progression during the course of the disease, demographic, environmental, genetic and molecular risk factors are more valuable at earlier disease stages. Demographic and environmental risk factors such as age and smoking are consistently reported to be related to disease progression, while other factors such as sex, body mass index (BMI) and education are less often associated. Of all known AMD variants, variants that are most consistently reported with disease progression are rs10922109 and rs570618 in CFH, rs116503776 in C2/CFB/SKIV2L, rs3750846 in ARMS2/HTRA1 and rs2230199 in C3. However, it seems likely that other AMD variants also contribute to disease progression but to a lesser extent. Rare variants have probably a large effect on disease progression in highly affected families. Furthermore, current prediction models do not include molecular risk factors, while these factors can be measured accurately in the blood. Possible promising molecular risk factors are High-Density Lipoprotein Cholesterol (HDL-C), Docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), zeaxanthin and lutein. SUMMARY:Phenotypic, demographic, environmental, genetic and molecular risk factors can be combined in prediction models to predict disease progression, but the selection of the proper risk factors for personalised risk prediction will differ among individuals and is dependent on their current disease stage. Future prediction models should include a wider set of genetic variants to determine the genetic risk more accurately, and rare variants should be taken into account in highly affected families. In addition, adding molecular factors in prediction models may lead to preventive strategies and personalised advice.

Project description:PurposeTo expand our predictive models for progression to advanced stages of age-related macular degeneration (AMD) based on demographic, environmental, genetic, and ocular factors, using longer follow-up, time varying analyses, calculation of absolute risks, adjustment for competing risks, and detailed baseline AMD and drusen status.DesignProspective, longitudinal study.ParticipantsWe included 2937 individuals in the Age-Related Eye Disease Study, of which 819 subjects progressed to advanced AMD during 12 years of follow-up.MethodsCox proportional hazards regression analyses were performed to calculate hazard ratios for progression. Covariates included demographic and environmental factors, 6 variants in 5 genes, baseline macular drusen size, and presence and type of advanced AMD in 1 eye at baseline. To assess the ability of risk scores based on all covariates to discriminate between progressors and nonprogressors, an algorithm was developed and the area under the receiver operating characteristic curve (AUC) was calculated. To validate the overall model, the total sample was randomly subdivided into derivation and test samples. Another model was built based on the derivation sample and assessed for calibration and discrimination in the test sample. Sample sizes needed for testing new treatments in clinical trials were estimated based on models with and without genetic variables.Main outcome measuresProgression to advanced AMD, including geographic atrophy and neovascular disease.ResultsIn multivariate models, age, smoking, body mass index, single nucleotide polymorphisms in the CFH, ARMS2/HTRA1, C3, C2, and CFB genes, as well as presence of advanced AMD in 1 eye and drusen size in both eyes were all independently associated with progression. The AUC for progression at 10 years in the model with genetic factors, drusen size, and environmental covariates was 0.915 in the total sample. In the test sample, based on a model estimated from the derivation sample, the AUC was 0.908. The sample sizes needed for clinical trials were estimated to be lower when genetic susceptibility was considered.ConclusionsFactors reflective of nature and nurture were incorporated into an expanded algorithm for risk prediction, which performed very well in both derivation and test samples. Risk scores and predicted progression rates will be useful for AMD surveillance and for designing clinical trials.Financial disclosure(s)Proprietary or commercial disclosure may be found after the references.

Project description:PurposeTo determine the contribution of common and rare genetic risk variants in families with age-related macular degeneration (AMD).DesignCase-control study.ParticipantsA family cohort (355 affected and 342 unaffected family members from 144 families with AMD) and an unrelated case-control cohort (1078 patients, 952 controls), recruited from the European Genetic Database.MethodsGenetic data of both cohorts were filtered for carriership of rare genetic variants in the coding and splice-site regions of the complement factor H (CFH) and complement factor I (CFI) genes, and 52 AMD-associated variants were extracted for calculation of genetic risk scores (GRS). To compare GRSs between familial and nonfamilial rare CFH and CFI variant carriers and noncarriers and between AMD disease stages, we performed a 2-way analysis of variance, with Bonferroni correction for multiple testing. Within families with AMD carrying rare CFH and CFI variants, we analyzed segregation patterns by calculating the proportion of affected among carriers.Main outcome measuresGRSs and segregation of rare CFH and CFI variants.ResultsWe observed higher GRSs in familial versus nonfamilial individuals without rare CFH and CFI variants: mean GRS, 1.76 (standard error [SE], 0.08) versus 0.83 (SE, 0.03; P < 0.001). In 51 of 144 families (35.4%), rare CFH and CFI variants were identified. Within the AMD family cohort, carriers of rare CFH and CFI variants showed lower GRSs compared with noncarriers (mean GRS, 1.05 [SE, 0.23] vs. 1.76 [SE, 0.08]; P = 0.02). The proportion of affected family members with a high GRS was 57.3% (176/307). Of the affected family members with a low or intermediate GRS, 40.0% carried rare CFH or CFI variants. Among carriers of 11 rare CFH or CFI variants, the proportion affected by AMD was more than 75%.ConclusionsGenetic risk in families with AMD often is attributed to high GRSs based on common variants. However, in part of the families with a low or intermediate GRS, rare CFH and CFI variants contributed to disease development. We recommend computing GRSs and sequencing the CFH and CFI genes in families with AMD, in particular in the light of ongoing gene-specific clinical trials.

Project description:PURPOSE:To determine whether oral beta-blockers (BBs) are associated with the development of neovascular age-related macular degeneration (nAMD). METHODS:Retrospective cohort study of patients from 2000 to 2014 using data from a large national U.S. insurer's administrative medical claims database. Patients with nonexudative AMD who initiated (index date) BB, a calcium channel blocker (CCB), an angiotensin-converting enzyme/angiotensin receptor blocker, or a diuretic. Patients were excluded for <2 years in the plan before the index date, any history of nAMD or diagnosis, or treatment for an ocular disease that could be confused with nAMD. Hazard of developing of nAMD was the main outcome measure. Primary analysis compared BB with CCB patients with BB versus the other classes as secondary analyses. In addition, a sensitivity analysis was performed between BB and CCB cohorts using 1:1 propensity score matching. Cox proportional hazard regression was performed to estimate the hazard ratio (HR) of developing nAMD at 90, 180, and 365 days for BB. Covariates of interest included demographic information, year of index date, number of antihypertensive medications, and other comorbid systemic conditions. RESULTS:Eighteen thousand seven hundred and fifty-four BB patients and 12,784 CCB patients met criteria for inclusion. After controlling for covariates, patients on BB had a lower hazard for nAMD at both 90 and 180 days than patients on CCB (HRs: 0.67-0.71; P < 0.01 for both) and diuretics (HRs: 0.55-0.62; P < 0.01). Patients on BB versus angiotensin-converting enzyme/angiotensin receptor blocker at all time points and BB versus CCB and diuretics at 365 days did not have a significantly lower association with nAMD (HR: 0.73-0.85; P > 0.06 for all comparisons). A sensitivity analysis using propensity score matching yielded similar results with patients on BB significantly less likely to develop nAMD at 90 and 180 days (HR: 0.70-0.76; P < 0.049 for both) but not at 365 days (HR: 0.88; P = 0.30) compared with patients on CCB. CONCLUSION:No evidence was found that BB usage increased the hazard for nAMD relative to other antihypertensive medications.

Dataset Information

Bivariate Analysis of Age-Related Macular Degeneration Progression Using Genetic Risk Scores.

Publications

Bivariate Analysis of Age-Related Macular Degeneration Progression Using Genetic Risk Scores.

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