Dataset Information

Assessing susceptibility to age-related macular degeneration with genetic markers and environmental factors.

ABSTRACT: To evaluate the independent and joint effects of genetic factors and environmental variables on advanced forms of age-related macular degeneration (AMD), including geographic atrophy and choroidal neovascularization, and to develop a predictive model with genetic and environmental factors included.Demographic information, including age at onset, smoking status, and body mass index, was collected for 1844 participants. Genotypes were evaluated for 8 variants in 5 genes related to AMD. Unconditional logistic regression analyses were performed to generate a risk predictive model.All genetic variants showed a strong association with AMD. Multivariate odds ratios were 3.52 (95% confidence interval, 2.08-5.94) for complement factor H, CFH rs1061170 CC, 4.21 (2.30-7.70) for CFH rs2274700 CC, 0.46 (0.27-0.80) for C2 rs9332739 CC/CG, 0.44 (0.30-0.66) for CFB rs641153 TT/CT, 10.99 (6.04-19.97) for HTRA1/LOC387715 rs10490924 TT, and 2.66 (1.43-4.96) for C3 rs2230199 GG. Smoking was independently associated with advanced AMD after controlling for age, sex, body mass index, and all genetic variants.CFH confers more risk to the bilaterality of geographic atrophy, whereas HTRA1/LOC387715 contributes more to the bilaterality of choroidal neovascularization. C3 confers more risk for geographic atrophy than choroidal neovascularization. Risk models with combined genetic and environmental factors have notable discrimination power.Early detection and risk prediction of AMD could help to improve the prognosis of AMD and to reduce the outcome of blindness. Targeting high-risk individuals for surveillance and clinical interventions may help reduce disease burden.

SUBMITTER: Chen Y

PROVIDER: S-EPMC4134685 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Assessing susceptibility to age-related macular degeneration with genetic markers and environmental factors.

Chen Yuhong Y Zeng Jiexi J Zhao Chao C Wang Kevin K Trood Elizabeth E Buehler Jeanette J Weed Matthew M Kasuga Daniel D Bernstein Paul S PS Hughes Guy G Fu Victoria V Chin Jessica J Lee Clara C Crocker Maureen M Bedell Matthew M Salasar Francesca F Yang Zhenglin Z Goldbaum Michael M Ferreyra Henry H Freeman William R WR Kozak Igor I Zhang Kang K

Archives of ophthalmology (Chicago, Ill. : 1960) 20110301 3

<h4>Objectives</h4>To evaluate the independent and joint effects of genetic factors and environmental variables on advanced forms of age-related macular degeneration (AMD), including geographic atrophy and choroidal neovascularization, and to develop a predictive model with genetic and environmental factors included.<h4>Methods</h4>Demographic information, including age at onset, smoking status, and body mass index, was collected for 1844 participants. Genotypes were evaluated for 8 variants in ...[more]

PMID: 21402993

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Project description:Age-related macular degeneration (AMD) is a progressive disease and major cause of severe visual loss. Toward the discovery of tools for early identification of AMD susceptibility, we evaluated the combined predictive capability of proteomic and genomic AMD biomarkers. We quantified plasma carboxyethylpyrrole (CEP) oxidative protein modifications and CEP autoantibodies by ELISA in 916 AMD and 488 control donors. CEP adducts are uniquely generated from oxidation of docosahexaenoate-containing lipids that are abundant in the retina. Mean CEP adduct and autoantibody levels were found to be elevated in AMD plasma by approximately 60 and approximately 30%, respectively. The odds ratio for both CEP markers elevated was 3-fold greater or more in AMD than in control patients. Genotyping was performed for AMD risk polymorphisms associated with age-related maculopathy susceptibility 2 (ARMS2), high temperature requirement factor A1 (HTRA1), complement factor H, and complement C3, and the risk of AMD was predicted based on genotype alone or in combination with the CEP markers. The AMD risk predicted for those exhibiting elevated CEP markers and risk genotypes was 2-3-fold greater than the risk based on genotype alone. AMD donors carrying the ARMS2 and HTRA1 risk alleles were the most likely to exhibit elevated CEP markers. The results compellingly demonstrate higher mean CEP marker levels in AMD plasma over a broad age range. Receiver operating characteristic curves suggest that CEP markers alone can discriminate between AMD and control plasma donors with approximately 76% accuracy and in combination with genomic markers provide up to approximately 80% discrimination accuracy. Plasma CEP marker levels were altered slightly by several demographic and health factors that warrant further study. We conclude that CEP plasma biomarkers, particularly in combination with genomic markers, offer a potential early warning system for assessing susceptibility to this blinding, multifactorial disease.

Project description:PurposeTo analyze the correlations between age-related macular degeneration (AMD) and genetic and environmental risk factors for in a Brazilian population.DesignCross-sectional study with a control group.MethodsWe collected data on 236 participants 50 years of age or older (141 with AMD and 95 controls without the disease). Data was obtained using a questionnaire and included information on demographics, ocular and medical history, family history of AMD, lifestyle, and smoking and drinking habits. Genetic evaluations included direct sequencing for the LOC387715 (rs10490924) variant, as well as PCR and enzymatic digestion for the CFH Y402H (rs1061170) and HTRA1 (rs11200638) variants. We performed a risk assessment of environmental risk factors and genetic variants associated with AMD and determined correlations between AMD and the data collected using multiple linear regression analysis.ResultsOf the 141 AMD cases, 99 (70%) had advanced AMD in at least one eye (57% neovascular AMD and 13% geographic atrophy), and 42 (30%) had not-advanced AMD. Family history of AMD (OR: 6.58; 95% CI: 1.94-22.31), presence of cardiovascular disease (CVD) (OR: 2.39; 95% CI: 1.08-5.28), low physical activity level (OR: 1.39; 95% CI: 0.82-2.37), and high serum cholesterol (OR: 1.49; 95% CI: 0.84-2.65) were associated with an increased risk for AMD. There was a significant association between CVD and incidence of advanced AMD (OR: 2.29; 95% CI 0.81-6.44). The OR for the risk allele of the LOC387715 gene, the CFH gene and the HTRA1 gene were 2.21 (95% CI: 1.47-3.35), 2.27 (95% CI: 1.52-3.37), and 2.76 (95% CI: 1.89-4.03), respectively. In the stepwise multiple linear regression analyses, the HTRA1 and CFH risk alleles, family history of AMD, the LOC387715 risk allele, and CVD were associated with an increased risk of AMD for a total of 25.6% contribution to the AMD phenotype.ConclusionsThe analysis correlating environmental and genetic risk factors such as family history of AMD, and CVD and the variants of HTRA1, CFH, and LOC387715 genes showed an expressive contribution for the development of AMD among this admixed population.

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.

Dataset Information

Assessing susceptibility to age-related macular degeneration with genetic markers and environmental factors.

Publications

Assessing susceptibility to age-related macular degeneration with genetic markers and environmental factors.

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