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Assessing susceptibility to age-related macular degeneration with proteomic and genomic biomarkers.

Gu J, Pauer GJ, Yue X, Narendra U, Sturgill GM, Bena J, Gu X, Peachey NS, Salomon RG, Hagstrom SA, Crabb JW, Clinical Genomic and Proteomic AMD Study Gro - Mol. Cell Proteomics (2009)

Bottom Line: Mean CEP adduct and autoantibody levels were found to be elevated in AMD plasma by approximately 60 and approximately 30%, respectively.The results compellingly demonstrate higher mean CEP marker levels in AMD plasma over a broad age range.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.

View Article: PubMed Central - PubMed

Affiliation: Cole Eye Institute, Lerner Research Inst., Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, USA.

ABSTRACT
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.

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Related in: MedlinePlus

Plasma CEP markers stratified by demographic and health factors. Plasma CEP adduct and CEP autoantibody levels in the AMD and control study populations are plotted based on donor status with regard to race, gender, smoking status, hypertension, hyperlipidemia, diabetes, and cardiovascular diseases. Sample size per group is indicated, and asterisks reflect p values from a two-sided t test of log-transformed CEP marker concentrations (***, p < 0.001; **, p < 0.01; and *, p < 0.05). Cauc, Caucasian; Afr Am, African-American; F, female; M, male; S, smoking; NS, non-smoking; w, with; w/o, without. Error bars reflect standard deviation.
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f5: Plasma CEP markers stratified by demographic and health factors. Plasma CEP adduct and CEP autoantibody levels in the AMD and control study populations are plotted based on donor status with regard to race, gender, smoking status, hypertension, hyperlipidemia, diabetes, and cardiovascular diseases. Sample size per group is indicated, and asterisks reflect p values from a two-sided t test of log-transformed CEP marker concentrations (***, p < 0.001; **, p < 0.01; and *, p < 0.05). Cauc, Caucasian; Afr Am, African-American; F, female; M, male; S, smoking; NS, non-smoking; w, with; w/o, without. Error bars reflect standard deviation.

Mentions: Plasma CEP marker concentrations were also compared by gender, race, and health history, including smoking, hypertension, hyperlipidemia, diabetes, and cardiovascular disease (Fig. 5). For each comparison, significant differences in CEP adduct and autoantibody concentrations were observed between AMD and control donors. For several of the comparisons, small but significant differences were also detected within the AMD or control cohorts. Specifically in AMD patients, mean CEP adduct levels were higher in Caucasians relative to African-Americans, in females relative to males, and in donors exhibiting hypertension and hyperlipidemia. Within the control cohorts, no significant differences were detected in mean amounts of CEP adducts. However, mean CEP autoantibody titers were slightly higher in control males, control smokers, and controls with diabetes or cardiovascular disease. AMD donors with hypertension and hyperlipidemia also exhibited slightly higher amounts of CEP autoantibodies (Fig. 5).


Assessing susceptibility to age-related macular degeneration with proteomic and genomic biomarkers.

Gu J, Pauer GJ, Yue X, Narendra U, Sturgill GM, Bena J, Gu X, Peachey NS, Salomon RG, Hagstrom SA, Crabb JW, Clinical Genomic and Proteomic AMD Study Gro - Mol. Cell Proteomics (2009)

Plasma CEP markers stratified by demographic and health factors. Plasma CEP adduct and CEP autoantibody levels in the AMD and control study populations are plotted based on donor status with regard to race, gender, smoking status, hypertension, hyperlipidemia, diabetes, and cardiovascular diseases. Sample size per group is indicated, and asterisks reflect p values from a two-sided t test of log-transformed CEP marker concentrations (***, p < 0.001; **, p < 0.01; and *, p < 0.05). Cauc, Caucasian; Afr Am, African-American; F, female; M, male; S, smoking; NS, non-smoking; w, with; w/o, without. Error bars reflect standard deviation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2690477&req=5

f5: Plasma CEP markers stratified by demographic and health factors. Plasma CEP adduct and CEP autoantibody levels in the AMD and control study populations are plotted based on donor status with regard to race, gender, smoking status, hypertension, hyperlipidemia, diabetes, and cardiovascular diseases. Sample size per group is indicated, and asterisks reflect p values from a two-sided t test of log-transformed CEP marker concentrations (***, p < 0.001; **, p < 0.01; and *, p < 0.05). Cauc, Caucasian; Afr Am, African-American; F, female; M, male; S, smoking; NS, non-smoking; w, with; w/o, without. Error bars reflect standard deviation.
Mentions: Plasma CEP marker concentrations were also compared by gender, race, and health history, including smoking, hypertension, hyperlipidemia, diabetes, and cardiovascular disease (Fig. 5). For each comparison, significant differences in CEP adduct and autoantibody concentrations were observed between AMD and control donors. For several of the comparisons, small but significant differences were also detected within the AMD or control cohorts. Specifically in AMD patients, mean CEP adduct levels were higher in Caucasians relative to African-Americans, in females relative to males, and in donors exhibiting hypertension and hyperlipidemia. Within the control cohorts, no significant differences were detected in mean amounts of CEP adducts. However, mean CEP autoantibody titers were slightly higher in control males, control smokers, and controls with diabetes or cardiovascular disease. AMD donors with hypertension and hyperlipidemia also exhibited slightly higher amounts of CEP autoantibodies (Fig. 5).

Bottom Line: Mean CEP adduct and autoantibody levels were found to be elevated in AMD plasma by approximately 60 and approximately 30%, respectively.The results compellingly demonstrate higher mean CEP marker levels in AMD plasma over a broad age range.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.

View Article: PubMed Central - PubMed

Affiliation: Cole Eye Institute, Lerner Research Inst., Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus