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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 adducts and autoantibodies by donor age. Plasma CEP adduct (A) and CEP autoantibody levels (C) in the AMD (▵) and control (•) cohorts are shown plotted by donor age. Pearson's correlation analysis (horizontal color-coded lines and p value from log-transformed data) revealed little change in mean CEP marker concentrations with age except for a gradual increase in CEP autoantibody titer in the control cohort. CEP adduct (B) and CEP autoantibody levels (D) in AMD and control donors are plotted by age group, including controls ≤50 years (y) (n = 98), 51–60 years (n = 138 control, n = 26 AMD), 61–70 years (n = 153 control, n = 123 AMD), 71–80 years (n = 154 control, n = 389 AMD), and >80 years (n = 43 control, n = 378 AMD). -Fold difference in CEP marker concentrations is indicated between the control and AMD groups. Asterisks reflect p values from a two-sided t test (***, p < 0.001; **, p < 0.01; and *, p < 0.05). Error bars reflect standard deviation.
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f4: Plasma CEP adducts and autoantibodies by donor age. Plasma CEP adduct (A) and CEP autoantibody levels (C) in the AMD (▵) and control (•) cohorts are shown plotted by donor age. Pearson's correlation analysis (horizontal color-coded lines and p value from log-transformed data) revealed little change in mean CEP marker concentrations with age except for a gradual increase in CEP autoantibody titer in the control cohort. CEP adduct (B) and CEP autoantibody levels (D) in AMD and control donors are plotted by age group, including controls ≤50 years (y) (n = 98), 51–60 years (n = 138 control, n = 26 AMD), 61–70 years (n = 153 control, n = 123 AMD), 71–80 years (n = 154 control, n = 389 AMD), and >80 years (n = 43 control, n = 378 AMD). -Fold difference in CEP marker concentrations is indicated between the control and AMD groups. Asterisks reflect p values from a two-sided t test (***, p < 0.001; **, p < 0.01; and *, p < 0.05). Error bars reflect standard deviation.

Mentions: Study population characteristics, including age, gender, race, and health history, are summarized in Table VII. Comparison of plasma CEP marker levels by donor age (Fig. 4) revealed that CEP adduct concentrations are relatively stable with age and that AMD patients had significantly higher mean levels than controls at all ages. Mean CEP autoantibody titer remained stable with age in AMD patients and was higher than in controls but increased gradually with age in control donors (Fig. 4). Comparison of log-transformed CEP marker concentrations (not shown) confirmed these results.


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 adducts and autoantibodies by donor age. Plasma CEP adduct (A) and CEP autoantibody levels (C) in the AMD (▵) and control (•) cohorts are shown plotted by donor age. Pearson's correlation analysis (horizontal color-coded lines and p value from log-transformed data) revealed little change in mean CEP marker concentrations with age except for a gradual increase in CEP autoantibody titer in the control cohort. CEP adduct (B) and CEP autoantibody levels (D) in AMD and control donors are plotted by age group, including controls ≤50 years (y) (n = 98), 51–60 years (n = 138 control, n = 26 AMD), 61–70 years (n = 153 control, n = 123 AMD), 71–80 years (n = 154 control, n = 389 AMD), and >80 years (n = 43 control, n = 378 AMD). -Fold difference in CEP marker concentrations is indicated between the control and AMD groups. Asterisks reflect p values from a two-sided t test (***, p < 0.001; **, p < 0.01; and *, p < 0.05). Error bars reflect standard deviation.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Plasma CEP adducts and autoantibodies by donor age. Plasma CEP adduct (A) and CEP autoantibody levels (C) in the AMD (▵) and control (•) cohorts are shown plotted by donor age. Pearson's correlation analysis (horizontal color-coded lines and p value from log-transformed data) revealed little change in mean CEP marker concentrations with age except for a gradual increase in CEP autoantibody titer in the control cohort. CEP adduct (B) and CEP autoantibody levels (D) in AMD and control donors are plotted by age group, including controls ≤50 years (y) (n = 98), 51–60 years (n = 138 control, n = 26 AMD), 61–70 years (n = 153 control, n = 123 AMD), 71–80 years (n = 154 control, n = 389 AMD), and >80 years (n = 43 control, n = 378 AMD). -Fold difference in CEP marker concentrations is indicated between the control and AMD groups. Asterisks reflect p values from a two-sided t test (***, p < 0.001; **, p < 0.01; and *, p < 0.05). Error bars reflect standard deviation.
Mentions: Study population characteristics, including age, gender, race, and health history, are summarized in Table VII. Comparison of plasma CEP marker levels by donor age (Fig. 4) revealed that CEP adduct concentrations are relatively stable with age and that AMD patients had significantly higher mean levels than controls at all ages. Mean CEP autoantibody titer remained stable with age in AMD patients and was higher than in controls but increased gradually with age in control donors (Fig. 4). Comparison of log-transformed CEP marker concentrations (not shown) confirmed these results.

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