Systemic Soluble Receptor for Advanced Glycation Endproducts Is a Biomarker of Emphysema and Associated with AGER Genetic Variants in Patients with Chronic Obstructive Pulmonary Disease

Cheng, Donavan T.; Kim, Deog Kyeom; Cockayne, Debra A.; Belousov, Anton; Bitter, Hans; Cho, Michael H.; Duvoix, Annelyse; Edwards, Lisa; Lomas, David A.; Miller, Bruce E.; Reynaert, Niki L.; Tal‐Singer, Ruth; Wouters, Emiel F.M.; Agustí, Àlvar; Fabbri, Leonardo M.; Rames, Alex; Visvanathan, Sudha; Rennard, Stephen I.; Jones, Paul; Parmar, H.; MacNee, William; Wolff, Gerhard; Silverman, Edwin K.; Mayer, Ruth; Pillai, Sreekumar

doi:10.1164/rccm.201302-0247oc

Cited by 140 publications

(151 citation statements)

References 47 publications

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“…In a GWAS of quantitative imaging phenotypes in smokers with and without COPD, we identified genome-wide significant associations with loci previously shown to be associated with COPD or with spirometric measures related to airflow limitation, including the 15q25, HHIP, and AGER loci, the latter also identified in association with emphysema in a general population sample (15) and with emphysema and sRAGE levels in COPD (42). We also describe a genome-wide association with emphysema and variants near SERPINA10 and show that this association is in strong linkage disequilibrium with the Z-allele of SERPINA1 and not due the presence of PI ZZ individuals.…”

Section: Discussionmentioning

confidence: 88%

A Genome-Wide Association Study of Emphysema and Airway Quantitative Imaging Phenotypes

Cho

Castaldi²,

Hersh

et al. 2015

Am J Respir Crit Care Med

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Rationale: Chronic obstructive pulmonary disease (COPD) is defined by the presence of airflow limitation on spirometry, yet subjects with COPD can have marked differences in computed tomography imaging. These differences may be driven by genetic factors. We hypothesized that a genome-wide association study (GWAS) of quantitative imaging would identify loci not previously identified in analyses of COPD or spirometry. In addition, we sought to determine whether previously described genome-wide significant COPD and spirometric loci were associated with emphysema or airway phenotypes.Objectives: To identify genetic determinants of quantitative imaging phenotypes.Methods: We performed a GWAS on two quantitative emphysema and two quantitative airway imaging phenotypes in the COPDGene (non-Hispanic white and African American), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints), NETT (National Emphysema Treatment Trial), and GenKOLS (Genetics of COPD, Norway) studies and on percentage gas trapping in COPDGene. We also examined specific loci reported as genomewide significant for spirometric phenotypes related to airflow limitation or COPD. Measurements and Main Results:The total sample size across all cohorts was 12,031, of whom 9,338 were from COPDGene. We identified five loci associated with emphysema-related phenotypes, one with airway-related phenotypes, and two with gas trapping. These loci included previously reported associations, including the HHIP, 15q25, and AGER loci, as well as novel associations near SERPINA10 and DLC1. All previously reported COPD and a significant number of spirometric GWAS loci were at least nominally (P , 0.05) associated with either emphysema or airway phenotypes.Conclusions: Genome-wide analysis may identify novel risk factors for quantitative imaging characteristics in COPD and also identify imaging features associated with previously identified lung function loci.

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Section: Discussionmentioning

confidence: 88%

A Genome-Wide Association Study of Emphysema and Airway Quantitative Imaging Phenotypes

Cho

Castaldi²,

Hersh

et al. 2015

Am J Respir Crit Care Med

Self Cite

138

126

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“…Cheng et al (2013) investigated 21 SNPs in the AGER locus with sRAGE levels and found that the G82S polymorphism of the RAGE gene was associated with circulating levels of sRAGE levels in COPD patients. Young et al (2011b) found that the minor allele (T allele or CT/TT genotype) of the G82S polymorphism of RAGE was more commonly found in smokers who did not have COPD compared with those with COPD in a Western population.…”

Section: Discussionmentioning

confidence: 99%

Association of Polymorphisms of the Receptor for Advanced Glycation End Products Gene with COPD in the Chinese Population

Cheng²,

Ma³

et al. 2014

DNA and Cell Biology

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The receptor for advanced glycation end products (RAGE) is a cell surface molecule of the immunoglobulin superfamily that binds diverse endogenous ligands involved in the development of chronic diseases and inflammatory damage. A growing body of evidence has suggested that RAGE is involved in the development and progression of chronic obstructive pulmonary disease (COPD). The present study investigated the existence of an association among three polymorphisms (-374T/A, -429T/C, and G82S) of the RAGE gene with the risk of COPD in the Chinese population. The RAGE genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism in 216 patients with COPD and 239 age-matched healthy individuals. Our study demonstrated that the frequencies of the GS genotype and the S allele in the G82S mutation were significantly higher in COPD patients than in controls (odds ratios [OR]=1.70, 95% confidence interval [CI]: 1.15-2.50, p=0.0098 and OR=1.42, 95% CI: 1.06-1.91, p=0.023, respectively). Further stratification analysis by smoking status revealed that the presence of the GS genotype conferred a higher risk of developing COPD in current smokers (p=0.044). In contrast, mutations at -374T/A and -429T/C did not demonstrate any association with COPD, even after taking into account the patients' smoking history. Our study provides preliminary evidence that the G82S polymorphism in the RAGE gene is associated with an increased risk of COPD and that the GS genotype of the G82S variant is a risk factor for COPD in the Chinese population.

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“…sRAGE is the resulting product of both alternative splicing (esRAGE) and cleavage of membrane-bound RAGE [101,102] . Circulating levels of sRAGE are decreased in COPD patients when compared to healthy smoking controls and appear to be associated with emphysema independently of COPD severity [65] . In addition to the association of sRAGE with emphysema, two SNPs in the gene coding for RAGE (AGER locus) were significantly associated with systemic sRAGE levels.…”

Section: Prioritized Copd Protein Biomarkersmentioning

confidence: 90%

“…Accumulating evidence indicates that chronic inflammatory and immune responses play key roles in the development and progression of COPD [60,61] . In this respect, most of the potential biomarkers included in our list are proteins involved in inflammation or the immune response such as CRP, IL-6, beta defensin 2, among many others [25][26][27]29,36,37,54,[62][63][64][65][66][67][68][69][70][71][72][73][74] . One of the main causes leading to COPD is chronic smoking which exposes the respiratory tract to reactive oxygen species, resulting in oxidative stress and injury (which in the last instance leads also to inflammation) [59,75] .…”

Section: Copd Protein Biomarkersmentioning

confidence: 99%

Prioritization of COPD protein biomarkers, based on a systematic study of the literature

Camacho¹,

Klont²,

Horvatovich³

et al. 2016

Adv Precis Med

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Chronic Obstructive Pulmonary Disease (COPD) is a chronic lung disease mostly due to smoking and until now diagnosed by spirometry (post bronchodilator FEV 1 /FVC <70%). However, in spite of the usefulness of FEV 1 as diagnostic and prognostic tool, it has proven to be a weak indicator of future exacerbations, unable to predict lung function decline within COPD patients, as well as unable to identify the smokers "susceptible" to developing COPD at an early stage. Thus, there is an urgent need for biomarkers that address these questions and support clinical decision making in the diagnosis and treatment of (early) COPD. In this respect, considerable efforts have been devoted to identifying protein biomarkers that enable a better understanding of this complex disease and leading to better diagnostic and prognostic tools. However, in spite of the wide range of candidates that have been suggested as potentially useful COPD biomarkers, most remained at the level of the initial discovery, and only fibrinogen has been approved by the Food and Drug Administration (FDA) as predictor for all-cause mortality and COPD exacerbations. There is thus a need for future investigations of these biomarkers in large-scale and well characterized studies in order to prove their usefulness as surrogate endpoints. Based on this, the aim of the present review is to advance COPD biomarker development by providing a comprehensive overview of protein biomarker candidates which have been evaluated in clinical studies and prioritize them according to their potential of becoming valid, clinically useful COPD biomarkers.

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Systemic Soluble Receptor for Advanced Glycation Endproducts Is a Biomarker of Emphysema and Associated with AGER Genetic Variants in Patients with Chronic Obstructive Pulmonary Disease

Abstract: Lower circulating sRAGE levels are associated with emphysema severity and genetic polymorphisms in the AGER locus are associated with systemic sRAGE levels. Clinical trial registered with www.clinicaltrials.gov (NCT 00413205 and NCT 00292552).

Cited by 140 publications

References 47 publications

A Genome-Wide Association Study of Emphysema and Airway Quantitative Imaging Phenotypes

A Genome-Wide Association Study of Emphysema and Airway Quantitative Imaging Phenotypes

Association of Polymorphisms of the Receptor for Advanced Glycation End Products Gene with COPD in the Chinese Population

Prioritization of COPD protein biomarkers, based on a systematic study of the literature

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