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

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

doi:10.1164/rccm.201302-0247OC

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

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

Pulmonary, Critical Care, & Sleep Medicine

Research output: Contribution to journal › Article

91 Scopus citations

Abstract

Rationale: Emphysema in chronic obstructive pulmonary disease (COPD) can be characterized by high-resolution chest computed tomography (HRCT); however, the repeated use of HRCT is limited because of concerns regarding radiation exposure and cost. Objectives: To evaluate biomarkers associated with emphysema and COPD-related clinical characteristics, and to assess the relationships of soluble receptor for advanced glycation endproducts (sRAGE), a candidate systemicbiomarker identifiedinthis study, with single-nucleotide polymorphisms (SNPs) in the gene coding for RAGE (AGER locus) and with clinical characteristics. Methods: Circulating levels of 111 biomarkers were analyzed for association with clinical characteristics in 410 patients with COPD enrolled in the TESRA study. sRAGE was also measured in the ECLIPSE cohort in 1,847 patients with COPD, 298 smokers and 204 nonsmokers. The association between 21 SNPs in the AGER locus with sRAGE levels and clinical characteristics was also investigated. Measurements and Main Results: sRAGE was identified as a biomarker of diffusing capacity of carbon monoxide and lung density in the TESRA cohort. In the ECLIPSE cohort, lower sRAGE levels were associated with increased emphysema, increased Global Initiative for Chronic Obstructive Lung Disease stage, and COPD disease status. The associations with emphysema in both cohorts remained significant after covariate adjustment (P < 0.0001). One SNP in the AGER locus, rs2070600, was associated with circulating sRAGE levels both in TESRA (P = 0.0014) and ECLIPSE (7.07 × 10^-16), which exceeded genome-wide significance threshold. Another SNP (rs2071288) was also associated with sRAGE levels (P = 0.01) and diffusing capacity of carbonmonoxide (P=0.01) in the TESRA study. Conclusions: Lower circulating sRAGE levels are associated with emphysema severity and genetic polymorphisms in the AGER locus are associated with systemic sRAGE levels.

Original language	English (US)
Pages (from-to)	948-957
Number of pages	10
Journal	American Journal of Respiratory and Critical Care Medicine
Volume	188
Issue number	8
DOIs	https://doi.org/10.1164/rccm.201302-0247OC
State	Published - Oct 15 2013

Keywords

DL
Lung density
Single-nucleotide polymorphism

ASJC Scopus subject areas

Pulmonary and Respiratory Medicine
Critical Care and Intensive Care Medicine

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Cheng, D. T., Kim, D. K., Cockayne, D. A., Belousov, A., Bitter, H., Cho, M. H., Duvoix, A., Edwards, L. D., Lomas, D. A., Miller, B. E., Reynaert, N., Tal-Singer, R., Wouters, E. F. M., Agustí, A., Fabbri, L. M., Rames, A., Visvanathan, S., Rennard, S. I., Jones, P., ... Pillai, S. G. (2013). 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. American Journal of Respiratory and Critical Care Medicine, 188(8), 948-957. https://doi.org/10.1164/rccm.201302-0247OC

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 D.; Lomas, David A.; Miller, Bruce E.; Reynaert, Niki; Tal-Singer, Ruth; Wouters, Emiel F.M.; Agustí, Alvar; Fabbri, Leonardo M.; Rames, Alex; Visvanathan, Sudha; Rennard, Stephen I.; Jones, Paul; Parmar, Harsukh; MacNee, William; Wolff, Gerhard; Silverman, Edwin K.; Mayer, Ruth J.; Pillai, Sreekumar G.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 188, No. 8, 15.10.2013, p. 948-957.

Research output: Contribution to journal › Article

Cheng, DT, Kim, DK, Cockayne, DA, Belousov, A, Bitter, H, Cho, MH, Duvoix, A, Edwards, LD, Lomas, DA, Miller, BE, Reynaert, N, Tal-Singer, R, Wouters, EFM, Agustí, A, Fabbri, LM, Rames, A, Visvanathan, S, Rennard, SI, Jones, P, Parmar, H, MacNee, W, Wolff, G, Silverman, EK, Mayer, RJ & Pillai, SG 2013, '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', American Journal of Respiratory and Critical Care Medicine, vol. 188, no. 8, pp. 948-957. https://doi.org/10.1164/rccm.201302-0247OC

Cheng DT, Kim DK, Cockayne DA, Belousov A, Bitter H, Cho MH et al. 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. American Journal of Respiratory and Critical Care Medicine. 2013 Oct 15;188(8):948-957. https://doi.org/10.1164/rccm.201302-0247OC

Cheng, Donavan T. ; Kim, Deog Kyeom ; Cockayne, Debra A. ; Belousov, Anton ; Bitter, Hans ; Cho, Michael H. ; Duvoix, Annelyse ; Edwards, Lisa D. ; Lomas, David A. ; Miller, Bruce E. ; Reynaert, Niki ; Tal-Singer, Ruth ; Wouters, Emiel F.M. ; Agustí, Alvar ; Fabbri, Leonardo M. ; Rames, Alex ; Visvanathan, Sudha ; Rennard, Stephen I. ; Jones, Paul ; Parmar, Harsukh ; MacNee, William ; Wolff, Gerhard ; Silverman, Edwin K. ; Mayer, Ruth J. ; Pillai, Sreekumar G. / 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. In: American Journal of Respiratory and Critical Care Medicine. 2013 ; Vol. 188, No. 8. pp. 948-957.

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title = "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 = "Rationale: Emphysema in chronic obstructive pulmonary disease (COPD) can be characterized by high-resolution chest computed tomography (HRCT); however, the repeated use of HRCT is limited because of concerns regarding radiation exposure and cost. Objectives: To evaluate biomarkers associated with emphysema and COPD-related clinical characteristics, and to assess the relationships of soluble receptor for advanced glycation endproducts (sRAGE), a candidate systemicbiomarker identifiedinthis study, with single-nucleotide polymorphisms (SNPs) in the gene coding for RAGE (AGER locus) and with clinical characteristics. Methods: Circulating levels of 111 biomarkers were analyzed for association with clinical characteristics in 410 patients with COPD enrolled in the TESRA study. sRAGE was also measured in the ECLIPSE cohort in 1,847 patients with COPD, 298 smokers and 204 nonsmokers. The association between 21 SNPs in the AGER locus with sRAGE levels and clinical characteristics was also investigated. Measurements and Main Results: sRAGE was identified as a biomarker of diffusing capacity of carbon monoxide and lung density in the TESRA cohort. In the ECLIPSE cohort, lower sRAGE levels were associated with increased emphysema, increased Global Initiative for Chronic Obstructive Lung Disease stage, and COPD disease status. The associations with emphysema in both cohorts remained significant after covariate adjustment (P < 0.0001). One SNP in the AGER locus, rs2070600, was associated with circulating sRAGE levels both in TESRA (P = 0.0014) and ECLIPSE (7.07 × 10-16), which exceeded genome-wide significance threshold. Another SNP (rs2071288) was also associated with sRAGE levels (P = 0.01) and diffusing capacity of carbonmonoxide (P=0.01) in the TESRA study. Conclusions: Lower circulating sRAGE levels are associated with emphysema severity and genetic polymorphisms in the AGER locus are associated with systemic sRAGE levels.",

keywords = "DL, Lung density, Single-nucleotide polymorphism",

author = "Cheng, {Donavan T.} and Kim, {Deog Kyeom} and Cockayne, {Debra A.} and Anton Belousov and Hans Bitter and Cho, {Michael H.} and Annelyse Duvoix and Edwards, {Lisa D.} and Lomas, {David A.} and Miller, {Bruce E.} and Niki Reynaert and Ruth Tal-Singer and Wouters, {Emiel F.M.} and Alvar Agust{\'i} and Fabbri, {Leonardo M.} and Alex Rames and Sudha Visvanathan and Rennard, {Stephen I.} and Paul Jones and Harsukh Parmar and William MacNee and Gerhard Wolff and Silverman, {Edwin K.} and Mayer, {Ruth J.} and Pillai, {Sreekumar G.}",

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doi = "10.1164/rccm.201302-0247OC",

language = "English (US)",

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journal = "American Journal of Respiratory and Critical Care Medicine",

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TY - JOUR

T1 - 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

AU - Cheng, Donavan T.

AU - Kim, Deog Kyeom

AU - Cockayne, Debra A.

AU - Belousov, Anton

AU - Bitter, Hans

AU - Cho, Michael H.

AU - Duvoix, Annelyse

AU - Edwards, Lisa D.

AU - Lomas, David A.

AU - Miller, Bruce E.

AU - Reynaert, Niki

AU - Tal-Singer, Ruth

AU - Wouters, Emiel F.M.

AU - Agustí, Alvar

AU - Fabbri, Leonardo M.

AU - Rames, Alex

AU - Visvanathan, Sudha

AU - Rennard, Stephen I.

AU - Jones, Paul

AU - Parmar, Harsukh

AU - MacNee, William

AU - Wolff, Gerhard

AU - Silverman, Edwin K.

AU - Mayer, Ruth J.

AU - Pillai, Sreekumar G.

PY - 2013/10/15

Y1 - 2013/10/15

N2 - Rationale: Emphysema in chronic obstructive pulmonary disease (COPD) can be characterized by high-resolution chest computed tomography (HRCT); however, the repeated use of HRCT is limited because of concerns regarding radiation exposure and cost. Objectives: To evaluate biomarkers associated with emphysema and COPD-related clinical characteristics, and to assess the relationships of soluble receptor for advanced glycation endproducts (sRAGE), a candidate systemicbiomarker identifiedinthis study, with single-nucleotide polymorphisms (SNPs) in the gene coding for RAGE (AGER locus) and with clinical characteristics. Methods: Circulating levels of 111 biomarkers were analyzed for association with clinical characteristics in 410 patients with COPD enrolled in the TESRA study. sRAGE was also measured in the ECLIPSE cohort in 1,847 patients with COPD, 298 smokers and 204 nonsmokers. The association between 21 SNPs in the AGER locus with sRAGE levels and clinical characteristics was also investigated. Measurements and Main Results: sRAGE was identified as a biomarker of diffusing capacity of carbon monoxide and lung density in the TESRA cohort. In the ECLIPSE cohort, lower sRAGE levels were associated with increased emphysema, increased Global Initiative for Chronic Obstructive Lung Disease stage, and COPD disease status. The associations with emphysema in both cohorts remained significant after covariate adjustment (P < 0.0001). One SNP in the AGER locus, rs2070600, was associated with circulating sRAGE levels both in TESRA (P = 0.0014) and ECLIPSE (7.07 × 10-16), which exceeded genome-wide significance threshold. Another SNP (rs2071288) was also associated with sRAGE levels (P = 0.01) and diffusing capacity of carbonmonoxide (P=0.01) in the TESRA study. Conclusions: Lower circulating sRAGE levels are associated with emphysema severity and genetic polymorphisms in the AGER locus are associated with systemic sRAGE levels.

AB - Rationale: Emphysema in chronic obstructive pulmonary disease (COPD) can be characterized by high-resolution chest computed tomography (HRCT); however, the repeated use of HRCT is limited because of concerns regarding radiation exposure and cost. Objectives: To evaluate biomarkers associated with emphysema and COPD-related clinical characteristics, and to assess the relationships of soluble receptor for advanced glycation endproducts (sRAGE), a candidate systemicbiomarker identifiedinthis study, with single-nucleotide polymorphisms (SNPs) in the gene coding for RAGE (AGER locus) and with clinical characteristics. Methods: Circulating levels of 111 biomarkers were analyzed for association with clinical characteristics in 410 patients with COPD enrolled in the TESRA study. sRAGE was also measured in the ECLIPSE cohort in 1,847 patients with COPD, 298 smokers and 204 nonsmokers. The association between 21 SNPs in the AGER locus with sRAGE levels and clinical characteristics was also investigated. Measurements and Main Results: sRAGE was identified as a biomarker of diffusing capacity of carbon monoxide and lung density in the TESRA cohort. In the ECLIPSE cohort, lower sRAGE levels were associated with increased emphysema, increased Global Initiative for Chronic Obstructive Lung Disease stage, and COPD disease status. The associations with emphysema in both cohorts remained significant after covariate adjustment (P < 0.0001). One SNP in the AGER locus, rs2070600, was associated with circulating sRAGE levels both in TESRA (P = 0.0014) and ECLIPSE (7.07 × 10-16), which exceeded genome-wide significance threshold. Another SNP (rs2071288) was also associated with sRAGE levels (P = 0.01) and diffusing capacity of carbonmonoxide (P=0.01) in the TESRA study. Conclusions: Lower circulating sRAGE levels are associated with emphysema severity and genetic polymorphisms in the AGER locus are associated with systemic sRAGE levels.

KW - DL

KW - Lung density

KW - Single-nucleotide polymorphism

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