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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

Cheng, DT and Kim, DK and Cockayne, DA and Belousov, A and Bitter, H and Cho, MH and Duvoix, A and Edwards, LD and Lomas, DA and Miller, BE and Reynaert, N and Tal-Singer, R and Wouters, EFM and Agusti, A and Fabbri, LM and Rames, A and Visvanathan, S and Rennard, SI and Jones, P and Parmar, H and MacNee, W and Wolff, G and Silverman, EK and Mayer, RJ and 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. pp. 948-957.

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 systemic biomarker identified in this 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 MainResults: 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 x 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

Item Type: Article
Additional Information: pubid: 213 nvp_institute: NIBR contributor_address: Hoffmann La Roche Inc, Nutley, NJ 07110 USA, Mem Sloan Kettering Canc, New York, NY USA ; Seoul Natl Univ, Div Pulm & Crit Care Med, Boramae Med Ctr, Seoul, South Korea, Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med, Boston, MA 02115 USA ; Hoffmann La Roche Inc, Nutley, NJ 07110 USA, Boston Sci, San Jose, CA USA ; Hoffmann La Roche, Penzberg, Germany ; Novartis Inst Biomed Res, Cambridge, MA USA, Hoffmann La Roche Inc, Nutley, NJ 07110 USA ; Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Div Network Med, Boston, MA 02115 USA ; Univ Cambridge, Dept Med, Cambridge Inst Med Res, Cambridge CB2 2QQ, England, UCL, Fac Med Sci, Div Med, London, England ; GlaxoSmithKline Res & Dev Ltd, Res Triangle Pk, NC USA ; GlaxoSmithKline Res & Dev Ltd, King Of Prussia, PA USA ; Maastricht Univ, Med Ctr, Dept Resp Med, Maastricht, Netherlands ; Univ Barcelona, Inst Torax, Hosp Clin, IDIBAPS, Barcelona, Spain ; Univ Modena & Reggio Emilia, Dept Resp Dis, Modena, Italy ; Hoffmann La Roche AG, Basel, Switzerland ; Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA, Hoffmann La Roche Inc, Nutley, NJ 07110 USA ; Univ Nebraska Med Ctr, Omaha, NE USA ; Univ London, London, England ; EMD Serono, Billerica, MA USA, Hoffmann La Roche Inc, Nutley, NJ 07110 USA ; Queens Med Res Inst, Edinburgh, Midlothian, Scotland ; Mitsubishi Tanabe, Warren, NJ USA, Hoffmann La Roche Inc, Nutley, NJ 07110 USA ; Hoffmann La Roche Inc, Nutley, NJ 07110 USA pillaisreekumar@yahoo.com; Hoffmann La Roche Inc, Nutley, NJ 07110 USA; Mem Sloan Kettering Canc, New York, NY USA; Pillai, S G; Eli Lilly & Co, Lilly Corp Ctr, DC1522, Indianapolis, IN 46285 USA
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/22031

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