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

Rationale: Emphysema in COPD can be characterized by high resolution chest CT (HRCT); however, the repeated use of HRCT is limited due to 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 end products (sRAGE), a candidate systemic biomarker identified in this study, with SNPs in the gene coding for RAGE (AGER locus) and with clinical characteristics. Methods and Measurements: Circulating levels of 111 biomarkers were analyzed for association with clinical characteristics in 410 COPD patients enrolled in the TESRA study. sRAGE was also measured in the ECLIPSE cohort in 1847 COPD patients, 298 smokers and 204 nonsmokers. The association between 21 SNPs in the AGER locus with sRAGE levels and clinical characteristics was also investigated. Main results: sRAGE was identified as a biomarker of DLCO and lung density in the TESRA cohort. In the ECLIPSE cohort, lower sRAGE levels were associated with increased emphysema, increased GOLD 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 (7.07x10-16), which exceeded genome-wide significance threshold. Another SNP (rs2071288) was also associated with sRAGE levels (p=0.01) and DLCO (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. Abstract word count: 249 words.