Abstract
BackgroundSoluble receptor for advanced glycation end products (sRAGE) is a proposed emphysema and airflow obstruction biomarker; however, previous publications have shown inconsistent associations and only one study has investigate the association between sRAGE and emphysema. No cohorts have examined the association between sRAGE and progressive decline of lung function. There have also been no evaluation of assay compatibility, receiver operating characteristics, and little examination of the effect of genetic variability in non-white population. This manuscript addresses these deficiencies and introduces novel data from Pittsburgh COPD SCCOR and as well as novel work on airflow obstruction. A meta-analysis is used to quantify sRAGE associations with clinical phenotypes.MethodssRAGE was measured in four independent longitudinal cohorts on different analytic assays: COPDGene (n = 1443); SPIROMICS (n = 1623); ECLIPSE (n = 2349); Pittsburgh COPD SCCOR (n = 399). We constructed adjusted linear mixed models to determine associations of sRAGE with baseline and follow up forced expiratory volume at one second (FEV1) and emphysema by quantitative high-resolution CT lung density at the 15th percentile (adjusted for total lung capacity).ResultsLower plasma or serum sRAGE values were associated with a COPD diagnosis (P < 0.001), reduced FEV1 (P < 0.001), and emphysema severity (P < 0.001). In an inverse-variance weighted meta-analysis, one SD lower log10-transformed sRAGE was associated with 105 ± 22 mL lower FEV1 and 4.14 ± 0.55 g/L lower adjusted lung density. After adjusting for covariates, lower sRAGE at baseline was associated with greater FEV1 decline and emphysema progression only in the ECLIPSE cohort. Non-Hispanic white subjects carrying the rs2070600 minor allele (A) and non-Hispanic African Americans carrying the rs2071288 minor allele (A) had lower sRAGE measurements compare to those with the major allele, but their emphysema-sRAGE regression slopes were similar.ConclusionsLower blood sRAGE is associated with more severe airflow obstruction and emphysema, but associations with progression are inconsistent in the cohorts analyzed. In these cohorts, genotype influenced sRAGE measurements and strengthened variance modelling. Thus, genotype should be included in sRAGE evaluations.
Highlights
Soluble receptor for advanced glycation end products is a proposed emphysema and airflow obstruction biomarker; previous publications have shown inconsistent associations and only one study has investigate the association between sRAGE and emphysema
This study uses four independent cohorts and four distinct sRAGE assay platforms to confirm that sRAGE is an independent blood biomarker for the presence and severity of both emphysema and chronic obstructive pulmonary disease (COPD); the association between baseline sRAGE and emphysema progression or COPD progression is less consistent
Correlation of different sRAGE assays Among the four platforms used to measure the same samples in COPDGene, correlations were highest between Myriad-RBM Myriad-Rules Based Medicine (RBM) and liquid chromatographymass spectrometry (LCMS) (0.79), RBM and SOMAscan (0.73), SOMAscan and LCMS (0.63), Quotient Bioresearch (QBR) and RBM (0.53), QBR and LCMS (0.46) and lowest for QBR and SOMAscan (0.45) (Fig. 1)
Summary
Soluble receptor for advanced glycation end products (sRAGE) is a proposed emphysema and airflow obstruction biomarker; previous publications have shown inconsistent associations and only one study has investigate the association between sRAGE and emphysema. There have been no evaluation of assay compatibility, receiver operating characteristics, and little examination of the effect of genetic variability in non-white population This manuscript addresses these deficiencies and introduces novel data from Pittsburgh COPD SCCOR and as well as novel work on airflow obstruction. Engagement of RAGE by AGEs activates inflammatory signalling pathways, including nuclear factor (NF)-kB [14] and several mitogen-activated protein kinases [15, 16]. This RAGE signalling may contribute to the sustained inflammation seen in COPD. When the extracellular portion of RAGE is cleaved, the protein becomes soluble (sRAGE) and can be measured in serum and plasma. sRAGE has been hypothesized to bind competitively to AGEs, reducing the transmembrane signalling of RAGE and of other pathogen-associated molecular patterns (PAMPs) or damage-associated molecular pattern (DAMPs) receptors through other pattern recognition receptors (PRRs) implicated in chronic lung inflammation [17]
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