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Soluble Receptor for Advanced Glycation End Products (sRAGE) as a Biomarker of COPD
Russell P. Bowler
Department of Biostatistics, National Jewish Health, Denver, CO
Corresponding Author
ORCiD: https://orcid.org/0000-0003-4651-363X
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background:
Soluble receptor for advanced glycation end products (sRAGE) is a proposed emphysema and airflow obstruction biomarker; however, previous publication 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.
Methods: sRAGE was measured in four independent longitudinal cohorts on different analytic assays: COPDGene (n=1,443), SPIROMICS (n=1,623); ECLIPSE (n=2,349); 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).
Results: Lower 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.
Conclusions: Lower 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.
Keywords
COPD, emphysema, biomarkers, progression
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CURRENT STATUS: Under Review
Version 1
Posted 30 Dec, 2020
No community comments so far
Review #2 received
Received 17 Jan, 2021
Review #3 received
Received 17 Jan, 2021
Review #1 received
Received 17 Jan, 2021
Review #4 received
Received 16 Jan, 2021
Reviewer #4 agreed
On 06 Jan, 2021
Reviewer #3 agreed
On 05 Jan, 2021
Reviewer #2 agreed
On 04 Jan, 2021
Reviewers invited
Invitations sent on 04 Jan, 2021
Reviewer #1 agreed
On 04 Jan, 2021
Editor assigned
On 19 Dec, 2020
Submission checks complete
On 19 Dec, 2020
Editor invited
On 19 Dec, 2020
First submitted
On 17 Dec, 2020
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This preprint is under consideration at Respiratory Research. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Soluble Receptor for Advanced Glycation End Products (sRAGE) as a Biomarker of COPD
Russell P. Bowler
Department of Biostatistics, National Jewish Health, Denver, CO
Corresponding Author
ORCiD: https://orcid.org/0000-0003-4651-363X
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 30 Dec, 2020
No community comments so far
Review #2 received
Received 17 Jan, 2021
Review #3 received
Received 17 Jan, 2021
Review #1 received
Received 17 Jan, 2021
Review #4 received
Received 16 Jan, 2021
Reviewer #4 agreed
On 06 Jan, 2021
Reviewer #3 agreed
On 05 Jan, 2021
Reviewer #2 agreed
On 04 Jan, 2021
Reviewers invited
Invitations sent on 04 Jan, 2021
Reviewer #1 agreed
On 04 Jan, 2021
Editor assigned
On 19 Dec, 2020
Submission checks complete
On 19 Dec, 2020
Editor invited
On 19 Dec, 2020
First submitted
On 17 Dec, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background:
Soluble receptor for advanced glycation end products (sRAGE) is a proposed emphysema and airflow obstruction biomarker; however, previous publication 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.
Methods: sRAGE was measured in four independent longitudinal cohorts on different analytic assays: COPDGene (n=1,443), SPIROMICS (n=1,623); ECLIPSE (n=2,349); 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).
Results: Lower 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.
Conclusions: Lower 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.
Figure 1
Figure 2
Figure 3
Figure 4