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.
BACKGROUND
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.


OBJECTIVE
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.


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 carbon monoxide (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. Clinical trial registered with www.clinicaltrials.gov (NCT 00413205 and NCT 00292552).
1 Hoffmann-La Roche Inc., Nutley, New Jersey.
Donavan T
DT
Cheng
Deog Kyeom
DK
Kim
Debra A
DA
Cockayne
Anton
A
Belousov
Hans
H
Bitter
Michael H
MH
Cho
Annelyse
A
Duvoix
Lisa D
LD
Edwards
David A
DA
Lomas
Bruce E
BE
Miller
Niki
N
Reynaert
Ruth
R
Tal-Singer
Emiel F M
EF
Wouters
Alvar
A
Agustí
Leonardo M
LM
Fabbri
Alex
A
Rames
Sudha
S
Visvanathan
Stephen I
SI
Rennard
Paul
P
Jones
Harsukh
H
Parmar
William
W
MacNee
Gerhard
G
Wolff
Edwin K
EK
Silverman
Ruth J
RJ
Mayer
Sreekumar G
SG
Pillai
D000368:Aged; D015415:Biomarkers / Q000097:blood; D004646:Emphysema / Q000097:blood* / Q000000981:diagnostic imaging / Q000235:genetics; D005260:Female; D006801:Humans; D008168:Lung / Q000000981:diagnostic imaging; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000235:genetics*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000097:blood / Q000235:genetics*; D012720:Severity of Illness Index; D036542:Tomography, Spiral Computed
D015415:Biomarkers; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic