Elevated circulating MMP-9 is linked to increased COPD exacerbation risk in SPIROMICS and COPDGene.

TitleElevated circulating MMP-9 is linked to increased COPD exacerbation risk in SPIROMICS and COPDGene.
Publication TypePublication
Year2018
AuthorsJ Wells M, Parker MM, Oster RA, Bowler RP, Dransfield MT, Bhatt SP, Cho MH, Kim V, Curtis JL, Martinez FJ, Paine R, O'Neal W, Labaki WW, Kaner RJ, Barjaktarevic I, Han MK, Silverman EK, Crapo JD, R Barr G, Woodruff P, Castaldi PJ, Gaggar A
Corporate AuthorsSPIROMICS and COPDGene Investigators
JournalJCI Insight
Volume3
Issue22
Date Published2018 11 15
ISSN2379-3708
KeywordsAged, biomarkers, Clinical Trials as Topic, Cohort Studies, Female, Humans, Male, Matrix Metalloproteinase 9, Middle Aged, Pulmonary Disease, Chronic Obstructive, Risk Factors
Abstract

BACKGROUND: Matrix metalloprotease 9 (MMP-9) is associated with inflammation and lung remodeling in chronic obstructive pulmonary disease (COPD). We hypothesized that elevated circulating MMP-9 represents a potentially novel biomarker that identifies a subset of individuals with COPD with an inflammatory phenotype who are at increased risk for acute exacerbation (AECOPD).METHODS: We analyzed Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) and Genetic Epidemiology of COPD (COPDGene) cohorts for which baseline and prospective data were available. Elevated MMP-9 was defined based on >95th percentile plasma values from control (non-COPD) sample in SPIROMICS. COPD subjects were classified as having elevated or nonelevated MMP-9. Logistic, Poisson, and Kaplan-Meier analyses were used to identify associations with prospective AECOPD in both cohorts.RESULTS: Elevated MMP-9 was present in 95/1,053 (9%) of SPIROMICS and 41/140 (29%) of COPDGene participants with COPD. COPD subjects with elevated MMP-9 had a 13%-16% increased absolute risk for AECOPD and a higher median (interquartile range; IQR) annual AECOPD rate (0.33 [0-0.74] versus 0 [0-0.80] events/year and 0.9 [0.5-2] versus 0.5 [0-1.4] events/year for SPIROMICS and COPDGene, respectively). In adjusted models within each cohort, elevated MMP-9 was associated with increased odds (odds ratio [OR], 1.71; 95%CI, 1.00-2.90; and OR, 3.03; 95%CI, 1.02-9.01), frequency (incidence rate ratio [IRR], 1.45; 95%CI, 1.23-1.7; and IRR, 1.24; 95%CI, 1.03-1.49), and shorter time-to-first AECOPD (21.7 versus 31.7 months and 14 versus 21 months) in SPIROMICS and COPDGene, respectively.CONCLUSIONS: Elevated MMP-9 was independently associated with AECOPD risk in 2 well-characterized COPD cohorts. These findings provide evidence for MMP-9 as a prognostic biomarker and potential therapeutic target in COPD.TRIAL REGISTRATION: ClinicalTrials.gov: NCT01969344 (SPIROMICS) and NCT00608764 (COPDGene).FUNDING: This work was funded by K08 HL123940 to JMW; R01HL124233 to PJC; Merit Review I01 CX000911 to JLC; R01 (R01HL102371, R01HL126596) and VA Merit (I01BX001756) to AG. SPIROMICS (Subpopulations and Intermediate Outcomes in COPD Study) is funded by contracts from the NHLBI (HHSN268200900013C, HHSN268200900014C,HHSN268200900015C HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, and HHSN268200900020C) and a grant from the NIH/NHLBI (U01 HL137880), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals Inc.; Chiesi Farmaceutici; Forest Research Institute Inc.; GlaxoSmithKline; Grifols Therapeutics Inc.; Ikaria Inc.; Novartis Pharmaceuticals Corporation; Nycomed GmbH; ProterixBio; Regeneron Pharmaceuticals Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; and Theravance Biopharma and Mylan. COPDGene is funded by the NHLBI (R01 HL089897 and R01 HL089856) and by the COPD Foundation through contributions made to an Industry Advisory Board composed of AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion.

DOI10.1172/jci.insight.123614
Alternate JournalJCI Insight
PubMed ID30429371
PubMed Central IDPMC6302944
Grant ListHHSN268200900019C / HL / NHLBI NIH HHS / United States
R01 HL089897 / HL / NHLBI NIH HHS / United States
HHSN268200900016C / HL / NHLBI NIH HHS / United States
HHSN268200900015C / HL / NHLBI NIH HHS / United States
HHSN268200900014C / HL / NHLBI NIH HHS / United States
I01 CX000911 / CX / CSRD VA / United States
HHSN268200900018C / HL / NHLBI NIH HHS / United States
U01 HL137880 / HL / NHLBI NIH HHS / United States
R01 HL124233 / HL / NHLBI NIH HHS / United States
HHSN268200900013C / HL / NHLBI NIH HHS / United States
T32 HL007427 / HL / NHLBI NIH HHS / United States
U01 HL089897 / HL / NHLBI NIH HHS / United States
K24 HL140108 / HL / NHLBI NIH HHS / United States
R01 HL102371 / HL / NHLBI NIH HHS / United States
HHSN268200900020C / HL / NHLBI NIH HHS / United States
HHSN268200900017C / HL / NHLBI NIH HHS / United States
U01 HL089856 / HL / NHLBI NIH HHS / United States
K08 HL123940 / HL / NHLBI NIH HHS / United States
R01 HL126596 / HL / NHLBI NIH HHS / United States
MS#: 
MS077
Manuscript Full Title: 
Elevated circulating MMP-9 is linked to increased COPD exacerbation risk in SPIROMICS and COPDGene.
Manuscript Lead/Corresponding Author Affiliation: 
Clinical Center: Birmingham (University of Alabama at Birmingham)
ECI: 
Manuscript Status: 
Published and Public