Associations of osteopontin and NT-proBNP with circulating miRNA levels in acute coronary syndrome

Lydia Coulter Kwee, Megan L Neely, Elizabeth Grass, Simon G Gregory, Matthew T Roe, E Magnus Ohman, Keith A A Fox, Harvey D White, Paul W Armstrong, Lenden M Bowsman, Joseph V Haas, Kevin L Duffin, Mark Y Chan, Svati H Shah, Lydia Coulter Kwee, Megan L Neely, Elizabeth Grass, Simon G Gregory, Matthew T Roe, E Magnus Ohman, Keith A A Fox, Harvey D White, Paul W Armstrong, Lenden M Bowsman, Joseph V Haas, Kevin L Duffin, Mark Y Chan, Svati H Shah

Abstract

The genomic regulatory networks underlying the pathogenesis of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) are incompletely understood. As intermediate traits, protein biomarkers report on underlying disease severity and prognosis in NSTE-ACS. We hypothesized that integration of dense microRNA (miRNA) profiling with biomarker measurements would highlight potential regulatory pathways that underlie the relationships between prognostic biomarkers, miRNAs, and cardiovascular phenotypes. We performed miRNA sequencing using whole blood from 186 patients from the TRILOGY-ACS trial. Seven circulating prognostic biomarkers were measured: NH2-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein, osteopontin (OPN), myeloperoxidase, growth differentiation factor 15, monocyte chemoattractant protein, and neopterin. We tested miRNAs for association with each biomarker with generalized linear models and controlled the false discovery rate at 0.05. Ten miRNAs, including known cardiac-related miRNAs 25-3p and 423-3p, were associated with NT-proBNP levels (min. P = 7.5 × 10-4) and 48 miRNAs, including cardiac-related miRNAs 378a-3p, 20b-5p and 320a, -b, and -d, were associated with OPN levels (min. P = 1.6 × 10-6). NT-proBNP and OPN were also associated with time to cardiovascular death, myocardial infarction (MI), or stroke in the sample. By integrating large-scale miRNA profiling with circulating biomarkers as intermediate traits, we identified associations of known cardiac-related and novel miRNAs with two prognostic biomarkers and identified potential genomic networks regulating these biomarkers. These results, highlighting plausible biological pathways connecting miRNAs with biomarkers and outcomes, may inform future studies seeking to delineate genomic pathways underlying NSTE-ACS outcomes.

Keywords: acute coronary syndrome; biomarkers; microRNA.

Conflict of interest statement

The TRILOGY-ACS Advanced Biomarker SubStudy was supported by Eli Lilly and Company (Indianapolis, Indiana). M. Chan reports receiving a research grant from Eli Lilly. M. T. Roe reports receiving research grants from Eli Lilly, Sanofi-Aventis, Daiichi Sankyo, Amgen, and the Familial Hypercholesterolemia Foundation, and consulting/advisory board/other payments from Eli Lilly, Janssen, Elsevier, AstraZeneca, Merck, Amgen, and Bristol-Myers Squibb. S. G. Goodman reports receiving research grants from Daiichi Sankyo, Eli Lilly, AstraZeneca, Bristol-Myers Squibb, and Sanofi-Aventis, and consulting payments/honoraria from Eli Lilly, AstraZeneca, and Sanofi-Aventis. K. A. A. Fox reports receiving research grants from AstraZeneca and the British Heart Foundation. P. W. Armstrong reports receiving research grants from Boehringer Ingelheim, Merck Sharp & Dohme, GlaxoSmithKline, Amylin, Merck, Sanofi-Aventis, and Regado, and consulting/advisory board payments from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck, Axio/Orexigen, Eli Lilly, Bayer, and Hoffman-La Roche. H. D. White reports receiving consulting/advisory board payments from AstraZeneca, Merck Sharpe & Dohme, Roche, and Regado Biosciences, and research grants from Sanofi-Aventis, Eli Lilly, The Medicines Company, NIH, Roche, Merck Sharpe & Dohme, AstraZeneca, GlaxoSmithKline, and Daiichi Sankyo Pharma Development. E. M. Ohman reports receiving research grants from Daiichi Sankyo, Eli Lilly, and Gilead, and consulting/advisory board payments from AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, Pozen, The Medicines Company, WebMD, Abiomed, Sanofi- Aventis, and Janssen. L. M. Bowsman, J. V. Haas, and K. L. Duffin are employees of Eli Lilly. All other authors report no conflicts of interest.

Figures

Fig. 1.
Fig. 1.
Consort flow diagram for the analysis cohort.
Fig. 2.
Fig. 2.
Heat maps of differential microRNA (miRNA) expression across biomarker levels. A: miRNA fold change estimates were standardized across each biomarker independently: hs-CRP, high-sensitivity C-reactive protein; OPN, osteopontin; NT-proBNP, NH2-terminal pro B-type natriuretic peptide; GDF-15, growth differentiation factor 15; neopterin; MCP1, monocyte chemoattractant protein; and MPO, myeloperoxidase. Individual miRNAs are displayed on the y-axis. B: unadjusted –log10P values for each generalized linear model association analysis are shown. MiRNAs are in the same order as in A.

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