Plasma microRNA profiles identify distinct clinical phenotypes in human asthmatics

Abstract

Aim: Asthma is a chronic inflammatory syndrome that is characterized by heterogeneous disease pathogeneses that produce distinct subtypes. There is a great need to develop biomarkers to distinguish these subtypes and help guide specific therapy and better predict outcomes, particularly in severe asthma where a number of targeted therapeutics are now available. We sought to determine whether expression of asthma-specific microRNAs (miRNAs) could distinguish phenotypic differences in a diverse cohort of asthmatic subjects that spanned a range of disease severity.

Methods: RNA was isolated from peripheral blood from human subjects. Expression of 39 miRNAs was then screened. Sample cycle threshold values were normalized. Normally distributed data were analyzed and hierarchical cluster was performed.

Results: Peripheral blood was obtained from 62 adults. We identified four clusters of asthmatics defined by 5 distinct miRNA expression patterns. Cluster 1 was associated with mild asthma, low inhaled corticosteroid use, and low eosinophil levels. Cluster 3 and 4 consisted primarily of severe asthmatics with poor asthma control, and Cluster 3 was specifically associated with high IgE, high blood eosinophil levels, and racial disparity (higher proportion of Black subjects). Cluster 2 was comprised predominantly of mild-moderate asthmatics that had higher blood eosinophils than Cluster 1.

Conclusion: These results indicate the miRNA expression profiling can be useful to identify distinct asthma phenotypes, and have potential to better understand disease pathogenesis and help guide therapy.

Keywords

Asthma / allergic rhinitis / microRNA / biomarker / real-time PCR / predictive modeling

References

[1] World Health OrganizationGlobal surveillance, prevention and control of chronic respiratory diseases: a comprehensive approach..Available from: http://www.who.int/gard/publications/GARD%20Book%202007.pdf. [Last accessed on 24 Oct 2018]

[2] BousquetJ,CruzAA,Baena-CagnaniCE.Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization consultation on severe asthma..J Allergy Clin Immunol2010;126:926-38

[3] ChungKF,BrozekJL,CastroM.International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma..Eur Respir J2014;43:343-73

[4] WenzelSE.Asthma phenotypes: the evolution from clinical to molecular approaches..Nat Med2012;18:716-25

[5] MooreWC,WenzelSE,LiH.Identification of asthma phenotypes using cluster analysis in the severe asthma research program..Am J Respir Crit Care Med2010;181:315-23 PMCID:PMC2822971

[6] McGrathKW,BousheyHA,SutherlandER.A large subgroup of mild-to-moderate asthma is persistently noneosinophilic..Am J Respir Crit Care Med2012;185:612-9 PMCID:PMC3326288

[7] PanganibanRP,HowrylakJ,CraigTJ.Circulating microRNAs as biomarkers in patients with allergic rhinitis and asthma..J Allergy Clin Immunol2016;137:1423-32

[8] PerryMM,ChungKF.Role of microRNAs in allergic asthma: present and future..Curr Opin Allergy Clin Immunol2015;15:156-62

[9] RebaneA.MicroRNAs in allergy and asthma..Curr Allergy Asthma Rep2014;14:424

[10] NathanRA,KosinskiM,LiJT.Development of the asthma control test: a survey for assessing asthma control..J Allergy Clin Immunol2004;113:59-65

[11] de HoonMJ,NolanJ.Open source clustering software..Bioinformatics2004;20:1453-4

[12] ChenL,ChuX.MicroRNA-98 interferes with thrombospondin 1 expression in peripheral B cells of patients with asthma..Biosci Rep2017; PMCID:PMC5577176

[13] KumarM,SharmaA,KulshreshthaA.Let-7 microRNA-mediated regulation of IL-13 and allergic airway inflammation..J Allergy Clin Immunol2011;128:1077-85

[14] PolikepahadS,NaghaviAO,CreightonCJ.Proinflammatory role for let-7 microRNAS in experimental asthma..J Biol Chem2010;285:30139-49 PMCID:PMC2943272

[15] LeeHY,HurJ,KimYK.Inhibition of MicroRNA-21 by an antagomir ameliorates allergic inflammation in a mouse model of asthma..Exp Lung Res2017;43:109-19

[16] QiuL,DoDC,ZhangS.miR-155 modulates cockroach allergen- and oxidative stress-induced cyclooxygenase-2 in asthma..J Immunol2018;201:916-29

[17] DanielE,HsuMH,LambertK.Effects of allergic stimulation and glucocorticoids on miR-155 in CD4+ T-cells..Am J Clin Exp Immunol2018;7:57-66 PMCID:PMC6146153

[18] MalmhällC,LuY,BossiosA.MicroRNA-155 is essential for T(H)2-mediated allergen-induced eosinophilic inflammation in the lung..J Allergy Clin Immunol2014;133:1429-38

[19] KimRY,PinkertonJW,EssilfieAT.MicroRNA-21 drives severe, steroid-insensitive experimental asthma by amplifying phosphoinositide 3-kinase-mediated suppression of histone deacetylase 2..J Allergy Clin Immunol2017;139:519-32

[20] TakyarS,ZhangJG,NiuN.VEGF controls lung Th2 inflammation via the miR-1-Mpl (myeloproliferative leukemia virus oncogene)-P-selectin axis..J Exp Med2013;210:1993-2010 PMCID:PMC3782056

[21] SunJ,LiS,LiX.miR-330-5p/Tim-3 axis regulates macrophage M2 polarization and insulin resistance in diabetes mice..Mol Immunol2018;95:107-13

[22] RoffAN,AugustA,IshmaelFT.MicroRNA-570-3p regulates HuR and cytokine expression in airway epithelial cells..Am J Clin Exp Immunol2014;3:68-83 PMCID:PMC4138130