Defining the Blood Cytokine Profile in Asthma to Understand Asthma Heterogeneity

Bingham, Karina; Zahrani, Yousef Al; Stewart, Iain; Portelli, Michael A.; Fogarty, Andrew; McKeever, Tricia M.; Singapuri, Ananga; Heaney, Liam G.; Mansur, Adel H.; Chaudhuri, Rekha; Thomson, Neil C.; Holloway, John W.; Howarth, Peter H.; Djukanovic, Ratko; Blakey, John D.; Chauhan, Anoop; Brightling, Christopher E.; Pogson, Zara E. K.; Hall, Ian P.; Martinez‐Pomares, Luisa; Shaw, Dominick; Sayers, Ian

Abstract

Background:

Asthma is a heterogeneous disease characterized by overlapping clinical and inflammatory features.

Objective:

This study aimed to provide insight into the systemic inflammatory profile in asthma, greater understanding of asthma endotypes and the contribution of genetic risk factors to both.

Methods:

4205 patients with asthma aged 16-60 were recruited from UK centers; serum cytokines were quantified from 708, including cytokines associated with Type 1, 2 and 17 inflammation. 3037 patients were genotyped for 25 single nucleotide polymorphisms associated with moderate-severe asthma.

Results:

Serum cytokines associated with Th2 inflammation showed high coordinated expression for example, IL-4/IL-5 (R2 = 0.513). The upper quartile of the serum cytokine data identified 43.7% of patients had high levels for multiple Th2 cytokines. However, the groups defined by serum cytokine profile were not clinically different. Childhood-onset asthma was characterized by elevated total IgE, allergic rhinitis and dermatitis. Exacerbation prone patients had a higher BMI, smoking pack-years, asthma control questionnaire score and reduced lung function. Patients with blood eosinophils of > 300 cells/µL had elevated total IgE and lower smoking pack-years. None of these groups had a differential serum cytokine profile. Asthma risk alleles for; rs61816764 (FLG) and rs9303277 (IKFZ3) were associated with childhood onset disease (p = 2.67 × 10- 4 and 2.20 × 10- 7; retrospectively). No genetic variant was associated with cytokine levels.

Conclusion:

Systemic inflammation in asthma is complex. Patients had multiple overlapping inflammatory profiles suggesting several disease mechanisms. Genetic risk factors for moderate-severe asthma confirmed previous associations with childhood onset of asthma.

Citation

Bingham, K., Zahrani, Y. A., Stewart, I., Portelli, M. A., Fogarty, A., McKeever, T. M., Singapuri, A., Heaney, L. G., Mansur, A. H., Chaudhuri, R., Thomson, N. C., Holloway, J. W., Howarth, P. H., Djukanovic, R., Blakey, J. D., Chauhan, A., Brightling, C. E., Pogson, Z. E. K., Hall, I. P., Martinez‐Pomares, L., …Sayers, I. (2025). Defining the Blood Cytokine Profile in Asthma to Understand Asthma Heterogeneity. Immunity, Inflammation and Disease, 13(3), Article e70116. https://doi.org/10.1002/iid3.70116

• Journal Article Type: Article
• Acceptance Date: Dec 17, 2024
• Online Publication Date: Mar 19, 2025
• Publication Date: 2025-03
• Deposit Date: Mar 28, 2025
• Publicly Available Date: Mar 28, 2025
• Journal: Immunity, Inflammation and Disease
• Electronic ISSN: 2050-4527
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 13
• Issue: 3
• Article Number: e70116
• DOI: https://doi.org/10.1002/iid3.70116
• Keywords: asthma | blood cytokines | endotypes | genetics
• Public URL: https://nottingham-repository.worktribe.com/output/47006151
• Publisher URL: https://onlinelibrary.wiley.com/doi/10.1002/iid3.70116
• Additional Information: Received: 2024-05-03; Accepted: 2024-12-17; Published: 2025-03-19