A dual covariant biomarker approach to Kawasaki disease, using vascular endothelial growth factor A and B gene expression; implications for coronary pathogenesis

Rashid, Asrar; Benakatti, Govind; Al-Obeidat, Feras; Phatak, Rajesh; Malik, Zainab A.; Sharief, Javed; Kadwa, Raziya; Hafez, Wael; Toufiq, Mohammed; Chaussabel, Damien; Malik, Rayaz; Quraishi, Nasir; Zaki, Syed Ahmed; Shaikh, Guftar; Hussain, Amir

Abstract

Introduction
Kawasaki disease (KD) is the most common vasculitis in young children, with coronary artery lesions (CALs) and coronary aneurysms (CAAs) being responsible for most KD-related deaths.

Objective
We hypothesized that Vascular Endothelial Growth Factors (VEGFs) are pivotal in KD inflammation and coronary artery lesions. This study assessed VEGF-A and VEGF-B gene expression (GE) as potential biomarkers in KD inflammation.

Study design
We analyzed NCBI-GEO datasets, categorizing gene expression patterns as "inflammatory" or "non-inflammatory". We focused on TNF-, NFKB1, VEGF-A, and VEGF-B GEs. Datasets were filtered based on differential changes in TNF and NFKB1 levels to isolate those with inflammatory shifts.

Results
Inflammatory datasets (GSE63881, GSE73464, and GSE68004) displayed elevated TNF, NFKB1, and VEGF-A GE levels during acute KD. VEGF-B GE exhibited a distinctive trend: an initial drop and subsequent rise during recovery, a pattern that was missing in the non-inflammatory group. The treatment response was also studied, with intravenous immunoglobulin (IVIG) responders showing significant downregulation of NFKB1 GE after treatment: GSE16797 [IVIG ± methylprednisolone; p = 8.6443-03], GSE48498 [IVIG; p = 6.618e-02, infliximab; p = 3.240e-03], and GSE18606 [IVIG; p = 3.518e-02]. Considering the similar binding of VEGF-A and VEGF-B to the VEGFR1 receptor, a co-variate and inverse relationship is suggested.

Conclusion
Temporal VEGF-A, VEGF-B, and GE changes show promise as new post-inflammatory biomarkers for KD. Novelty results with the biomarker approach, with the potential for a dual temporal relationship between VEGF-A and VEGF-A. A comprehensive exploration of VEGF-A and VEGF-B genes and protein analysis in KD is warranted to understand the functional aspects of these changes and how best to utilize the pattern of changes for therapeutic benefit.

Citation

Rashid, A., Benakatti, G., Al-Obeidat, F., Phatak, R., Malik, Z. A., Sharief, J., Kadwa, R., Hafez, W., Toufiq, M., Chaussabel, D., Malik, R., Quraishi, N., Zaki, S. A., Shaikh, G., & Hussain, A. (2023). A dual covariant biomarker approach to Kawasaki disease, using vascular endothelial growth factor A and B gene expression; implications for coronary pathogenesis. Informatics in Medicine Unlocked, 43, Article 101384. https://doi.org/10.1016/j.imu.2023.101384

• Journal Article Type: Article
• Acceptance Date: Oct 17, 2023
• Online Publication Date: Oct 21, 2023
• Publication Date: 2023
• Deposit Date: Jan 5, 2024
• Publicly Available Date: Jan 5, 2024
• Journal: Informatics in Medicine Unlocked
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 43
• Article Number: 101384
• DOI: https://doi.org/10.1016/j.imu.2023.101384
• Keywords: Temporal, Kawasaki disease, Gene-expression, VEGF-A, VEGF-B, TNF, NFKB1
• Public URL: http://researchrepository.napier.ac.uk/Output/3445769