Investigation of lactotransferrin messenger RNA expression levels as an anti–type 2 asthma biomarker - 13/06/24

Doi : 10.1016/j.jaci.2024.05.013

Nicholas C. Li ^a, Natalie Iannuzo, PhD ^b, Stephanie A. Christenson, MD ^c, Paul R. Langlais, PhD ^d, Monica Kraft, MD ^e, Julie G. Ledford, PhD ^b, Xingnan Li, PhD ^e,^f,^⁎
^a University of Arizona Internship, Basis Tucson North, Tucson, Ariz
^b Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Ariz
^c Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy, University of California, San Francisco, Calif
^d Department of Medicine, Division of Endocrinology, University of Arizona, Tucson, Ariz
^e Samuel Bronfman Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
^f Department of Medicine, Division of Genetics, Genomics and Precision Medicine, University of Arizona, Tucson, Ariz

^∗Corresponding author: Xingnan Li, PhD, MS, Department of Medicine, Division of Genetics, Genomics and Precision Medicine, University of Arizona College of Medicine, 1230 N Cherry Ave, PO Box 210242, Tucson, AZ 85719; Department of Medicine, Division of Data Driven and Digital Medicine (D3M) and Division of Pulmonary, Critical Care, and Sleep Medicine, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Box 1118, Annenberg, Room 5-02, New York, NY 10029.Department of Medicine, Division of Genetics, Genomics and Precision Medicine, University of Arizona College of Medicine, 1230 N Cherry Ave, PO Box 210242, Tucson, AZ 85719; Department of MedicineDivision of Data Driven and Digital Medicine (D3M) and Division of Pulmonary, Critical Care, and Sleep Medicine, Icahn School of Medicine at Mount Sinai1 Gustave L. Levy Place, Box 1118Annenberg, Room 5-02New YorkNY10029

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Abstract

Background

Lactotransferrin (LTF) has an immunomodulatory function, and its expression levels are associated with asthma susceptibility.

Objectives

We sought to investigate LTF messenger RNA (mRNA) expression levels in human bronchial epithelial cells (BECs) as an anti–type 2 (T2) asthma biomarker.

Methods

Association analyses between LTF mRNA expression levels in BECs and asthma-related phenotypes were performed in the Severe Asthma Research Program (SARP) cross-sectional (n = 155) and longitudinal (n = 156) cohorts using a generalized linear model. Correlation analyses of mRNA expression levels between LTF and all other genes were performed by Spearman correlation.

Results

Low LTF mRNA expression levels were associated with asthma susceptibility and severity (P < .025), retrospective and prospective asthma exacerbations, and low lung function (P < 8.3 × 10⁻³). Low LTF mRNA expression levels were associated with high airway T2 inflammation biomarkers (sputum eosinophils and fractional exhaled nitric oxide; P < 8.3 × 10⁻³) but were not associated with blood eosinophils or total serum IgE. LTF mRNA expression levels were negatively correlated with expression levels of T_H2 or asthma-associated genes (POSTN, NOS2, and MUC5AC) and eosinophil-related genes (IL1RL1, CCL26, and IKZF2) and positively correlated with expression levels of T_H1 and inflammation genes (IL12A, MUC5B, and CC16) and T_H17-driven cytokines or chemokines for neutrophils (CXCL1, CXCL6, and CSF3) (P < 3.5 × 10⁻⁶).

Conclusions

Low LTF mRNA expression levels in BECs are associated with asthma susceptibility, severity, and exacerbations through upregulation of airway T2 inflammation. LTF is a potential anti-T2 biomarker, and its expression levels may help determine the balance of eosinophilic and neutrophilic asthma.

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Key words : Anti-T2 biomarker, asthma exacerbations, asthma susceptibility, bronchial epithelial cells, eosinophils, lactotransferrin, mRNA expression, severe asthma, neutrophils, T2 inflammation

Abbreviations used : BD, BEC, BMI, Feno, FEV₁, FVC, GTEx Portal, GWAS Catalog, LTF, mRNA, MTEC, OR, RNA-Seq, SARP, SNP, T2, WT