Cytokine TGFβ Gene Polymorphism in Asthma: TGF-Related SNP Analysis Enhances the Prediction of Disease Diagnosis (A Case-Control Study With Multivariable Data-Mining Model Development)

Abstract

Introduction: TGF-β and its receptors play a crucial role in asthma pathogenesis and bronchial remodeling in the course of the disease. TGF-β1, TGF-β2, and TGF-β3 isoforms are responsible for chronic inflammation, bronchial hyperreactivity, myofibroblast activation, fibrosis, bronchial remodeling, and change the expression of approximately 1000 genes in asthma. TGF-β SNPs are associated with the elevated plasma level of TGF-β1, an increased level of total IgE, and an increased risk of remodeling of bronchi.

Methods: The analysis of selected TGF-β1, TGF-β2, TGF-β3-related single-nucleotide polymorphisms (SNP) was conducted on 652 DNA samples with an application of the MassARRAY^® using the mass spectrometry (MALDI-TOF MS). Dataset was randomly split into training (80%) and validation sets (20%). For both asthma diagnosis and severity prediction, the C5.0 modelling with hyperparameter optimization was conducted on: clinical and SNP data (Clinical+TGF), only clinical (OnlyClinical) and minimum redundancy feature selection set (MRMR). Area under ROC (AUCROC) curves were compared using DeLong's test.

Results: Minor allele carriers (MACs) in SNP rs2009112 [OR=1.85 (95%CI:1.11-3.1), p=0.016], rs2796821 [OR=1.72 (95%CI:1.1-2.69), p=0.017] and rs2796822 [OR=1.71 (95%CI:1.07-2.71), p=0.022] demonstrated an increased odds of severe asthma. Clinical+TGF model presented better diagnostic potential than OnlyClinical model in both training (p=0.0009) and validation (AUCROC=0.87 vs. 0.80,p=0.0052). At the same time, the MRMR model was not worse than the Clinical+TGF model (p=0.3607 on the training set, p=0.1590 on the validation set), while it was better in comparison with the Only Clinical model (p=0.0010 on the training set, p=0.0235 on validation set, AUCROC=0.85 vs. 0.87). On validation set Clinical+TGF model allowed for asthma diagnosis prediction with 88.4% sensitivity and 73.8% specificity.

Discussion: Derived predictive models suggest the analysis of selected SNPs in TGF-β genes in combination with clinical factors could predict asthma diagnosis with high sensitivity and specificity, however, the benefit of SNP analysis in severity prediction was not shown.

Keywords: TGF — transforming growth factor; asthma; development; inflammation; prediction.