Soy isoflavones reduce asthma exacerbation in asthmatic patients with high PAI-1–producing genotypes

• Published in: Journal of allergy and clinical immunology Vol. 144; no. 1; pp. 109 - 117.e4
• Main Authors: Cho, Seong H., Jo, Ara, Casale, Thomas, Jeong, Su J., Hong, Seung-Jae, Cho, Joong K., Holbrook, Janet T., Kumar, Rajesh, Smith, Lewis J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2019; Elsevier Limited
• Subjects: Adolescent; Adrenal Cortex Hormones - therapeutic use; Adult; Allergies; Asthma; Asthma - blood; Asthma - drug therapy; Asthma - genetics; Biomarkers; Bronchi - cytology; Cell Line; Clinical outcomes; Clinical trials; Corticosteroids; Deoxyribonucleic acid; DNA; Eczema; Epithelial cells; Epithelial Cells - metabolism; exacerbation; Female; Gene polymorphism; Genistein; Genotype; Genotype & phenotype; Glycine max; Humans; Hypotheses; Isoflavones; Isoflavones - pharmacology; Isoflavones - therapeutic use; Male; Middle Aged; Patients; plasminogen activator inhibitor 1; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen Activator Inhibitor 1 - metabolism; Plasminogen activator inhibitors; Polymorphism, Single Nucleotide; polymorphisms; Population; Soy isoflavones; Studies; Transforming growth factor-b1; Young Adult; United States > US; SOYA; asthma; polymorphisms; plasminogen activator inhibitor 1; ECM; exacerbation; ACT; Soy isoflavones; genistein; SNP; ASUI; NHBE; PAI-1
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2019.01.020

The 4G4G genotype of plasminogen activator inhibitor 1 (PAI-1) is associated with increased plasma PAI-1 levels and poor asthma control. Previous studies suggest that soy isoflavones can reduce PAI-1 levels. We sought to investigate PAI-1 genotype-specific differences of the soy isoflavone response in asthma outcomes. A PAI-1 functional polymorphism (rs1799768, 4G5G) was characterized in subjects with poorly controlled asthma enrolled in a randomized clinical trial of soy isoflavones (n = 265). Genotype-specific treatment responses on asthma outcomes were compared between soy isoflavones and placebo. Normal human bronchial epithelial cells were cultured with or without TGF-β1, genistein, or both, and PAI-1 levels were measured. The 4G4G/4G5G genotype was associated with a greater risk for allergy-related worsened asthma symptoms and eczema at baseline compared with the 5G5G genotype. There was a significant interaction between the genotype and soy isoflavone intervention on oral corticosteroid use for asthma exacerbation (P = .005). In a subgroup analysis soy isoflavones significantly reduced the use of oral corticosteroids (number of events/person-year) by 4-fold compared with placebo in the 4G4G/4G5G genotype (0.2 vs 0.8; relative risk, 0.28; P < .001) but not in the 5G5G genotype. Soy isoflavones reduced plasma PAI-1 levels compared with placebo. Genistein treatment reduced TGF-β1–induced PAI-1 production in normal human bronchial epithelial cells. This study demonstrates that soy isoflavone treatment provides a significant benefit in reducing the number of severe asthma exacerbations in asthmatic patients with the high PAI-1–producing genotype. PAI-1 polymorphisms can be used as a genetic biomarker for soy isoflavone–responsive patients with asthma. [Display omitted]