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

Background: 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. Objective: We sought to investigate PAI-1 genotype-specific differences of the soy isoflavone response in asthma outcomes. Methods: 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. Results: 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. Conclusions: 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.