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 may 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 versus placebo. Normal human bronchial epithelial cells (NHBE) were cultured with or without TGF-β1 and/or genistein, and PAI-1 levels were measured.
The 4G4G/4G5G genotype was associated with a higher risk for allergy-related worsened asthma symptoms and eczema at baseline compared to the 5G5G genotype. There was a significant interaction between the genotype and soy isoflavone intervention on oral corticosteroid use for asthma exacerbation (p=0.005). In a subgroup analysis, soy isoflavones significantly reduced the use of oral corticosteroids (number of events/person-year) by four-fold compared to the placebo in the 4G4G/4G5G genotype (0.2 vs 0.8, relative risk 0.28, p <0.001) but not in the 5G5G genotype. Soy isoflavones reduced plasma PAI-1 levels compared to the placebo. Genistein treatment reduced TGF-β1-induced PAI-1 production in NHBE.
This study demonstrates that soy isoflavone treatment provides a significant benefit in reducing the number of severe asthma exacerbations in asthmatic subjects with the high PAI-1 producing genotype. PAI-1 polymorphisms can be used as a genetic biomarker for soy isoflavone responsive subjects with asthma.
Key words: soy isoflavones, genistein, asthma, exacerbation, PAI-1, polymorphisms