Methods: Plasma PAI-1 levels were measured by ELISA and a PAI-1 functional polymorphism (rs1799768, 4G/5G) was characterized in subjects with poorly controlled asthma enrolled in a 24-week randomized, controlled clinical trial of soy isoflavone. Demographic and clinical characteristics were determined for each PAI-1 genotype and genotype-specific treatment responses were compared between asthmatics randomized to soy isoflavone versus placebo. Normal human bronchial epithelial cells (NHBE) were cultured with or without TGF-β1 and/or genistein, and PAI-1 levels were measured in the supernatant.
Results: The 4G/5G+4G/4G genotype was associated with a higher risk for allergy-related worse asthma symptoms and eczema at baseline compared to the 5G/5G genotype (OR 2.3, p=0.03 and OR 2.6, p=0.02, respectively). Soy isoflavone treatment significantly reduced plasma PAI-1 levels compared to placebo regardless of the genotypes. Soy isoflavone treatment significantly reduced the use of oral corticosteroids (number of events/person-year) compared to placebo in the 4G/5G+4G/4G genotype (0.2 vs 0.8, relative risk 0.28, p <0.01) but not in the 5G/5G genotype. TGF-β1 significantly increased the production of PAI-1 from NHBE and genistein treatment reduced TGF-β1-induced PAI-1 production in a dose-dependent manner.
Conclusions: This study suggests that PAI-1 polymorphisms can be used as a genetic biomarker for soy isoflavone responsive subjects with asthma. Genistein-induced reduction of PAI-1 generation from airway epithelial cells may be a part of the underlying mechanism.