Seong H Cho1, Ara Jo2, Thomas Casale2, Su J Jeong3, Seung-Jae Hong4, Joong K Cho2, Janet T Holbrook5, Rajesh Kumar6, Lewis J Smith7. 1. Division of Allergy-Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Fla; Division of Rheumatology, Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul, Korea. Electronic address: scho2@health.usf.edu. 2. Division of Allergy-Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Fla. 3. Department of Statistics Support, Medical Science Research Institute, School of Medicine, Kyung Hee University, Seoul, Korea. 4. Division of Rheumatology, Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul, Korea. 5. Center for Clinical Trials and Evidence Synthesis Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Md. 6. Division of Allergy-Immunology, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Ill. 7. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Ill.
Abstract
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. Published by Elsevier Inc.
RCT Entities:
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. Published by Elsevier Inc.
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