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Variants in TGFB1, Dust Mite Exposure, and Disease Severity in Children with Asthma

¹ Channing Laboratory, ² Division of Pulmonary and Critical Care Medicine, and ³ Center for Genomic Medicine, Department of Medicine, Brigham and Women's Hospital, and ⁴ Harvard Medical School, Boston, Massachusetts; ⁵ Division of Pediatric Pulmonology, Hospital Nacional de Niños, San José, Costa Rica; ⁶ Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Sunita Sharma, M.D., Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115. E-mail: ssharma4{at}partners.org

Rationale: Polymorphisms in the gene for transforming growth factor-β1 (TGFB1) have been associated with asthma, but not with airway responsiveness or disease exacerbations in subjects with asthma.

Objectives: To test for association between single nucleotide polymorphisms (SNPs) in TGFB1 and markers of asthma severity in childhood.

Methods: We tested for the association between nine SNPs in TGFB1 and indicators of asthma severity (lung function, airway responsiveness, and disease exacerbations) in two cohorts: 416 Costa Rican parent-child trios and 465 families of non-Hispanic white children in the Childhood Asthma Management Program (CAMP). We also tested for the interaction between these polymorphisms and exposure to dust mite allergen on asthma severity.

Measurements and Main Results: The A allele of promoter SNP rs2241712 was associated with increased airway responsiveness in Costa Rica (P = 0.0006) and CAMP (P = 0.005), and the C allele of an SNP in the promoter region (rs1800469) was associated with increased airway responsiveness in both cohorts (P 0.01). Dust mite exposure modified the effect of the C allele of exonic SNP rs1800471 on airway responsiveness (P = 0.03 for interactions in both cohorts). The T allele of a coding SNP (rs1982073) was associated with a reduced risk of asthma exacerbations in Costa Rica (P = 0.009) and CAMP (P = 0.005). Dust mite exposure also significantly modified the effect of the A allele of the promoter SNP rs2241712 on asthma exacerbations in both cohorts.

Conclusions: SNPs in TGFB1 are associated with airway responsiveness and disease exacerbations in children with asthma. Moreover, dust mite exposure may modify the effect of TGFB1 SNPs on airway responsiveness and asthma exacerbations.

Key Words: airway responsiveness • asthma • dust mite allergen • single nucleotide polymorphisms • transforming growth factor-β1

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject DNA sequence variants in the gene for transforming growth factor-β1 (TGFB1) have been associated with airway inflammation and asthma. What This Study Adds to the Field Genetic polymorphisms in TGFB1 are associated with airway responsiveness and disease exacerbations in children with asthma. Dust mite exposure may modify the effect of TGF-β1 single nucleotide polymorphisms on airway responsiveness and disease exacerbations in children with asthma.

 

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