Polymorphisms in Signal Transducer and Activator of Transcription 3 and Lung Function in Asthma

Abstract

Background: Identifying genetic determinants for lung function is important in providing insight into the pathophysiology of asthma. Signal transducer and activator of transcription 3 is a transcription factor latent in the cytoplasm; the gene (STAT3) is activated by a wide range of cytokines, and may play a role in lung development and asthma pathogenesis. Methods: We genotyped six single nucleotide polymorphisms (SNPs) in the STAT3 gene in a cohort of 401 Caucasian adult asthmatics. The associations between each SNP and forced expiratory volume in 1 second (FEV({1})), as a percent of predicted, at the baseline exam were tested using multiple linear regression models. Longitudinal analyses involving repeated measures of FEV({1}) were conducted with mixed linear models. Haplotype analyses were conducted using imputed haplotypes. We completed a second association study by genotyping the same six polymorphisms in a cohort of 652 Caucasian children with asthma. Results: We found that three polymorphisms were significantly associated with baseline FEV({1}): homozygotes for the minor alleles of each polymorphism had lower FEV({1}) than homozygotes for the major alleles. Moreover, these associations persisted when we performed an analysis on repeated measures of FEV({1}) over 8 weeks. A haplotypic analysis based on the six polymorphisms indicated that two haplotypes were associated with baseline FEV({1}). Among the childhood asthmatics, one polymorphism was associated with both baseline FEV({1}) and the repeated measures of FEV({1}) over 4 years. Conclusion: Our results indicate that genetic variants in STAT3, independent of asthma treatment, are determinants of FEV(_{1}) in both adults and children with asthma, and suggest that STAT3 may participate in inflammatory pathways that have an impact on level of lung function.