Polymorphisms in signal transducer and activator of transcription 3 and lung function in asthma.
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 (FEV1), as a percent of predicted, at the baseline exam were tested using multiple linear regression models. Longitudinal analyses involving repeated measures of FEV1 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 FEV1: homozygotes for the minor alleles of each polymorphism had lower FEV1 than homozygotes for the major alleles. Moreover, these associations persisted when we performed an analysis on repeated measures of FEV1 over 8 weeks. A haplotypic analysis based on the six polymorphisms indicated that two haplotypes were associated with baseline FEV1. Among the childhood asthmatics, one polymorphism was associated with both baseline FEV1 and the repeated measures of FEV1 over 4 years.


CONCLUSIONS
Our results indicate that genetic variants in STAT3, independent of asthma treatment, are determinants of FEV1 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.
Litonjua
Augusto A
AA
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA 02115, USA. augusto.litonjua@channing.harvard.edu
Tantisira
Kelan G
KG
Lake
Stephen
S
Lazarus
Ross
R
Richter
Brent G
BG
Gabriel
Stacey
S
Silverman
Eric S
ES
Weiss
Scott T
ST
D000328:Adult; D001249:Asthma / Q000453:epidemiology* / Q000503:physiopathology*; D002648:Child; D015331:Cohort Studies; D005260:Female; D005541:Forced Expiratory Volume; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D005820:Genetic Testing / Q000379:methods; D014644:Genetic Variation; D006801:Humans; D008168:Lung / Q000503:physiopathology*; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018570:Risk Assessment / Q000379:methods*; D012307:Risk Factors; D050796:STAT3 Transcription Factor / Q000235:genetics*; D014481:United States / Q000453:epidemiology
D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human