Transforming Growth Factor-β₁ Promoter Polymorphism C–509T Is Associated with Asthma

Abstract

Transforming growth factor-beta1 (TGF-beta1) is increased in the lungs of individuals with asthma and may modulate airway inflammation and remodeling. Some genetic studies have found that a C-to-T single-nucleotide polymorphism (C-509T) in the TGF-beta1 gene promoter may be associated with altered gene expression and asthma phenotype. To build on these data, we performed a case-control association study at this locus involving 527 subjects with asthma and 170 control subjects without asthma. All individuals were white. Genotyping at 49 unlinked polymorphisms indicated that a subset of case subjects and all control subjects were well matched and without evidence of population stratification. Logistic regression was used to model the effects of age, sex, and genotype on case-control status. The diagnosis of asthma was positively associated with the T allele and TT genotype under a codominant model (odds ratio, 2.98; 95% confidence interval, 1.45 to 6.25; p = 0.003). Total serum IgE, eosinophil count, and FEV1% predicted levels were not associated with this polymorphism. Furthermore, we show that the C-509T polymorphism alters TGF-beta1 promoter-reporter activity and promoter interactions with the transcription factor Yin Yang 1. We conclude that the T allele of C-509T is associated with the diagnosis of asthma and may enhance TGF-beta1 gene transcription.

Th2 Cell-Selective Enhancement of HumanIL13Transcription byIL13-1112C>T, a Polymorphism Associated with Allergic Inflammation

“…Indeed, the magnitude of the effect was similar to other regulatory polymorphisms such as the SNP in SLC22A associated with rheumatoid arthritis and loss of transcriptional activity (41) and the variant CD14 and TGF-␤ promoters (29,42). Because the functional effects of individual polymorphisms may be small, risk for complex diseases is substantially increased by synergism between multiple SNPs arrayed along a single regulatory pathway.…”

TGF-β1 Variants in Chronic Beryllium Disease and Sarcoidosis

“…However, the genotypes associated with more severe CBD and sarcoidosis are the same ones which have been associated with lower TGF-␤ levels in previous studies (11,33). This might suggest that TGF-␤1 is not playing a role in fibrogenesis, but instead may be playing a role in immune regulation of these granulomatous diseases.…”

Interactions Between Secondhand Smoke and Genes That Affect Cystic Fibrosis Lung Disease

“…TGFβ1 has been found to modify the development and severity of asthma. [14][15][16] Although 2 studies did not demonstrate a gene-environment interaction between secondhand smoke exposure in the home and TGFβ1 in the development of asthma, 17,18 detection of interactions in common chronic lung diseases such as asthma may be hampered by etiologic heterogeneity. It may be easier to detect subtle interactions affecting disease severity using a continuous variable, and patients with CF often perform pulmonary function tests on a quarterly basis yielding the continuous variable outcome of FEV 1 .…”

“…TGFβ1 was selected for study because genotypic variants of TGFβ1 have been shown to modify the severity of CF [11][12][13] and the development and/or severity of other chronic respiratory tract conditions, including asthma [14][15][16][17][18] and chronic obstructive pulmonary disease. [19][20][21] …”