Interaction between a novel TGFB1 haplotype and CFTR genotype is associated with improved lung function in cystic fibrosis

Abstract

Cystic fibrosis (CF), the most common lethal single gene disorder in Caucasians, is due to mutations in the CFTR gene. Twin and sibling analysis indicates that modifier genes, rather than allelic variation in CFTR, are responsible for most of the variability in severity of lung disease, the major cause of mortality in CF patients. We used a family-based approach to test for association between lung function and two functional SNPs (rs1800469, '-509' and rs1982073, 'codon 10') in the 5' region of transforming growth factor-beta1 (TGFB1), a putative CF modifier gene. Quantitative transmission disequilibrium testing of 472 CF patient-parent-parent trios revealed that both TGFB1 SNPs showed significant transmission distortion when patients were stratified by CFTR genotype. Although lung function and nutritional status are correlated in CF patients, there was no evidence of association between the TGFB1 SNPs and variation in nutritional status. Additional tagging SNPs (rs8179181, rs2278422, rs8110090, rs4803455 and rs1982072) that capture most of the diversity in TGFB1 were also typed but none showed association with variation in lung function. However, a haplotype composed of the -509 C and codon 10 T alleles along with the C allele of the 3' SNP rs8179181 was highly associated with increased lung function in patients grouped by CFTR genotype. These results demonstrate that TGFB1 is a modifier of CF lung disease and reveal a previously unrecognized beneficial effect of TGFB1 variants upon the pulmonary phenotype.

A Putatively Functional Haplotype in the Gene Encoding Transforming Growth Factor Beta-1 as a Potential Biomarker for Radiosensitivity

“…This might be particularly relevant if more than one functional locus is supposed as counterbalancing each other (28). That hypothesis is supported by a recent report having elicited positive associations between the course of lung function in cystic fibrosis with a TGFB1 haplotype but not with the underlying single variants (29). Following that, haplotypes instead of single SNPs could also be helpful to better characterize the individual radiosensitivity if TGF-b1 is assumed to be a key player.…”

The Influence of Genetics on Cystic Fibrosis Phenotypes

“…Alleles in the promotor (-509) and first exon (codon 10) of TGF-b1 are associated with worse lung function, and was replicated in the Genetic Modifier Study (GMS) of .1300 CF patients (Drumm et al 2005). This discovery was independently replicated when haplotypes of alleles at -509 and codon 10 were analyzed in a separate population (Bremer et al 2008). Further, other gene and environmental interactions are relevant to TGF-b1, because interactions with variants in MBL2 and second-hand smoke exposure modify TGF-b1 association with lung disease.…”

Genetic Causes of Bronchiectasis

“…38 In CFTR genotypes, the increased expression of TGF-b1 has been correlated with worse lung function. 39,40 In addition to mucociliary clearance impairment, MBL and TGF-b1 likely contribute to the pathologic cycle of CF bronchiectasis as a result of increased pathogen susceptibility and altered host response.…”