Human Molecular Genetics Advance Access originally published online on April 17, 2008
Human Molecular Genetics 2008 17(14):2228-2237; doi:10.1093/hmg/ddn123
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Interaction between a novel TGFB1 haplotype and CFTR genotype is associated with improved lung function in cystic fibrosis
1 McKusick-Nathans Institute of Genetic Medicine 2 Division of Pediatric Endocrinology, Johns Hopkins University School of Medicine, Baltimore, MD, USA 3 Department of Pediatrics, National Naval Medical Center, Bethesda, MD, USA 4 Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
* To whom correspondence should be addressed at: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N. Broadway, Broadway Research Building 559, Baltimore, MD 21205, USA. Tel: +1 4109551773; Fax: +1 4106140213; Email: gcutting{at}jhmi.edu
Received December 28, 2007; Accepted April 11, 2008
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.