Genetic modifiers of lung disease in cystic fibrosis

BACKGROUND Polymorphisms in genes other than the cystic fibrosis transmembrane conductance regulator ( CFTR) gene may modify the severity of pulmonary disease in patients with cystic fibrosis. METHODS We performed two studies with different patient samples. We first tested 808 patients who were homozygous for the Delta F508 mutation and were classified as having either severe or mild lung disease, as defined by the lowest or highest quartile of forced expiratory volume in one second (FEV1), respectively, for age. We genotyped 16 polymorphisms in 10 genes reported by others as modifiers of disease severity in cystic fibrosis and tested for an association in patients with severe disease ( 263 patients) or mild disease ( 545). In the replication ( second) study, we tested 498 patients, with various CFTR genotypes and a range of FEV1 values, for an association of the TGF beta 1 codon 10 CC genotype with low FEV1. RESULTS In the initial study, significant allelic and genotypic associations with phenotype were seen only for TGF beta 1 ( the gene encoding transforming growth factor beta 1), particularly the - 509 and codon 10 polymorphisms ( with P values obtained with the use of Fisher's exact test and logistic regression ranging from 0.006 to 0.0002). The odds ratio was about 2.2 for the highest-risk TGF beta 1 genotype ( codon 10 CC) in association with the phenotype for severe lung disease. The replication study confirmed the association of the TGF beta 1 codon 10 CC genotype with more severe lung disease in comparisons with the use of dichotomized FEV1 for severity status ( P= 0.0002) and FEV1 values directly ( P= 0.02). CONCLUSIONS Genetic variation in the 5' end of TGF beta 1 or a nearby upstream region modifies disease severity in cystic fibrosis.