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.

We performed two studies with different patient samples. We first tested 808 patients who were homozygous for the ΔF508 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 TGFβ1 codon 10 CC genotype with low FEV₁.

In the initial study, significant allelic and genotypic associations with phenotype were seen only for TGFβ1 (the gene encoding transforming growth factor β1), 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 TGFβ1 genotype (codon 10 CC) in association with the phenotype for severe lung disease. The replication study confirmed the association of the TGFβ1 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).

Genetic variation in the 5' end of TGFβ1 or a nearby upstream region modifies disease severity in cystic fibrosis.