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Previous Volume 353:1443-1453 October 6, 2005 Number 14 Next

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ABSTRACT

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 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 TGF1 codon 10 CC genotype with low FEV₁.

Results In the initial study, significant allelic and genotypic associations with phenotype were seen only for TGF1 (the gene encoding transforming growth factor 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 TGF1 genotype (codon 10 CC) in association with the phenotype for severe lung disease. The replication study confirmed the association of the TGF1 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 TGF1 or a nearby upstream region modifies disease severity in cystic fibrosis.

Source Information

From the Departments of Pediatrics (M.L.D., M.W.K., M.D.S., J.M.D., R.J.D.), Genetics (M.L.D.), and Epidemiology and Biostatistics (K.G.), Case Western Reserve University, Cleveland; the Cystic Fibrosis–Pulmonary Research and Treatment Center, School of Medicine (A.H., R.P., M.Z., J.R.Y., M.R.K.), the Department of Biostatistics, School of Public Health (F.Z., F.A.W.), and the Molecular Biology–Biotechnology Center for Bioinformatics (D.F., A.X.), University of North Carolina at Chapel Hill, Chapel Hill; the Program in Integrative Biology (P.D.), Program in Genetics and Genomic Biology (R.D., J.Z.), and Population Health Sciences (M.C.), Hospital for Sick Children, Toronto; and the James Hogg iCAPTURE Center for Cardiovascular and Pulmonary Research, University of British Columbia, Vancouver, B.C., Canada (A.J.S.).

Address reprint requests to Dr. Knowles at the Cystic Fibrosis–Pulmonary Research and Treatment Center, 7019 Thurston-Bowles Bldg., CB# 7248, University of North Carolina, Chapel Hill, NC 27599, or at knowles{at}med.unc.edu.

Full Text of this Article

Related Letters:

Genetic Modifiers in Cystic Fibrosis
Stanke F., Tümmler B., Becker T., Rossi G., Rossi V., Drumm M., Wright F., Knowles M.
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N Engl J Med 2006; 354:88-90, Jan 5, 2006. Correspondence

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