Correspondence

Genetic Modifiers in Cystic Fibrosis

N Engl J Med 2006; 354:88-90January 5, 2006

Article

To the Editor:

Drumm and colleagues (Oct. 6 issue)1 identified sequence variants in the TGFβ1 gene as genetic modifiers of lung disease in cystic fibrosis. TGFβ1 is encoded on chromosome 19q13, 4.5 Mbp from the CFM1 locus that confers a risk of meconium ileus.2 We scanned this region on 19q13 with use of single-nucleotide polymorphisms (SNPs) and microsatellites in a cohort of sibling pairs homozygous for the ΔF508 mutation with extreme clinical phenotypes3 for a modulator of disease severity. Neither the two TGFβ1 SNPs (−509 and codon 10)1 nor the microsatellite D19S112 at CFM1 2 was associated with disease severity in our cohort.

Interrogation of the region between TGFβ1 and CFM1 by four microsatellites, however, revealed a significant transmission disequilibrium in clinically discordant sibling pairs (a peak at D19S197, P=0.003), suggesting a modulation of factors acting in trans3 (Figure 1Figure 1Transmission Disequilibrium among Clinically Discordant Sibling Pairs Homozygous for the ΔF508 Mutation.). The region contains the CEACAM gene family encoding cell-adhesion molecules involved in the binding of pathogens and the regulation of differentiation, angiogenesis, and cancer. The TGFβ1CEACAM region apparently contains at least one clinically relevant genetic modifier of cystic fibrosis.

Frauke Stanke, Ph.D.
Burkhard Tümmler, M.D., Ph.D.
Hannover Medical School, 30623 Hannover, Germany
mekus.frauke@mh-hannover.de

Tim Becker, Ph.D.
University of Bonn, 53105 Bonn, Germany

4 References

1. 1

   Drumm ML, Konstan MW, Schluchter MD, et al. Genetic modifiers of lung disease in cystic fibrosis. N Engl J Med 2005;353:1443-1453
   Full Text | Web of Science | Medline

2. 2

   Zielenski J, Corey M, Rozmahel R, et al. Detection of a cystic fibrosis modifier locus for meconium ileus on human chromosome 19q13. Nat Genet 1999;22:128-129
   CrossRef | Web of Science | Medline

3. 3

   Mekus F, Laabs U, Veeze H, Tummler B. Genes in the vicinity of CFTR modulate the cystic fibrosis phenotype in highly concordant or discordant F508del homozygous sib pairs. Hum Genet 2003;112:1-11
   CrossRef | Web of Science | Medline

4. 4

   Becker T, Knapp M. A powerful strategy to account for multiple testing in the context of haplotype analysis. Am J Hum Genet 2004;75:561-570
   CrossRef | Web of Science | Medline

To the Editor:

Drumm et al. fail to include in their analysis the HLA class II genes and the neutrophil Fcγ receptor IIA (FcγRIIA) genes among those previously reported as potential modifiers in cystic fibrosis.1,2 In patients with this disease, the HLA-DR7 allele and the FcγRIIA R allele have been associated with an increased risk of colonization by Pseudomonas aeruginosa. The finding related to the FcγRIIA R allele was obtained from a study of patients with cystic fibrosis who have the same CFTR genotype as the patients studied by Drumm et al.

Since the TGFβ1 alleles have previously been shown to have a protective effect in smokers,3 it may be reasonable to consider in the statistical analysis the covariate of the presence or absence of a history of smoking in order to avoid a potential confounding factor.

Gabriele Rossi, M.D.
Via Como, 17, 20095 Cusano Milanino, Italy
gab.rossi@tiscali.it

Valeria Rossi, M.D.
Azienda Ospedaliera Luigi Sacco, 20157 Milan, Italy

3 References

1. 1

   Aron Y, Polla BS, Bienvenu T, Dall'ava J, Dusser D, Hubert D. HLA class II polymorphism in cystic fibrosis: a possible modifier of pulmonary phenotype. Am J Respir Crit Care Med 1999;159:1464-1468
   Web of Science | Medline

2. 2

   De Rose V, Arduino C, Cappello N, et al. Fcgamma receptor IIA genotype and susceptibility to P. aeruginosa infection in patients with cystic fibrosis. Eur J Hum Genet 2005;13:96-101
   CrossRef | Web of Science | Medline

3. 3

   Celedon JC, Lange C, Raby BA, et al. The transforming growth factor-beta1 (TGFB1) gene is associated with chronic obstructive pulmonary disease (COPD). Hum Mol Genet 2004;13:1649-1656
   CrossRef | Web of Science | Medline

Author/Editor Response

Rossi and Rossi call attention to two genetic variants associated with an increased risk of colonization by P. aeruginosa in cystic fibrosis. In a study of 98 adults with mixed CFTR genotypes, Aron et al.1 reported that carriers of HLA-DR7 had a slight increase in colonization (100 percent, vs. 83 percent for noncarriers), but there was no difference in the age at which colonization occurred or in pulmonary function. HLA typing of our 808 patients who are homozygous for ΔF508 is ongoing. Last year, a study by De Rose et al.2 reported that FcγRIIA variants were not associated with colonization by P. aeruginosa among 167 patients with mixed CFTR genotypes, but colonization was more prevalent among the 47 patients who were homozygous for the ΔF508 mutation who carried the R variant than among the 22 noncarriers when the results were analyzed by logistic regression (P=0.04). It will be interesting to see whether this variant is associated with the severity of lung disease in our larger population of ΔF508 homozygotes. A very small percentage of patients with cystic fibrosis have an appreciable smoking history, so this factor was not a potential confounder in our study.

Stanke (née Mekus) and colleagues3 did not replicate the association we found of TGFβ1 −509 and codon 10 variants with the severity of lung disease when they tested these two SNPs in sibling pairs with extreme clinical phenotypes. Since we obtained a robust association (P=6×10⁻⁸) with severity status for the TGFβ1 codon 10 CC genotype in our total sample of 1306 subjects (808 in the initial study and 498 in the replication study), perhaps their study is underpowered. The study of patients with extreme clinical phenotypes cited by Stanke and colleagues involved a sample of 21 highly concordant sibling pairs (10 with severe disease and 11 with mild disease) and 13 discordant sibling pairs. In contrast to their negative findings with respect to TGFβ1, Stanke and colleagues report substantial transmission disequilibrium in their discordant sibling pairs as assessed by microsatellite testing, but the multiple testing they performed probably weakens this evidence. Even considering that only the eight loci reported in their letter were examined, the possibility of separate hypothesis tests for the concordant sibling pairs with mild or severe disease indicates that the most conservative Bonferroni method would generate an adjusted P=0.07. We look forward to examining studies reporting these new findings on chromosome 19q in the peer-reviewed literature, since the possibility of additional disease-severity loci or transacting modulators should be vigorously pursued.

Mitchell Drumm, Ph.D.
Case Western Reserve University, Cleveland, OH 44106-4948

Fred Wright, Ph.D.
Michael Knowles, M.D.
University of North Carolina, Chapel Hill, NC 27599-7248
knowles@med.unc.edu

3 References

1. 1

   Aron Y, Polla BS, Bienvenu T, Dall'ava J, Dusser D, Hubert D. HLA class II polymorphism in cystic fibrosis: a possible modifier of pulmonary phenotype. Am J Respir Crit Care Med 1999;159:1464-1468
   Web of Science | Medline

2. 2

   De Rose V, Arduino C, Cappello N, et al. Fcgamma receptor IIA genotype and susceptibility to P. aeruginosa infection in patients with cystic fibrosis. Eur J Hum Genet 2005;13:96-101
   CrossRef | Web of Science | Medline

3. 3

   Mekus F, Laabs U, Veeze H, Tummler B. Genes in the vicinity of CFTR modulate the cystic fibrosis phenotype in highly concordant or discordant F508del homozygous sib pairs. Hum Genet 2003;112:1-11
   CrossRef | Web of Science | Medline

Citing Articles (6)

Citing Articles

1. 1

   Carlo Castellani, Milan Macek, Jean-Jacques Cassiman, Alistair Duff, John Massie, Leo P. ten Kate, David Barton, Garry Cutting, Bruno Dallapiccola, Elisabeth Dequeker, Emmanuelle Girodon, Wayne Grody, Edward W. Highsmith, Helenal Kääriäinen, Stephan Kruip, Michael Morris, Pier Franco Pignatti, Ulrike Pypops, Martin Schwarz, Maria Soller, Manfred Stuhrman, Harry Cuppens. (2010) Benchmarks for Cystic Fibrosis carrier screening: A European consensus document. Journal of Cystic Fibrosis 9:3, 165-178
   CrossRef

2. 2

   Frauke Stanke, Tim Becker, Silke Hedtfeld, Stephanie Tamm, Thomas F. Wienker, Burkhard Tümmler. (2010) Hierarchical fine mapping of the cystic fibrosis modifier locus on 19q13 identifies an association with two elements near the genes CEACAM3 and CEACAM6. Human Genetics 127:4, 383-394
   CrossRef

3. 3

   M. Esther Farez-Vidal, M. Amelia Gómez-Llorente, Carolina Gómez-Llorente, Sonia Blanco, Francisco Casas-Maldonado, Cristina Campoy, JoséAntonio Gómez-Capilla. (2008) A Family with Atypical Cystic Fibrosis: Brother and Sister with Heterozygosity for Both G542X and R117H. Pediatric and Developmental Pathology 11:3, 213-219
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4. 4

   L. A. Bremer, S. M. Blackman, L. L. Vanscoy, K. E. McDougal, A. Bowers, K. M. Naughton, D. J. Cutler, G. R. Cutting. (2008) Interaction between a novel TGFB1 haplotype and CFTR genotype is associated with improved lung function in cystic fibrosis. Human Molecular Genetics 17:14, 2228-2237
   CrossRef

5. 5

   Isabel Carvalho-Oliveira, Bob J Scholte, Deborah Penque. (2007) What have we learned from mouse models for cystic fibrosis?. Expert Review of Molecular Diagnostics 7:4, 407-417
   CrossRef

6. 6

   Tim Becker, Silke Jansen, Stephanie Tamm, Thomas F Wienker, Burkhard Tümmler, Frauke Stanke. (2007) Transmission ratio distortion and maternal effects confound the analysis of modulators of cystic fibrosis disease severity on 19q13. European Journal of Human Genetics 15:7, 774-778
   CrossRef