Protection against bronchial asthma by CFTR F508 mutation: A heterozygote advantage in cystic fibrosis

Cystic fibrosis (CF) is a multisystem autosomal recessive disorder caused by mutations of the cystic fibrosis transmembrane regulator (CFTR), a protein that regulates cyclic-AMP-media ted chloride conductance at the apical membrane of secretory epithelia¹. Mutations in the CFTR gene are common in many populations. In North America, 4−5% of the general population are heterozygous for a CFTR mutation². Although there are over 400 known CFTR mutations, a single mutation, a deletion of the phenylalanine at position 508 (F508) in exon 10, accounts for about 70% of all CF chromosomes worldwide³. The reasons for the high frequency of the F508 CFTR allele — the selective advantage associated with CF heterozygosity — are unknown¹. Many physiological abnormalities have been observed in CF heterozygotes⁴⁻⁶, although the clinical significance of these observations is unknown. Preliminary unpublished data and anecdotal information from CF families suggested that, remarkably, the F508 allele might protect heterozygotes against bronchial asthma prompted us to further investigate this possibility. Here we present evidence that the F508 CF allele protects against asthma in childhood and early adult life.

1. Tizzano, E.F. & Buchwald, M. Cystic fibrosis: Beyond the gene to therapy. J. Pediat. 120, 337−349 (1992). | PubMed  | ISI | ChemPort |
2. Lemna, W.K. et al. Mutation analysis for heterozygote detection and the prenatal diagnosis of cystic fibrosis. New Engl. J. Med. 322, 291−296 (1990). | PubMed  | ISI | ChemPort |
3. Morral, N. et al. The origin of the major cystic fibrosis mutation (F508) in European populations. Nature Genet. 7, 169−175 (1994). | Article | PubMed  | ISI | ChemPort |
4. Davis, P.B. & Vargo, K. Pulmonary abnormalities in obligate heterozygotes for cystic fibrosis. Thorax 42, 120−125 (1987). | PubMed  | ISI | ChemPort |
5. Davis, P.B. & Byard, P.J. Heterozygotes for cystic fibrosis: Models for study of airway and autonomic reactivity. J. appl. Physiol. 66, 2124−2128 (1989). | PubMed  | ISI | ChemPort |
6. Gyurkovitz, K., Markus, V. & Bittera, I. Cystic fibrosis heterozygosity in childhood bronchial asthma. Lancet 1, 203 (1977). | Article |
7. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am. Rev. resp. Dis. 136, 225−244 (1977).
8. National Asthma Education Program. Guidelines for the diagnosis and management of asthma. (National Institutes of Health, Bethesda, MD, 1991. DHMS publication no. NIH 91-3042).
9. Swift, M., Kupper, L.L. & Chase, C.L. Effective testing of gene-disease associations. Am. J. hum. Genet. 47, 266−274 (1990). | PubMed  | ISI | ChemPort |
10. Pignatti, P.F., Bombieri, C., Marigo, C., Benetazzo, M. & Luisetti, M. Increased incidence of cystic fibrosis gene mutations in adults with disseminated bronchiectasis. Hum. molec. Genet. 4, 635−639 (1995). | PubMed  | ISI | ChemPort |
11. Counahan, R. & Mearns, M.B. Prevalence of atopy and exercise-induced bronchial lability in relatives of patients with cystic fibrosis. Archs Dis. Childh. 50, 477−481 (1975). | ChemPort |
12. Bonforte, R.J. Pneumonia of infancy, in Pediatric Respiratory Disease (ed. Hilman, B.) Ch. 30, p. 263 (Saunders, Philadelphia, 1993).
13. Baxter, P.S., Goldhill, J., Hardcastle, J., Hardcastle, P.T. & Taylor, C.J. Accounting for cystic fibrosis. Nature 335, 211 (1988). | Article | PubMed  | ISI | ChemPort |
14. Quinton, P.M. Cystic fibrosis: A disease in electrocyte transport. FASEB J. 4, 2709−2717 (1990). | PubMed  | ISI | ChemPort |
15. Friedman, K.J., Highsmith, W.E. & Silverman, L.M. Detecting multiple cystic fibrosis mutations by polymerase chain reaction-mediated site-directed mutagenesis. Clin. Chem. 37, 753−755 (1991). | PubMed  | ISI | ChemPort |

	Top

	Top