- Email: [email protected]
δF508 heterozygosity and asthma
CORRESPONDENCE 3 4
Warner JO. Immunology of cystic fibrosis. Br Med Bull 1992; 48: 893–911. Counahan R, Mearns M. Prevalence of atopy and exercise induced bronchial lability in relatives of patients with cystic fibrosis. Arch Dis Child 1975; 50: 477–81.
Sir—Morten Dahl and colleagues 1 suggest that the frequency of asthma may be increased in carriers of the cystic fibrosis ⌬F508 mutation. Despite the high frequency of carriers for the cystic fibrosis gene, little is known about the health status of these individuals, especially with regard to the risk of cancer which is reported to be high for the digestive tract in cystic fibrosis patients2 which, in some other autosomal recessive disorders, can also be increased.3 To find out the health status of individuals heterozygous for the ⌬F508 mutation, we contacted all members of the International Association of Cystic Fibrosis Adults (IACFA), a multinational organisation of about 1800 people who have the disorder or are related to a person with cystic fibrosis. Each member received two health questionnaires: one about the cystic fibrosis parent, the other to be given to a parent or a friend without a family history of the disorder. We compared frequency of self-reported benign illnesses in 1113 cystic fibrosis heterozygotes (mean age 53·4 [SD 12] years) with disease frequency in 688 controls (mean age 54·6 [12] years) by means of logistic regression analysis. We adjusted for age, parental status, sex, and geographical region. For malignant disease, we report the standardised incidence ratio (SIR), the ratio of observed cancers in the carriers to the expected number based on cancer rates in the general population. Benign diseases, allergic disorders, sinus and upper-digestive-tract diseases were significantly more common in the carriers than in the controls.* The prevalence of asthma in cystic fibrosis heterozygotes was 9·6%, which is similar to that reported by Dahl, but the odds ratio was only slightly raised. There was a reduction in smokingrelated cancers among cystic fibrosis parents (SIR 0·5 [95% CI 0·3–0·8]), whereas the rate of other cancers was similar to that of the general population (1·0 [0·8–1·2]). When we restricted the analysis of benign and malignant disease to the subset of cystic fibrosis heterozygotes with the identified ⌬F508 mutation, the most common cystic fibrosis genetic abnormality, the results were similar. Because there are so many cystic fibrosis carriers, there has been much speculation about a potential survival value for carriers, particularly with
THE LANCET • Vol 352 • September 19, 1998
respect to response to infectious disease.4 Although this study is the largest study of cystic fibrosis carriers to date, we could not detect a reduced risk for any single disorder or disease category in the carriers. If carriers have a reduced risk of disease, this advantage would probably be too small to detect in a case-control study of manageable size. In our study, genetic testing of the controls, which would have identified about 30–40 cystic fibrosis carriers, was not done. If these carriers had been excluded from the control group, the positive findings would have been stronger. This study had multiple endpoints, so chance could explain some of the positive findings. Also, parents of cystic fibrosis cases may be more likely to report or complain about diseases commonly associated with cystic fibrosis. Our findings with respect to allergy, however, confirm Warner and colleagues’ report of an excess of allergic disorders.5 *Data available from the authors or from The Lancet. This study was supported in part by an unrestricted grant from Solvay Pharmaceuticals (Marietta USA), Kalie-Chemie, AG, Hannover, Germany) and by a grant from the Italian Association for Cancer Research. We thank Peter Boyle and Doris B Lowenfels for their contributions.
Albert B Lowenfels, *Patrick Maisonneuve, Barbara Palys, Martin H Schöni, Beatrix Redemann Department of Surgery and Community and Preventive Medicine, New York Medical College, Valhalla, New York, USA; *Division of Epidemiology and Biostatistics, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy; Department of Pediatrics, Inselspital, Bern, Switzerland; and International Association of Cystic Fibrosis Adults, Harvard, MA (e-mail: [email protected]) 1
2
3
4
5
Dahl M, Tybjoerg-Hansen A, Lange P, Nordestgaard BG. ⌬F508 heterozygosity in cystic fibrosis and susceptibility to asthma. Lancet 1998; 351: 1911–13. Neglia JP, FitzSimmons SC, Maisonneuve P, et al. The risk of cancer among patients with cystic fibrosis. N Engl J Med 1995; 332: 494–99. Heim RA, Lench NJ, Swift M. Heterozygous manifestations in four autosomal recessive human cancer-prone syndromes: ataxia telangiectasia, xeroderma pigmentosum, Fanconi anemia, and Bloom syndrome. Mutat Res 1992; 284: 25–36. Romeo G, Devoto M, Galietta LJ. Why is the cystic fibrosis gene so frequent? Hum Genet 1989; 84: 1–5. Warner JO, Norman AP, Soothill JF. Cystic fibrosis heterozygosity in the pathogenesis of allergy. Lancet 1976; i: 990–91.
Sir—Whether cystic fibrosis heterozygotes are at risk of respiratory disease is a matter of debate. The hypothesis of a harmful effect is
supported by the report by Morten Dahl and colleagues1 of lower lung function in individuals heterozygous for ⌬F508 than in non-carriers among asthmatics from the general population. They propose that a higher frequency of bronchial hyperresponsiveness in heterozygotes could explain the relation, and suggest that a certain context was necessary for the expression of a harmful effect of ⌬F508 heterozygosity. The potential associations of asthma, bronchial hyper-responsiveness, and atopy with ⌬F508 carrier has been studied in 208 parents of asthmatics (at increased risk of asthmarelated traits) and a control group of 144 individuals (98 controls and 46 spouses of asthmatics from the Epidemiological Study on the Genetics and Environment of Asthma, bronchial hyper-responsiveness, and atopy2). Four (2·8%) controls and six (2·9%) parents of asthmatics were ⌬F508 heterozygotes, which was a proportion we expected and was similar to that in Dahl’s study.* As expected, the rate of asthma was significantly higher (odds ratio 2·97 [95% CI 1·60–5·50]) in parents of asthmatics than in the controls, and the parents also had significantly higher IgE (p=0·02) and a higher rate of skinprick test positivity to any of 11 allergens (weal 肁3 mm odds ratio 2·85 [1·78–4·56]; weal >0 mm 2·28 [1·46–3·55]). ⌬F508 carriers and non-carriers did not differ with regard to asthma prevalence, forced expiratory volume in 1s (FEV1), bronchial responsiveness (challenge in those with FEV1 肁80% predicted), IgE concentrations, and eosinophilia. Among the ten heterozygotes, one was asthmatic. Atopy to 11 allergens was higher in carriers than in non-carriers, but this difference was not significant (weal 肁3 mm 2·64; Fisher exact test p=0·18; weal >0 mm 3·05 p=0·11). Aspergillus positivity was significantly higher in ⌬F508 carriers than in noncarriers (weal 肁3 mm 5·62, p=0·03; weal >0 mm, 6·18, p=0·01). Aspergillosis occurs in patients with cystic fibrosis and in asthmatics. No individual had suspected allergic aspergillosis and the results did not change with exclusion of asthmatics (weal 肁3 mm 8·57, p=0·02; weal >0 mm 9·56, p=0·005). None of the other ten allergens was significantly related to ⌬F508 carrier with a weal of 3 mm or greater. For a weal larger than 10 mm, only birch exhibited a significant association (p=0·02). Although greater sensitivity to skinprick tests in obligate
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Warner JO. Immunology of cystic fibrosis. Br Med Bull 1992; 48: 893–911. Counahan R, Mearns M. Prevalence of atopy and exercise induced bronchial lability in relatives of patients with cystic fibrosis. Arch Dis Child 1975; 50: 477–81.
Sir—Morten Dahl and colleagues 1 suggest that the frequency of asthma may be increased in carriers of the cystic fibrosis ⌬F508 mutation. Despite the high frequency of carriers for the cystic fibrosis gene, little is known about the health status of these individuals, especially with regard to the risk of cancer which is reported to be high for the digestive tract in cystic fibrosis patients2 which, in some other autosomal recessive disorders, can also be increased.3 To find out the health status of individuals heterozygous for the ⌬F508 mutation, we contacted all members of the International Association of Cystic Fibrosis Adults (IACFA), a multinational organisation of about 1800 people who have the disorder or are related to a person with cystic fibrosis. Each member received two health questionnaires: one about the cystic fibrosis parent, the other to be given to a parent or a friend without a family history of the disorder. We compared frequency of self-reported benign illnesses in 1113 cystic fibrosis heterozygotes (mean age 53·4 [SD 12] years) with disease frequency in 688 controls (mean age 54·6 [12] years) by means of logistic regression analysis. We adjusted for age, parental status, sex, and geographical region. For malignant disease, we report the standardised incidence ratio (SIR), the ratio of observed cancers in the carriers to the expected number based on cancer rates in the general population. Benign diseases, allergic disorders, sinus and upper-digestive-tract diseases were significantly more common in the carriers than in the controls.* The prevalence of asthma in cystic fibrosis heterozygotes was 9·6%, which is similar to that reported by Dahl, but the odds ratio was only slightly raised. There was a reduction in smokingrelated cancers among cystic fibrosis parents (SIR 0·5 [95% CI 0·3–0·8]), whereas the rate of other cancers was similar to that of the general population (1·0 [0·8–1·2]). When we restricted the analysis of benign and malignant disease to the subset of cystic fibrosis heterozygotes with the identified ⌬F508 mutation, the most common cystic fibrosis genetic abnormality, the results were similar. Because there are so many cystic fibrosis carriers, there has been much speculation about a potential survival value for carriers, particularly with
THE LANCET • Vol 352 • September 19, 1998
respect to response to infectious disease.4 Although this study is the largest study of cystic fibrosis carriers to date, we could not detect a reduced risk for any single disorder or disease category in the carriers. If carriers have a reduced risk of disease, this advantage would probably be too small to detect in a case-control study of manageable size. In our study, genetic testing of the controls, which would have identified about 30–40 cystic fibrosis carriers, was not done. If these carriers had been excluded from the control group, the positive findings would have been stronger. This study had multiple endpoints, so chance could explain some of the positive findings. Also, parents of cystic fibrosis cases may be more likely to report or complain about diseases commonly associated with cystic fibrosis. Our findings with respect to allergy, however, confirm Warner and colleagues’ report of an excess of allergic disorders.5 *Data available from the authors or from The Lancet. This study was supported in part by an unrestricted grant from Solvay Pharmaceuticals (Marietta USA), Kalie-Chemie, AG, Hannover, Germany) and by a grant from the Italian Association for Cancer Research. We thank Peter Boyle and Doris B Lowenfels for their contributions.
Albert B Lowenfels, *Patrick Maisonneuve, Barbara Palys, Martin H Schöni, Beatrix Redemann Department of Surgery and Community and Preventive Medicine, New York Medical College, Valhalla, New York, USA; *Division of Epidemiology and Biostatistics, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy; Department of Pediatrics, Inselspital, Bern, Switzerland; and International Association of Cystic Fibrosis Adults, Harvard, MA (e-mail: [email protected]) 1
2
3
4
5
Dahl M, Tybjoerg-Hansen A, Lange P, Nordestgaard BG. ⌬F508 heterozygosity in cystic fibrosis and susceptibility to asthma. Lancet 1998; 351: 1911–13. Neglia JP, FitzSimmons SC, Maisonneuve P, et al. The risk of cancer among patients with cystic fibrosis. N Engl J Med 1995; 332: 494–99. Heim RA, Lench NJ, Swift M. Heterozygous manifestations in four autosomal recessive human cancer-prone syndromes: ataxia telangiectasia, xeroderma pigmentosum, Fanconi anemia, and Bloom syndrome. Mutat Res 1992; 284: 25–36. Romeo G, Devoto M, Galietta LJ. Why is the cystic fibrosis gene so frequent? Hum Genet 1989; 84: 1–5. Warner JO, Norman AP, Soothill JF. Cystic fibrosis heterozygosity in the pathogenesis of allergy. Lancet 1976; i: 990–91.
Sir—Whether cystic fibrosis heterozygotes are at risk of respiratory disease is a matter of debate. The hypothesis of a harmful effect is
supported by the report by Morten Dahl and colleagues1 of lower lung function in individuals heterozygous for ⌬F508 than in non-carriers among asthmatics from the general population. They propose that a higher frequency of bronchial hyperresponsiveness in heterozygotes could explain the relation, and suggest that a certain context was necessary for the expression of a harmful effect of ⌬F508 heterozygosity. The potential associations of asthma, bronchial hyper-responsiveness, and atopy with ⌬F508 carrier has been studied in 208 parents of asthmatics (at increased risk of asthmarelated traits) and a control group of 144 individuals (98 controls and 46 spouses of asthmatics from the Epidemiological Study on the Genetics and Environment of Asthma, bronchial hyper-responsiveness, and atopy2). Four (2·8%) controls and six (2·9%) parents of asthmatics were ⌬F508 heterozygotes, which was a proportion we expected and was similar to that in Dahl’s study.* As expected, the rate of asthma was significantly higher (odds ratio 2·97 [95% CI 1·60–5·50]) in parents of asthmatics than in the controls, and the parents also had significantly higher IgE (p=0·02) and a higher rate of skinprick test positivity to any of 11 allergens (weal 肁3 mm odds ratio 2·85 [1·78–4·56]; weal >0 mm 2·28 [1·46–3·55]). ⌬F508 carriers and non-carriers did not differ with regard to asthma prevalence, forced expiratory volume in 1s (FEV1), bronchial responsiveness (challenge in those with FEV1 肁80% predicted), IgE concentrations, and eosinophilia. Among the ten heterozygotes, one was asthmatic. Atopy to 11 allergens was higher in carriers than in non-carriers, but this difference was not significant (weal 肁3 mm 2·64; Fisher exact test p=0·18; weal >0 mm 3·05 p=0·11). Aspergillus positivity was significantly higher in ⌬F508 carriers than in noncarriers (weal 肁3 mm 5·62, p=0·03; weal >0 mm, 6·18, p=0·01). Aspergillosis occurs in patients with cystic fibrosis and in asthmatics. No individual had suspected allergic aspergillosis and the results did not change with exclusion of asthmatics (weal 肁3 mm 8·57, p=0·02; weal >0 mm 9·56, p=0·005). None of the other ten allergens was significantly related to ⌬F508 carrier with a weal of 3 mm or greater. For a weal larger than 10 mm, only birch exhibited a significant association (p=0·02). Although greater sensitivity to skinprick tests in obligate
985