- Email: [email protected]
δF508 heterozygosity and asthma
CORRESPONDENCE
COMMENTARY
CORRESPONDENCE
∆F508 heterozygosity and asthma Sir—The article1 by Morten Dahl and others1 sheds no light on the relation between asthma and heterozygosity for the ∆F508 cystic fibrosis allele. The basic data are unreliable, since participants were allowed to classify themselves as having asthma, chronic bronchitis, or chronic obstructive pulmonary disease. Physicians must use detailed histories, physical examinations, and radiography to differentiate between these conditions. Their report does not indicate whether these three categories were mutually exclusive. However, assuming that they are independent, the proportion of ∆F508 heterozygotes with one of these three conditions is 0·272, which is not significantly different from the proportion of 0·279 among non-carriers. The only conclusion one can draw from their data is that the proportion of individuals self-described as having chronic airways disease was not different between the two groups. Perhaps Dahl and colleagues can provide the total number of patients in each group with chronic airways disease if their clinical categories were, in fact, non-exclusive. The study results may not represent the situation in the general population, since only 9141 of 17 180 people were genotyped. The criteria for selecting the 17 180 individuals were not given. Bias may have been introduced if individuals were more likely to participate if they had chronic airways disease or had a relative with cystic fibrosis. Dahl and colleagues claim that there is a “positive association between ∆F508 and asthma” while stating, in their final paragraph, that “individuals heterozygous with ∆F508 may account for up to 2% of people with asthma in the general population”. If there were a positive association, the proportion of ∆F508 heterozygotes among asthma patients would be higher than that in
984
the general population. 2% is, instead, less than the 2·7% they themselves detected in their general population survey. By contrast with Dahl and colleagues’ report, our findings2 that the ∆F508 allele protected against asthma was based on medically documented cases of asthma that occurred in non-smokers. Two independent analyses in cystic fibrosis families segregating for ∆F508 showed with robust methods that such carriers were protected against asthma as we defined it. Dahl and colleagues could rigorously test the association of the ∆F508 CFTR allele and asthma in the Danish population by using the ∆F508 heterozygotes they identified as the index individuals, identifying relatives with accurately diagnosed asthma, and comparing the observed number of ∆F508 carriers in these asthmatics with that expected from the laws of inheritance and the population allele frequency.3 *Michael Swift, Yun Su Institute for the Genetic Analysis of Common Diseases, New York Medical College, Hawthorne, NY 10532, USA 1
2
3
Dahl M, Tybjaerg A, Lange P, Nordestgaard BG. ∆F508 heterozygosity in cystic fibrosis and susceptibility to asthma. Lancet 1998; 351: 1911–13. Schroeder SA, Gaughan DM, Swift M. Protection against bronchial asthma by CFTR ∆F508 mutation: a heterozygote advantage in cystic fibrosis. Nat Med 1995; 1: 703–05. Swift M, Kupper LL, Chase CL. Effective testing of gene-disease associations. Am J Hum Genet 1990; 47: 266–74.
Sir—Morten Dahl and colleagues 1 report on cystic fibrosis heterozygosity and susceptibility to asthma. Some 22 years ago, I made the observation that there was an over-representation of atopy and atopic disease among individuals heterozygous for the cystic fibrosis mutation.2
Dahl and co-workers are able to use molecular genetic techniques not available in 1976. They concentrate on lung function and a history of asthma. Unfortunately their observations did not include any attempt to identify allergy since it is a key component of asthma. A difference in allergy could explain their findings. My own study 2 was in a small number of patients and identified that 47% of cystic fibrosis heterozygotes had at least one positive skinprick test, compared with only 20% of controls. A history of asthma, seasonal or perennial rhinitis, was also more frequent in the heterozygotes than the controls, though this difference was not significant, possibly because of the small sample size. Allergy, particularly to the mould Aspergillus fumigatus, is more common in homozygotes with cystic fibrosis.3 Thus, an investigation of atopic predisposition in relation to the cystic fibrosis genotype would be useful. Counahan and Mearns,4 reported an increased frequency of bronchial hyper-responsiveness in heterozygotes, but were unable to show an increase in allergy, although they did not test for grass pollens. Given the importance of the observations made by Dahl and colleagues, it would be fruitful for them to revisit their population and undertake allergy skinprick tests and take a more detailed history for other atopic manifestations. J O Warner Child Health, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK 1
2
Dahl M. Tybjaerg-Hansen A, Lange P, Nordestgaard BG. ⌬F508 heterozygosity in cystic fibrosis and susceptibility of asthma. Lancet 1998; 351: 1911–13. Warner JO, Norman AP, Soothill JF. Cystic fibrosis hterozygosity in the pathogenesis of allergy. Lancet 1976; 1: 990–91.
THE LANCET • Vol 352 • September 19, 1998
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
985
COMMENTARY
CORRESPONDENCE
∆F508 heterozygosity and asthma Sir—The article1 by Morten Dahl and others1 sheds no light on the relation between asthma and heterozygosity for the ∆F508 cystic fibrosis allele. The basic data are unreliable, since participants were allowed to classify themselves as having asthma, chronic bronchitis, or chronic obstructive pulmonary disease. Physicians must use detailed histories, physical examinations, and radiography to differentiate between these conditions. Their report does not indicate whether these three categories were mutually exclusive. However, assuming that they are independent, the proportion of ∆F508 heterozygotes with one of these three conditions is 0·272, which is not significantly different from the proportion of 0·279 among non-carriers. The only conclusion one can draw from their data is that the proportion of individuals self-described as having chronic airways disease was not different between the two groups. Perhaps Dahl and colleagues can provide the total number of patients in each group with chronic airways disease if their clinical categories were, in fact, non-exclusive. The study results may not represent the situation in the general population, since only 9141 of 17 180 people were genotyped. The criteria for selecting the 17 180 individuals were not given. Bias may have been introduced if individuals were more likely to participate if they had chronic airways disease or had a relative with cystic fibrosis. Dahl and colleagues claim that there is a “positive association between ∆F508 and asthma” while stating, in their final paragraph, that “individuals heterozygous with ∆F508 may account for up to 2% of people with asthma in the general population”. If there were a positive association, the proportion of ∆F508 heterozygotes among asthma patients would be higher than that in
984
the general population. 2% is, instead, less than the 2·7% they themselves detected in their general population survey. By contrast with Dahl and colleagues’ report, our findings2 that the ∆F508 allele protected against asthma was based on medically documented cases of asthma that occurred in non-smokers. Two independent analyses in cystic fibrosis families segregating for ∆F508 showed with robust methods that such carriers were protected against asthma as we defined it. Dahl and colleagues could rigorously test the association of the ∆F508 CFTR allele and asthma in the Danish population by using the ∆F508 heterozygotes they identified as the index individuals, identifying relatives with accurately diagnosed asthma, and comparing the observed number of ∆F508 carriers in these asthmatics with that expected from the laws of inheritance and the population allele frequency.3 *Michael Swift, Yun Su Institute for the Genetic Analysis of Common Diseases, New York Medical College, Hawthorne, NY 10532, USA 1
2
3
Dahl M, Tybjaerg A, Lange P, Nordestgaard BG. ∆F508 heterozygosity in cystic fibrosis and susceptibility to asthma. Lancet 1998; 351: 1911–13. Schroeder SA, Gaughan DM, Swift M. Protection against bronchial asthma by CFTR ∆F508 mutation: a heterozygote advantage in cystic fibrosis. Nat Med 1995; 1: 703–05. Swift M, Kupper LL, Chase CL. Effective testing of gene-disease associations. Am J Hum Genet 1990; 47: 266–74.
Sir—Morten Dahl and colleagues 1 report on cystic fibrosis heterozygosity and susceptibility to asthma. Some 22 years ago, I made the observation that there was an over-representation of atopy and atopic disease among individuals heterozygous for the cystic fibrosis mutation.2
Dahl and co-workers are able to use molecular genetic techniques not available in 1976. They concentrate on lung function and a history of asthma. Unfortunately their observations did not include any attempt to identify allergy since it is a key component of asthma. A difference in allergy could explain their findings. My own study 2 was in a small number of patients and identified that 47% of cystic fibrosis heterozygotes had at least one positive skinprick test, compared with only 20% of controls. A history of asthma, seasonal or perennial rhinitis, was also more frequent in the heterozygotes than the controls, though this difference was not significant, possibly because of the small sample size. Allergy, particularly to the mould Aspergillus fumigatus, is more common in homozygotes with cystic fibrosis.3 Thus, an investigation of atopic predisposition in relation to the cystic fibrosis genotype would be useful. Counahan and Mearns,4 reported an increased frequency of bronchial hyper-responsiveness in heterozygotes, but were unable to show an increase in allergy, although they did not test for grass pollens. Given the importance of the observations made by Dahl and colleagues, it would be fruitful for them to revisit their population and undertake allergy skinprick tests and take a more detailed history for other atopic manifestations. J O Warner Child Health, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK 1
2
Dahl M. Tybjaerg-Hansen A, Lange P, Nordestgaard BG. ⌬F508 heterozygosity in cystic fibrosis and susceptibility of asthma. Lancet 1998; 351: 1911–13. Warner JO, Norman AP, Soothill JF. Cystic fibrosis hterozygosity in the pathogenesis of allergy. Lancet 1976; 1: 990–91.
THE LANCET • Vol 352 • September 19, 1998
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
985