Prognosis of cystic fibrosis is conditioned by the severity of pulmonary damage, which is related to infectious complications. The group of ∂F508 homozygous patients with cystic fibrosis shows a substantial variability in clinical expression of the severity of lung disease, which could be explained by the influence of modulating genes1 that are probably related to the efficiency of host immune factors in fighting against infection in patients' lungs.
Mannose binding lectin, a protein of the innate immune system, is involved in opsonisation and phagocytosis of micro-organisms. The mannose binding lectin gene shows three major allelic variants that are responsible for a decrease of the protein plasma concentration, an opsonic defect, and a common immunodeficiency.2
We investigated the possible modulating role of mannose binding lectin because studies have shown (a) that homozygosity or compound heterozygosity for mannose binding lectin variant alleles predisposes to recurrent infections including lung infections and (b) that Staphyloccus aureus and Pseudomonas aeruginosa—the two most common and deleterious pathogens found in lung infections in patients with cystic fibrosis—have been cultured from patients deficient in this gene.3–4
Subjects, methods, and results
We studied the association between the allelic variants of mannose binding lectin and phenotypical criteria describing the severity of pulmonary disease, such as spirometric measurement of forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and bacteriological examination of the sputum.
To avoid any phenotypical heterogeneity as a result of allelic heterogeneity in the cystic fibrosis transmembrane regulator gene, we identified, in association with the National Observatory for Cystic Fibrosis, the homogenous ∂F508 homozygous population with cystic fibrosis from adult and pediatric respiratory hospital units in France. The DNA of 164 patients was genotyped by means of denaturing gradient gel electrophoresis.5 We identified 11 patients homozygous or compound heterozygous for mutations of mannose binding lectin (mean (SD) age 19.0 (11.1) years). To avoid the influence of sex and age factors, each of these patients was paired with the patient of the same sex with wild type alleles of mannose binding lectin who was the closest in age from the whole population of 164 patients (mean (SD) age of the 11 controls 20.8 (10.4) years). Paired t test and McNemar test were then performed to compare these two groups.
Analysis of the data shows a significant decrease in FEV1 and FVC values in the group of patients homozygous or compound heterozygous for mutations of the mannose binding lectin gene compared with the group of patients homozygous for its wild type allele (table). In addition, we observed a higher frequency of colonisation by P aeruginosa in patients homozygous for mutated alleles of the mannose binding lectin gene than in patients with its wild type alleles, although the value was not significant in the studied population. Data for patients heterozygous for the mannose binding lectin gene are not significant and require further studies on a larger group.
Comment
The data show that the gene product of mannose binding lectin behaves as a modulating factor of the respiratory involvement in cystic fibrosis and that alleles of the protein's mutants are associated with earlier degradation of pulmonary function in ∂F508 homozygous patients with cystic fibrosis. The changes in the values of the respiratory variables between the patient groups (≥30% for FVC and FEV1) are high, which suggests that these effects are clinically relevant.
These results may also have clinical implications. Screening for patients with cystic fibrosis with deficient activity of mannose binding lectin would permit the identification of people in whom an increased risk of pulmonary infection may lead to a greater alteration of the respiratory function. These patients should benefit from a more intense follow up and adapted clinical care.
Table.
Clinical markers split by mannose binding lectin genotype
| Variable | Mannose binding lectin genotype
|
Mean difference | 95% CI | P value | |
|---|---|---|---|---|---|
| Wild type (n=11) | Homozygous or compound heterozygous (n=11) | ||||
| Mean FEV1 (% predicted) | 75.7 | 46.8 | 28.9 | 2.5 to 55.3 | 0.04* |
| Mean FVC (% predicted) | 88.8 | 63.2 | 25.6 | 1.1 to 52.5 | 0.05* |
| % positive for P aeruginosa | 36.3 | 81.8 | 0.08† | ||
Paired t test.
McNemar test with Yates correction. Clinical data for the 164 subjects in the study are as follows: mean FEV1=63.2; mean FVC=77.4; % positive for P aeruginosa=51.5. Nearly half of the population comes from adult centers.
Acknowledgments
We thank Professor J Y Le Gall and Dr M Blayau, Hôpital Pontchaillou, Rennes; Professor Ph Roussel and Dr V Dumur, Hôpital Calmette, Lille; Professor Navarro, Dr A Munck, and Dr E Denamur, Hôpital Robert Debré, Paris; Dr D Hubert and Dr T Bienvenu, Hôpital Cochin, Paris; Professor C Ferec, Brest; and Dr G Rault, Centre Héliomarin de Roscoff, for providing us with DNA samples.
Footnotes
Funding: This study was supported by a grant from the Association Française de Lutte contre la Mucoviscidose.
Competing interests: None declared.
References
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