Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis

Abstract

Mannose-binding lectin (MBL) is a key factor in innate immunity, and lung infections are the leading cause of morbidity and mortality in cystic fibrosis (CF). Accordingly, we investigated whether MBL variant alleles, which are associated with recurrent infections, might be risk factors for CF patients. In 149 CF patients, different MBL genotypes were compared with respect to lung function, microbiology, and survival to end-stage CF (death or lung transplantation). The lung function was significantly reduced in carriers of MBL variant alleles when compared with normal homozygotes. The negative impact of variant alleles on lung function was especially confined to patients with chronic Pseudomonas aeruginosa infection. Burkholderia cepacia infection was significantly more frequent in carriers of variant alleles than in homozygotes. The risk of end-stage CF among carriers of variant alleles increased 3-fold, and the survival time decreased over a 10-year follow-up period. Moreover, by using a modified life table analysis, we estimated that the predicted age of survival was reduced by 8 years in variant allele carriers when compared with normal homozygotes. Presence of MBL variant alleles is therefore associated with poor prognosis and early death in patients with CF.

Figure 1

MBL serum concentration in CF patients in relation to MBL structural alleles as well as the MBL promoter alleles in position –221 (X/Y). Boxes are interquartile ranges. Bars show range from 10th to 90th percentiles. The detection limit in the assay is 20 μg/L.

Figure 2

The lung function (FVC and FEV1, expressed as percentages) measured from 1989 to 1997 was stratified according to A/A (n = 96) and the X/Y promoter (base substitution in position –221) on the functional A chromosome in structural MBL allele heterozygotes (YA/0, n = 34; and XA/0, n = 15) and those with homozygous defect (0/0, n = 4). The numbers refer to those included in the study in 1989. Mean is indicated. The general improvement in lung function data from 1995 to 1997 probably is due to a combination of the change in analyzing equipment, the number of dropouts, and improved treatment.

Figure 3

The lung function (FVC and FEV1, expressed as percentages) measured from 1989 to 1997 was stratified according to whether it belonged to the MBL-sufficient group (A/A and YA/0; n = 130) or the MBL-insufficient group (XA/0 and 0/0; n = 19). The numbers refer to those included in the study in 1989. Mean and SE are indicated. The individual P values (Mann-Whitney U test) each year are given.

Figure 4

Lung function at 8 and 16 years of age. Parallel lung function (FEV1, expressed as a percentage) in CF patients at 8 and 16 years of age was stratified according to whether they belonged to the MBL-sufficient group (A/A and YA/0; n = 75) (open boxes) or the MBL-insufficient group (XA/0 and 0/0; n = 10) (gray boxes). Boxes are interquartile ranges. Bars show range from 10th to 90th percentiles.

Figure 5

Kaplan-Meier plot for 10 years, ranging from date of inclusion in 1989 to 1999, of survival rate of CF patients. Events are defined as date of death (n = 14) and lung transplantation (n = 12) (end-stage CF). Thin line indicates A/A patients, and thick line indicates variant allele carriers (A/0 and 0/0).

Figure 6

A modified life table analysis (annual age-specific mortality rate) that adjusts for age differences at inclusion. The figure shows that the expected median survival age in A/A patients was 36 years, compared with 28 years in carriers of variant alleles (A/0 and 0/0).