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.

Genetic polymorphisms in molecules of innate immunity and susceptibility to infection with Wuchereria bancrofti in South India

“…Structural variants have been associated with a wide range of infectious and autoimmune disorders. [38][39][40] In our study, there was no association observed between the structural variants of MBL2 and susceptibility to filarial infection. However, we found a possible association between the promoter polymorphism at bp −221 (designated X and Y) and resistance to infection; filarial infection is less common in individuals with the XX genotype, associated with decreased circulating levels of MBL, independent of the structural allele genotype.…”

“…The classification of haplotypes as sufficient and insufficient is well described and separates into two groups, based upon circulating levels and functional differences in vitro, secondary to a structural variant (B, C or D). 39 Comparative analysis was performed at each of three loci using a 2 analysis (3 × 2 tables with 2 degrees of freedom) or a Fisher's exact test (f). MF+ indicates asymptomatic microfilaremia and CP indicates chronic lymphatic obstruction/ elephantiasis or hydrocele, collectively also known as chronic pathology.…”

Association of MBL gene polymorphisms with major bacterial infection in patients treated with high-dose chemotherapy and autologous PBSCT

“…4 MBL deficiency is associated with infection in infants with immature immunity, 8,9 and patients with autoimmune disorders 10 and cystic fibrosis. 11,12 An association of MBL deficiency and infection is also reported in patients treated with conventional chemotherapy 13,14 or high-dose myeloablative chemotherapy followed by allogeneic stem cell transplantation, 15 which is not confirmed by others. 16,17 In the present study, we report an increased risk of major bacterial infection in patients carrying the MBL polymorphism when treated with high-dose chemotherapy (HDT) followed by autologous peripheral blood stem cell transplantation (auto-PBSCT).…”

Sequence analysis of the mannose-binding lectin (MBL2) gene reveals a high degree of heterozygosity with evidence of selection

“…[35][36][37] Structural exon 1 variants in MBL2 appear to modify pulmonary outcome in cystic fibrosis (CF) and rheumatological outcomes in chronic granulomatous disease. [38][39][40] We hypothesized that if there has been recent selection on MBL2 common genetic variation could result in selectively advantageous innate immune responses, depending upon the challenge. Moreover, the extent of linkage disequilibrium (LD) and haplotype diversity across MBL2 could provide signatures for selective pressure, however complex, and provide insight into whether the common alleles, B, C and D, have been maintained under balanced selection.…”