Mechanisms of DiseaseMBL genotype and risk of invasive pneumococcal disease: a case-control study
Introduction
Infection with Streptococcus pneumoniae is a major cause of morbidity and mortality worldwide. In developed countries, it is the main infectious cause of death and the most common cause of community-acquired bacteraemia in adults.1 In developing countries, it is a leading cause of mortality in children younger than 5 years of age, and probably accounts for over a million deaths annually.2 Although the organism is commonly found harmlessly colonising the mucosa of the upper respiratory tract, invasion can lead to pneumonia, bacteraemia, and meningitis with reported case-fatality rates of 7%, 20%, and 30%, respectively.1 The extent to which host genetics might influence susceptibility to invasive pneumococcal disease is unknown, and, unlike other major infectious causes of mortality, no susceptibility or resistance genes have been defined.
A protein belonging to the collectin group— mannose-binding lectin (MBL, also called mannose-binding protein)—is a calcium-dependent lectin produced in the liver during the acute-phase response to infection.3 Its function in host defence has been of interest since early studies showed it to bind baker's yeast mannans, opsonise some bacteria, and affect infection of lymphoblasts by HIV-1.4, 5 Two potentially protective functions are well defined. First, binding of mbl-associated serine proteases (MASP) leads to activation of the complement cascade independently of antibody;6 and second, MBL opsonises bacteria by binding to specific surface oligosaccharides, particularly N-acetyl glucosamine and mannose.4
The MBL gene on chromosome 10 encodes a homotrimeric molecule with a carbohydrate recognition domain and a collagenous tail.7 Formation of a triple helix in the collagenous tail is impaired by mutation in any one of codons 52, 54, or 57 (denoted variants D, B, and C, respectively), and this impaired helix formation disrupts polymerisation and leads to enzymatic degradation and functional deficiency of MBL.3, 8, 9 These three codon variants are very common: heterozygote and homozygote frequencies are about 33% and 5% in most populations.9 Sequence variation in the promoter region of the gene has also been described, and a single base-pair change at position -221 is common in white individuals.10 Concentrations of MBL in serum are about 20% lower in heterozygotes for any codon variant than in individuals with none of the mutations, and are very low (typically <2%) or absent in homozygotes or individuals heterozygous for two different codon mutations (hereafter simply termed homozygotes).9, 10 The -221 promoter G→C change, present in about 40% of Europeans, is the most relevant non-coding polymorphism and has a smaller but detectable effect on concentrations of MBL in serum.10
Results of clinical studies have shown associations between MBL codon mutations and hospital admissions due to infection in children,11 susceptibility to infection in patients with systemic lupus erythematosus,12 and a heterogeneous group of immunodeficiencies.13 MBL deficiency has also been associated with increased episodes of acute respiratory infection, but not acute otitis media, in children from Greenland.14, 15 However, there are no established associations between MBL deficiency and susceptibility to diseases caused by specific pathogens, since evidence is conflicting and studies limited.16, 21 In this study, we compare the frequency of the three codon mutations and the -221 promoter polymorphism in a large-scale investigation of cases of invasive pneumococcal disease and controls.
Section snippets
Patients and controls
Patients with invasive pneumococcal disease were recruited from three hospitals (John Radcliffe, Horton General, and Wycombe General Hospitals) in Oxfordshire, UK, as part of the enhanced active surveillance of the disorder. Controls were selected randomly from adult volunteer donors to the Oxford Blood Transfusion Service and from transplant donors. Individuals with non-UK ancestry were excluded, and all patients and controls were white. Further controls for a confirmatory study were 679
Results
229 consecutive patients with invasive pneumococcal disease and 353 controls were initially enrolled in the study. The patients were aged 0–94 years, mean age 59 years (SD 25·2). Eight were younger than 1 year, and 23 were younger than 10 years; 51% were male. 40 patients died in hospital and 46 died during follow up. The median duration of hospital stay for survivors was 10 days. The ages of the controls ranged from 23 to 62 years, and the mean of the 96 for whom age was known was 40 years (SD
Discussion
This study has shown an association between MBL genotype and risk of invasive pneumococcal disease in a population of white individuals. The primary analysis was a comparison of genotype frequencies defined by mutations in the first exon of the MBL gene in patients with invasive pneumococcal disease and controls. Functional mutant homozygotes—ie, individuals who are either homozygous for one MBL codon variant or doubly heterozygous for two different codon variants and have little or no serum
GLOSSARY
- allele-specific oligonucleotide hybridisation
- A technique used to detect DNA sequence differences by means of differential binding of DNA probes specific for each genetic variant.
- collectin
- A collagenous lectin, a sugar-binding molecule with a collagen-like structural domain.
- hardy-weinberg equilibrium
- A proportionality between the frequencies of heterozygotes and homozygotes for a genetic variant in the population determined by Mendel's laws of inheritance.
- ligation-detection reaction
- A method of
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