INTRODUCTION: According to hospital-based studies, increased susceptibility to certain infections is associated with genotypes that cause low serum levels of the protein mannose-binding lectin (MBL). However, the contribution of MBL insufficiency to the incidence of common childhood infections on a population basis is unknown. To investigate the effect of MBL insufficiency on the risk of acute respiratory infections (ARI) in unselected children, we performed a prospective population-based study of ARI in young children in Sisimiut, Greenland. MATERIAL AND METHODS: An open cohort of children aged 0-2 years was formed in 1996, and followed up with weekly morbidity surveillance visits for a two-year period. Episodes of ARI were diagnosed on medical history and clinical examinations. MBL genotypes were determined from blood samples according to the presence of structural alleles and promoter alleles. RESULTS: Altogether 294 children participated and 44 refused. Blood samples were taken from 252 participants. A 2.1-fold (95% confidence interval 1.4-3.1) increased risk of ARI was found in MBL-insufficient children compared with MBL-sufficient children (p
BACKGROUND: Individuals genetically deficient of properdin are more susceptible to meningococcal disease. Likewise low concentration or decreased biological activity of mannose-binding lectin (MBL) is associated with higher incidence of bacterial infections during childhood. In this study we report our findings in a Danish family with a remarkably high incidence of meningococcal meningitis-in total four cases, one of them fatal. METHODS: Properdin and MBL were quantified by ELISA and the properdin gene was screened for sequence variations using denaturing high-performance liquid chromatography (DHPLC) and subsequent sequencing of abnormal patterns. The MBL gene was genotyped for the three known variant alleles (B, C and D) as well as three promoter polymorphisms (-221Y/X, -550H/L and +4P/Q). RESULTS: Two out of six males with undetectable properdin activity had meningitis. They had also low MBL serum levels or carried an MBL variant allele, whereas high MBL concentrations were measured in three out of four properdin deficient males--without meningitis. A splice site mutation in exon 10 (c.1487-2A>G) was found in the properdin gene and co segregated with biochemically measured properdin deficiency. CONCLUSION: Our results indicate that a combined deficiency of both properdin and MBL increases the risk of infection with Neisseria meningitidis and stress the importance of epistatic genetic interactions in disease susceptibility.
Genetic factors may predispose critically ill patients to increased risk of developing sepsis. Mannose-binding lectin (MBL) is an important factor in innate immune defense. We investigated whether MBL gene polymorphisms causing low levels of MBL are associated with the development and progression of sepsis in adult patients in intensive care units. In 272 prospectively monitored patients with systemic inflammatory response syndrome, different MBL genotypes were compared, with respect to microbiology, sepsis development, and survival. The presence of MBL variant alleles was associated with the development of sepsis, severe sepsis, and septic shock. An increased risk of fatal outcome was observed in patients carrying variant alleles. These data show that MBL insufficiency plays an important role in the susceptibility of critically ill patients to the development and progression of sepsis and confers a substantial risk of fatal outcome.
C1q deficiency is a rare condition associated with a systemic lupus erythematosus (SLE)-like syndrome and recurrent infections. Here we present the molecular basis behind C1q deficiency in three sisters of Inuit origin. Initial examination for complement deficiency showed no function of the classical complement activation pathway in the patients; the lectin and alternative pathways were intact. No C1q or low molecular weight C1q was detected in sera and no anti-C1q autoantibodies were found. Sequencing of the C1q genes revealed a novel missense mutation (Gly-Arg) in codon 217 of the B chain. All sisters were homozygous for the mutation: both parents were heterozygous. None of 100 healthy controls carried the mutation. Our findings define a third class of molecular mechanisms behind C1q deficiency, where missense mutations cause a lack of detectable C1q-antigen in serum.
BACKGROUND: Patients with rheumatoid arthritis (RA) have increased risk of atherosclerosis and cardiovascular disease (CVD) that cannot be explained by excess of traditional risk factors. Several studies indicate that mannose-binding lectin (MBL) may modify the development of atherosclerosis; both high and low serum levels of MBL are reported to be associated with CVD. Intima-media thickness of the common carotid artery (ccIMT) is a validated non-invasive anatomic measure of subclinical CVD. We examined the relation between ccIMT and MBL in 114 RA patients. METHODS: In a cross-sectional study MBL2 genotypes and serum concentrations of MBL were assessed; ccIMT was determined by means of ultrasonography; traditional and RA related cardiovascular risk modifiers were measured. RESULTS: The median ccIMT was 0.67 mm. The investigated MBL2 genotypes were not significantly associated with ccIMT. Using a general linear model, ccIMT was not linearly associated with serum MBL but was highly associated with the quadratic term of serum MBL (MBL(2)) (P=0.001) reflecting a U-shaped relation. MBL(2) was also significantly associated with ccIMT in a multivariable analysis adjusting for traditional and RA related cardiovascular risk modifiers (P=0.025). CONCLUSION: In RA patients, a quadratic U-shaped relation between serum MBL and ccIMT was observed independently of the effects of traditional and RA related risk factors for CVD. These results provide further support to the notion that both high and low levels of MBL may be associated with CVD.
Mannose-Binding Lectin (MBL) is a prognostic marker in pulmonary diseases. Ficolins, sharing many structural and functional similarities with MBL, may also be involved in the pathogenesis of pulmonary diseases. The objectives of the study were to establish whether plasma concentrations of Ficolin-2, -3, and MBL in Danish patients with sarcoidosis and control persons differed and whether they were of prognostic significance. We retrospectively included 46 consecutive patients (26 male, 20 female) and 51 age- and sex-matched healthy control persons (28 male, 23 female). Information about the patients was obtained from their medical records. We measured plasma concentrations of Ficolin-2, -3, and MBL using ELISA. There was a significant difference in the patients' mean Ficolin-3 plasma level (14.9 microg/ml; +/-2SD: 6.7-23.1) compared with the control persons' (21.6 microg/ml; +/-2SD: 12.7-30.5). The difference was 6.7 microg/ml (95% CI: 5.0-8.4 microg/ml; p
Patients with systemic lupus erythematosus (SLE) have excess cardiovascular morbidity and mortality due to accelerated atherosclerosis that cannot be attributed to traditional cardiovascular risk factors alone. Variant alleles of the mannose-binding lectin gene (MBL2) causing low serum concentrations of functional mannose-binding lectin (MBL) are associated with SLE and development of atherosclerosis. Recent studies show that these variant alleles are associated with increased risk of arterial thrombosis and cardiovascular disease in patients with SLE. Intima-media thickness of the common carotid artery (ccIMT) is a validated noninvasive anatomic measure of subclinical atherosclerosis. In a cross-sectional study we examined the relation among ccIMT, MBL2 genotypes, and serum concentrations of MBL.
The MBL2 extended genotypes (YA/YA, YA/XA, XA/XA, YA/YO, XA/YO, YO/YO) and serum concentrations of MBL were determined in 41 outpatients with SLE. ccIMT was measured by means of ultrasonography. Traditional and nontraditional cardiovascular risk modifiers were assessed and controlled for.
Using nonparametric Mann-Whitney tests we found a significant difference in ccIMT between low-expressing (XA/XA+YA/YO+XA/YO+YO/YO) and high-expressing (YA/YA+YA/XA) MBL2 genotypes (p = 0.034). The difference in ccIMT remained significant in multivariable analysis adjusting for traditional and nontraditional cardiovascular risk modifiers (p = 0.049). ccIMT was negatively correlated to serum concentrations of MBL (Spearman rho = -0.33, p = 0.037). This relation also remained significant in multivariable analysis (p = 0.042).
In this group of SLE patients, MBL2 low-expressing genotypes and low serum levels of MBL were correlated with ccIMT, independent of the effects of traditional and nontraditional cardiovascular risk modifiers.
In Denmark, patients with serious nonspecific symptoms and signs of cancer (NSSC) are referred to the diagnostic outpatient clinics (DOCs) where an accelerated cancer diagnostic program is initiated. Various immunological and inflammatory biomarkers have been associated with cancer, including soluble urokinase plasminogen activator receptor (suPAR) and the pattern recognition receptors (PRRs) pentraxin-3, mannose-binding lectin, ficolin-1, ficolin-2 and ficolin-3. We aimed to evaluate these biomarkers and compare their diagnostic ability to classical biomarkers for diagnosing cancer in patients with NSSC. Patients were included from the DOC, Department of Infectious Diseases, Copenhagen University Hospital Hvidovre. Patients were given a final diagnosis based on the combined results from scans, blood work and physical examination. Weight loss, Charlson score and previous cancer were registered on admission, and plasma concentrations of biomarkers were measured. The primary outcome was incident cancer within 1 year. Out of 197 patients included, 39 patients (19.8%) were diagnosed with cancer. Patients with cancer were significantly older and had a higher burden of comorbidities and previous cancer diagnoses compared to patients who were not diagnosed with cancer. Previous cancer, C-reactive protein (CRP) and suPAR were significantly associated with newly diagnosed cancer during follow-up in multiple logistic regression analyses adjusted for age, sex and CRP. Neither any of the PRRs investigated nor self-reported weight loss was associated with cancer. In this study, previous cancer, CRP and suPAR were significantly associated with cancer diagnosis in patients with NSSC. Ficolin-1-3, MBL and pentraxin-3 were not associated with cancer.
Disturbance of the pro-coagulatant and anti-coagulant balance is associated with a poor outcome from critical illness. The objective of this study is to determine whether the Factor V Leiden (FVL) mutation is associated with susceptibility to or death from critical illness.
A genetic association study involving four case cohorts comprising two Gram negative sepsis, one invasive pneumococcal disease and one intensive care unit cohort with a total of 1,249 patients. Controls were derived from a population-based cohort study (N = 8,147). DNA from patients and controls was genotyped for the FVL mutation.
When all patients were investigated together no significant difference in the frequency of FVL mutation was observed compared with controls (odds ratio (OR), 1.03; 95% confidence interval (CI), 0.83 to 1.29). However, when stratified among patients admitted to intensive care (N = 237), susceptibility and the likelihood of long-term death was influenced by the FVL mutation. In adjusted logistic regression analysis, FVL carriers had an increased risk of ICU admission compared to non-carriers (OR 1.62; 95% CI, 1.08 to 2.42). In adjusted Cox regression analysis, FVL carriers were at increased risk of long-term death compared to non-carriers (relative risk 1.78; 95% CI, 1.13 to 2.81). FVL carrier status did not predict either susceptibility to or outcome from Gram negative, Escherichia coli or Streptococcus pneumoniae sepsis.
Overall, the FVL mutation did not appear to increase the risk of admission due to severe invasive infections. Nevertheless, in the subgroup of patients admitted to intensive care an increased risk and a poorer long-term outcome for individuals with critical illness were observed for FVL mutation carriers.
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Mannose-binding lectin (MBL) and ficolins activate the complement cascade, which is involved in atherogenesis. Based on a pilot study, we hypothesized that functional polymorphisms in the MBL gene (MBL2) leading to dysfunctional protein are related to development of myocardial infarction (MI). The aim of the present study was to study polymorphisms in MBL2 and ficolin genes in relation to the risk of MI.
Using the population-based HUNT Study in Norway, 57,133 persons were followed up for a first-time MI from 1995-1997 until the end of 2008. The 370 youngest MI patients were matched by age (range 29-62 years) and gender to 370 controls. A younger population was selected because disease in this group might be less dependent on non-genetic risk factors. The study size was based on power calculation. Polymorphisms in MBL2 and in the genes of ficolin-1, ficolin-2 and ficolin-3 were genotyped by pyrosequencing and related to the risk of MI, estimated as odds ratios (OR). Functional haplotypes were analyzed and stringent alpha levels of significance were set by permutation testing. Variant MBL2 haplotypes causing MBL deficiency were associated with a two-fold higher risk of MI (OR 2.04, 95%CI 1.29-3.24). Adjustments for conventional cardiovascular risk factors did not substantially influence the association. The ficolins were not associated with MI risk.
In a young to middle aged and relatively healthy Caucasian population, MBL2 variants related to functional MBL deficiency were associated with a doubling of the risk for MI, independent of conventional risk factors. This supports that MBL deficiency may lead to increased atherosclerosis or development of vulnerable plaques.