Severe sepsis and septic shock are a primary cause of death in patients in intensive care unit (ICU). Investigations upon genetic susceptibility profile to systemic complications during severe infections are a field of increasing scientific interest. Particularly when adaptive immune system is compromised or immature, innate immunity plays a key role in the immediate defense against invasive pathogens. Mannose-binding lectin (MBL) is a serum protein that recognizes a wide range of pathogenic microorganisms and activates complement cascade via the antibody-independent pathway. More than 30% of humans harbor mutations in MBL gene (MBL2) resulting in reduced plasmatic levels and activity. Increased risk of infection acquisition has been largely documented in MBL-deficient patients, but the real impact of this form of innate immunosuppression upon clinical outcome is not clear. In critically ill patients higher incidence and worse prognosis of severe sepsis/septic shock appear to be associated with low-producers haplotypes. However an excess of MBL activation might be also harmful due to the possibility of an unbalanced proinflammatory response and an additional host injury. Strategies of replacement therapies in critically ill patients with severe infections are under investigation but still far to be applied in clinical practice.

Mannose-binding lectin (MBL) insufficiency due to polymorphisms in the MBL2 gene causes an opsonization defect, which has been connected to infections and atopy. We investigated the significance of MBL2 genotypes with regard to persistent asthma and atopy among adults. The genotypes were determined in 243 adults with persistent asthma and 400 controls. Atopy was determined by skin-prick test. As a result, the carriage of -221 base pairs (bp) promoter region variant allele X (nucleotide change G->>C; alleles Y->>X, respectively) causing low MBL expression proved to be a significant risk factor for asthma in non-atopic males [odds ratio (OR) = 2.52, 95% confidence interval (CI) = 1.23-5.15; P = 0.01]. Furthermore, the X-allele carriage was associated with the decrease in lung function (forced expiratory volume at 1 s, FEV(1)) during follow-up in the patients with asthma (P = 0.033), the effect being strongest for non-atopic asthmatics (P = 0.042). The MBL2 genotype had no clear effect on the occurrence of atopy in adults. In conclusion, our results abrogate the previously suggested predisposing effect of MBL insufficiency on atopy at least in adults. However, as MBL is a complement component participating in immune defence against microbes, and as in the pathogenesis of non-atopic asthma infectious agents are probably involved, the gene-environment interactions between MBL and infections should be assessed further with regard to asthma.

OBJECTIVE

Mannan-binding lectin (MBL) is present in serum and synovial fluid; its levels vary widely, and the variations are strongly associated with polymorphisms in the MBL2 gene. Studies have compared MBL in patients with rheumatoid arthritis (RA) and in unrelated controls, but the findings have been contradictory. In the first family-based study, we compared MBL levels in patients with RA to population controls and also to their nonaffected first-degree relatives, who may be regarded as optimal controls because of less genetic variation.

METHODS

Serum levels of MBL and rheumatoid factor were analyzed in 210 patients with RA and 406 of their first-degree relatives from 74 extended families. Population controls for MBL levels were 330 randomly selected adult Icelanders.

RESULTS

Patients with RA had higher MBL levels in serum (median 1553 microg/l) than their first-degree relatives (1073 microg/l; p = 0.003) and the unrelated controls (938 microg/l; p < 0.0001). No association was found between MBL and rheumatoid factor.

CONCLUSIONS

Patients with RA had markedly higher MBL levels than their close relatives and controls, indicating that high MBL may predispose to RA. As MBL has been shown to bind potential arthritogenic agents including modified immunoglobulins, cellular debris, and microorganisms, our findings suggest that high MBL could trigger complement mediated inflammation within joints.

Mannose-binding lectin (MBL) is an evolutionarily conserved protein that functions in human innate immunity by binding to microbial surfaces and promoting opsonophagocytosis. MBL has been shown to bind to Cryptosporidium sporozoites, and earlier work has suggested that the protective role of MBL may be most important in childhood. We evaluated the association between polymorphisms in the MBL gene (MBL2), serum MBL deficiency, and infection with Cryptosporidium, Entamoeba histolytica, and Giardia intestinalis in children. A large, prospective cohort of Bangladeshi preschool children was followed up for >3 years. Clinical outcomes, serum MBL levels, and MBL2 polymorphisms and haplotypes were determined. Statistically significant associations with E. histolytica and G. intestinalis were not found. Serum MBL deficiency, polymorphisms in the -221 promoter region, and the YO/XA MBL2 haplotype were strongly associated with Cryptosporidium infections, particularly recurrent infection. Children with multiple infections with Cryptosporidium were more likely to be MBL deficient (odds ratio [OR], 10.45), carry the -221 promoter variant (OR, 4.02), and have the YO/XA haplotype (OR, 4.91). We have identified a potentially important component of the human innate immune response to Cryptosporidum infection. Further work is needed to evaluate the mechanism of protection of MBL in Cryptosporidium infection.

OBJECTIVE

The influence of functional polymorphisms in the genes coding for mannose-binding lectin (MBL) and interleukin-1 receptor antagonist (IL-1ra) on recurrent vulvovaginal candidiasis (RVVC) were examined in an urban Brazilian population.

METHODS

DNA was isolated from buccal swabs of 100 women with RVVC and 100 control women and tested by gene amplification for a single nucleotide polymorphism in codon 54 of the MBL2 gene and for a length polymorphism in intron 2 of the IL1RN gene. Genotype and allele frequencies were compared between groups.

RESULTS

The frequency of the variant MBL2 B allele, associated with reduced circulating and vaginal MBL concentrations, was 27.0% in RVVC and 8.5% in control women (p < .0001). The MBL2 B,B genotype was present in 12% of RVVC patients and 1% of controls (p = .0025). The IL1RN 2 allele frequency, associated with the highest level of unopposed IL-1β activity, was 24.0% in RVVC and 23.4% in controls. The IL1RN genotype distribution was also similar in both groups.

CONCLUSIONS

Carriage of the MBL2 codon 54 polymorphism, but not the IL1RN length polymorphism, predisposes to RVVC in Brazilian women.

BACKGROUND

Mannose-binding lectin (MBL) is a key molecule of the innate immune system and, in addition to the classical and alternative pathways, a principle driver of complement activation. Genetic mutations of MBL are common, result in low serum levels of MBL, and are associated with increased infection risk in solid-organ transplant recipients.

METHODS

We performed a retrospective study of MBL2 genotype and plasma and bronchoalveolar lavage (BAL) MBL levels in 37 lung transplant recipients (LTR). Plasma MBL levels were measured pretransplant and both plasma and BAL MBL levels were measured at 3, 6, and 12 months after lung transplantation. MBL2 genotyping was performed on recipient and donor peripheral blood mononuclear cells. Clinical variables analyzed included primary graft dysfunction, intensive care unit stay, acute allograft rejection, infection, bronchiolitis obliterans syndrome (BOS), and mortality.

RESULTS

Plasma MBL levels posttransplant were predicted by recipient, and not donor MBL2 genotype. Compared with pretransplant levels, plasma MBL was significantly increased at 3, 6, and 12 months posttransplant (P<0.05). LTR who developed BOS or died during the study period had higher plasma MBL levels at 6 and 12 months posttransplant (P ≤ 0.05) compared with LTR with stable graft function. MBL was not routinely detected in the lung allograft; however if present in the BAL at 3 and 6 months posttransplant, it was associated with the later development of BOS (P<0.05).

CONCLUSIONS

Plasma MBL levels increase after lung transplantation and persistently increased MBL levels are associated with poor long-term outcomes.

OBJECTIVE

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.

RESULTS

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.

CONCLUSIONS

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.

Children with cancer often have fever during chemotherapy-induced neutropenia, but only some develop serious infectious complications. Mannose-binding lectin (MBL) deficiency might increase infection susceptibility in these children. MBL genotype and phenotype were prospectively determined in 110 paediatric oncology patients. During febrile neutropenia, MBL concentrations were measured longitudinally in time. MBL genotype and phenotype were correlated to clinical and laboratory parameters. Structural exon-1 MBL2 mutations and the LX promoter polymorphism lead to deficient MBL concentrations. The capacity to increase MBL concentrations during febrile neutropenia was associated with MBL2 genotype. Infectious parameters did not differ between MBL-deficient and MBL-sufficient neutropenic children (n = 66). In contrast, MBL-sufficient patients had a greater risk of Intensive Care admittance (Relative Risk 1.6, 95% Confidence Interval 1.3-2.0, P = 0.04). MBL-deficient neutropenic children did not have more severe infections. However, most patients (61%) were severely neutropenic (<100 cells/microL), compromising the opsonophagocytic effector function of MBL. MBL substitution might still be beneficial in patients with phagocytic activity.

BACKGROUND

Albuminuria, a common marker of kidney damage, serves as an important predictive factor for the progression of kidney disease and for the development of cardiovascular disease. While the underlying etiology is unclear, chronic, low-grade inflammation is a suspected key factor. Genetic variants within genes involved in inflammatory processes may, therefore, contribute to the development of albuminuria.

METHODS

We evaluated 60 polymorphisms within 27 inflammatory response genes in participants from the second phase (1991-1994) of the Third National Health and Nutrition Examination Survey (NHANES III), a population-based and nationally representative survey of the United States. Albuminuria was evaluated as logarithm-transformed albumin-to-creatinine ratio (ACR), as ACR ≥ 30 mg/g, and as ACR above sex-specific thresholds. Multivariable linear regression and haplotype trend analyses were conducted to test for genetic associations in 5321 participants aged 20 years or older. Differences in allele and genotype distributions among non-Hispanic whites, non-Hispanic blacks, and Mexican Americans were tested in additive and codominant genetic models.

RESULTS

Variants in several genes were found to be marginally associated (uncorrected P value < 0.05) with log(ACR) in at least one race/ethnic group, but none remained significant in crude or fully-adjusted models when correcting for the false-discovery rate (FDR). In analyses of sex-specific albuminuria, IL1B (rs1143623) among Mexican Americans remained significantly associated with increased odds, while IL1B (rs1143623), CRP (rs1800947) and NOS3 (rs2070744) were significantly associated with ACR ≥ 30 mg/g in this population (additive models, FDR-P < 0.05). In contrast, no variants were found to be associated with albuminuria among non-Hispanic blacks after adjustment for multiple testing. The only variant among non-Hispanic whites significantly associated with any outcome was TNF rs1800750, which failed the test for Hardy-Weinberg proportions in this population. Haplotypes within MBL2, CRP, ADRB2, IL4R, NOS3, and VDR were significantly associated (FDR-P < 0.05) with log(ACR) or albuminuria in at least one race/ethnic group.

CONCLUSIONS

Our findings suggest a small role for genetic variation within inflammation-related genes to the susceptibility to albuminuria. Additional studies are needed to further assess whether genetic variation in these, and untested, inflammation genes alter the susceptibility to kidney damage.

Mannose-binding lectin (MBL) plays an important role in innate immunity mediating phagocytosis and activating the MBL complement pathway. Few studies, conducted in adult populations, have shown that genetically determined low MBL levels may confer partial protection against tuberculosis (TB). In this study we aimed to investigate the relationships between the susceptibility to TB and two low producing MBL2 gene polymorphisms (codons 54 and 57) and MBL levels in children. Forty-four TB children (27 pulmonary TB, 17 extrapulmonary TB) and 99 age-matched healthy control children were included in the study. The mean age in the study group was 7.02 +/- 4.5 years. Genotyping of the MBL2 gene for codon 54 and 57 polymorphisms was carried out, and MBL levels in serum were also detected in all subjects from both groups. None of the subjects from either group showed codon 57 polymorphisms. The frequency of the AB genotype which produces low level MBL is significantly lower in the patients (9.1%) compared to control subjects (27.3%) (p < 0.011). The difference was especially significant between the extrapulmonary group and healthy controls (p < 0.006). The BB genotype was observed in only one child from the healthy controls and no children from the patient group. The median MBL plasma concentration was also significantly lower in the control group than that found in the study group (p = 0.036). These results indicate that low levels of MBL and AB genotype may be involved in the protection against tuberculosis, especially extrapulmonary tuberculosis in children.

OBJECTIVE

To investigate the association of mannose-binding lectin (MBL)-deficient genotypes with cardiovascular disease in a large series of patients with systemic lupus erythematosus (SLE).

METHODS

A total of 114 patients diagnosed with SLE were included in the study. MBL polymorphisms were investigated by sequencing-based DNA typing of the promoter and exon 1 of the MBL2 gene. The genotypes 0/0, 0/XA and XA/XA were considered as MBL-low genotypes.

RESULTS

A higher prevalence of cardiovascular disease was observed in patients carrying MBL-low genotypes compared with those carrying MBL-high genotypes [30 vs 9%, P = 0.012, odds ratio (OR) 4.54, 95% confidence interval (CI) 1.20-16.46]. Patients with MBL-low genotypes also presented higher mean values for total cholesterol (228.6 vs 202.3 mg/dl, P = 0.017) and low-density lipoprotein (LDL) cholesterol (139.9 vs 121.9 mg/dl, P = 0.045), a higher frequency of chronic renal failure (30 vs 4%, P = 0.001), vasculitis (30 vs 11%, P = 0.043), heart valve lesions (71 vs 32%, P = 0.026), cardiac valve dysfunction (57 vs 7%, P = 0.0004) and associated APS (39 vs 12%, P = 0.005), a higher mean Systemic Lupus International Collaborating Clinics score (2.09 vs 1.26, P = 0.029) and a lower prevalence of low C4 levels (43 vs 71%, P = 0.015). Multivariate analysis of genetic, clinical and immunological variables showed that only antiphospholipid syndrome (APS) was independently associated with cardiovascular events (P = 0.001).

CONCLUSIONS

Although the prevalence of cardiovascular disease in our SLE patients carrying MBL-deficient genotypes was 3.3 times higher than in patients with non-deficient genotypes, only APS was independently associated with cardiovascular events. This suggests that the higher frequency of thrombotic events in SLE patients carrying MBL-deficient genotypes might be related to coexisting APS.

This paper summarizes the data concerning soluble defense lectins (mannan-binding lectin, M-ficolin, L-ficolin, and H-ficolin) with the unique ability to activate complement and their associated serine proteases (MASPs) in neonates. The clinical importance of deficiencies of these immune factors is presented in aspects of perinatal mortality, premature births, and low birthweight. Prenatal serum concentrations of L-ficolin, H-ficolin, and MASP-2 (and probably M-ficolin) correlate with gestational age and birthweight. The relationship of serum MBL to gestational age is controversial. The MBL2 genotypes XA/O and O/O (associated with low-serum MBL) are associated with perinatal infections, whereas the high serum MBL-conferring A/A genotypes may be associated with prematurity. Low-serum L-ficolin concentrations, but not low-serum H-ficolin concentrations, are also associated with perinatal infections. Much of the literature is inconsistent, and the relationships reported so far require independent confirmation at both gene and protein levels. Our preliminary conclusion is that these soluble defense lectins play a protective role in the neonate, and that insufficiency of such factors contributes to the adverse consequences of prematurity and low birthweight.

OBJECTIVE

This study investigates the role of mannose-binding lectin (MBL) in the susceptibility to HIV-1 infection analyzing polymorphisms located at the MBL2 promoter and exon 1 regions.

METHODS

The prevalence of MBL2 variant alleles was investigated in 410 HIV-1-infected patients from the South Brazilian HIV cohort and in 345 unexposed uninfected healthy individuals. The promoter variants were genotyped using polymerase chain reaction with sequence-specific primers (PCR-SSP) and exon 1 variants were analyzed by real-time PCR using a melting temperature assay and were confirmed by PCR-restriction fragment length polymorphism (RFLP). MBL2 genotypic and allelic frequencies were compared between HIV-1-infected patients and controls using the chi-squared tests.

RESULTS

The analyses were performed subdividing the individuals according to their ethnic origin. Among Euro-derived individuals a higher frequency of the LX/LX genotype was observed in patients when compared to controls (P < 0.001). The haplotypic analysis also showed a higher frequency of the haplotypes associated with lower MBL levels among HIV-1-infected patients (P = 0.0001). Among Afro-derived individuals the frequencies of LY/LY and HY/HY genotypes were higher in patients when compared to controls (P = 0.009 and P = 0.02).

CONCLUSIONS

An increased frequency of MBL2 genotypes associated with low MBL levels was observed in Euro-derived patients, suggesting a potential role for MBL in the susceptibility to HIV-1 infection in Euro-derived individuals.

Upper genital tract infections can inflict inadequate immune response and cause Fallopian tube damage and concomitant female infertility. However, the exact role of host genetic variation in the development of tubal factor infertility remains unclear. We selected nine genetic variations in four genes involved in immune response modulation (CCR5, TLR2, TLR4 and MBL2) and assessed their association with tubal factor infertility by comparing genotype frequencies among 163 women with tubal factor infertility and 400 control individuals. The CCR5, TLR2 and TLR4 genotypes were not associated with tubal factor infertility, although the TLR4 Asp299Gly and Thr399Ile heterozygosity was associated with a decreased incidence of pathogens associated with genital tract infections in tubal factor infertility patients. In contrast, MBL2 low-producing genotypes were associated with an increased incidence of such pathogens. In addition, hyper-producing MBL2 genotype HYA/HYA and low-producing MBL2 genotypes were associated with susceptibility to tubal factor infertility, while a protective effect was associated with the high-producing MBL2 genotype HYA/LYA. Overall, these data suggest that polymorphisms in TLR4 and MBL2 play a role in receptiveness to pathogens causing genital tract infections, while MBL2 genotypes contribute to susceptibility to tubal factor infertility.

OBJECTIVE

To examine whether IgG glycosylation changes and MBL2 genotypes are associated with systemic inflammation and joint destruction in rheumatoid arthritis (RA).

METHODS

IgG N-glycan content was determined from serum in 118 patients with RA by high-throughput glycan analysis using normal-phase high-pressure liquid chromatography. MBL2 extended genotypes (YA/YA, YA/XA, XA/XA, YA/YO, XA/YO, YO/YO) were determined. Systemic inflammation was assessed by serum levels of C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α). Joint destruction was assessed by total Sharp score (TSS) and alloplastic surgery records.

RESULTS

IgG hypogalactosylation was significantly correlated to IL-6 (Spearman's rho = 0.32, p < 0.001), CRP (Spearman's rho = 0.31, p < 0.001), TSS (Spearman's rho = 0.25, p = 0.01), and alloplastic replacement of joints (Spearman's rho = 0.18, p = 0.05). In multivariate analysis including age, CRP, anticitrullinated protein antibodies (ACPA), and other confounders, IgG hypogalactosylation was significantly associated with TSS (p = 0.014) and alloplastic joint replacement (OR 76.5, p = 0.041) in patients homozygous for the high expression MBL2 genotype YA/YA, but not in carriers of lower expression genotypes.

CONCLUSIONS

Decreased galactosylation of IgG correlated to markers of inflammation, i.e., IL-6 and CRP. Only in patients homozygous for high expression of the MBL2 genotype YA/YA was IgG hypogalactosylation associated with markers of joint destruction. Our results suggest that inflammation-associated decreased galactosylation of IgG combined with high expression MBL2 genotypes are involved in the pathophysiology of RA.

BACKGROUND

A subset (approximately 3%-5%) of patients with cystic fibrosis (CF) develops severe liver disease with portal hypertension.

OBJECTIVE

To assess whether any of 9 polymorphisms in 5 candidate genes (alpha(1)-antitrypsin or alpha(1)-antiprotease [SERPINA1], angiotensin-converting enzyme [ACE], glutathione S-transferase [GSTP1], mannose-binding lectin 2 [MBL2], and transforming growth factor beta1 [TGFB1]) are associated with severe liver disease in patients with CF.

METHODS

Two-stage case-control study enrolling patients with CF and severe liver disease with portal hypertension (CFLD) from 63 CF centers in the United States as well as 32 in Canada and 18 outside of North America, with the University of North Carolina at Chapel Hill as the coordinating site. In the initial study, 124 patients with CFLD (enrolled January 1999-December 2004) and 843 control patients without CFLD were studied by genotyping 9 polymorphisms in 5 genes previously studied as modifiers of liver disease in CF. In the second stage, the SERPINA1 Z allele and TGFB1 codon 10 genotype were tested in an additional 136 patients with CFLD (enrolled January 2005-February 2007) and 1088 with no CFLD.

METHODS

Differences in distribution of genotypes in patients with CFLD vs patients without CFLD.

RESULTS

The initial study showed CFLD to be associated with the SERPINA1 Z allele (odds ratio [OR], 4.72; 95% confidence interval [CI], 2.31-9.61; P = 3.3 x 10(-6)) and with TGFB1 codon 10 CC genotype (OR, 1.53; 95% CI, 1.16-2.03; P = 2.8 x 10(-3)). In the replication study, CFLD was associated with the SERPINA1 Z allele (OR, 3.42; 95% CI, 1.54-7.59; P = 1.4 x 10(-3)) but not with TGFB1 codon 10. A combined analysis of the initial and replication studies by logistic regression showed CFLD to be associated with SERPINA1 Z allele (OR, 5.04; 95% CI, 2.88-8.83; P = 1.5 x 10(-8)).

CONCLUSIONS

The SERPINA1 Z allele is a risk factor for liver disease in CF. Patients who carry the Z allele are at greater risk (OR, approximately 5) of developing severe liver disease with portal hypertension.

Hepatocellular carcinoma (HCC) is the world's third most widespread cancer. Currently available circulating biomarkers for this silently progressing malignancy are not sufficiently specific and sensitive to meet all clinical needs. There is an imminent and pressing need for the identification of novel circulating biomarkers to increase disease-free survival rate. In order to facilitate the selection of the most promising circulating protein biomarkers, we attempted to define an objective method likely to have a significant impact on the analysis of vast data generated from cutting-edge technologies. Current study exploits data available in seven publicly accessible gene and protein databases, unveiling 731 liver-specific proteins through initial enrichment analysis. Verification of expression profiles followed by integration of proteomic datasets, enriched for the cancer secretome, filtered out 20 proteins including 6 previously characterized circulating HCC biomarkers. Finally, interactome analysis of these proteins with midkine (MDK), dickkopf-1 (DKK-1), current standard HCC biomarker alpha-fetoprotein (AFP), its interacting partners in conjunction with HCC-specific circulating and liver deregulated miRNAs target filtration highlighted seven novel statistically significant putative biomarkers including complement component 8, alpha (C8A), mannose binding lectin (MBL2), antithrombin III (SERPINC1), 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1), alcohol dehydrogenase 6 (ADH6), beta-ureidopropionase (UPB1) and cytochrome P450, family 2, subfamily A, polypeptide 6 (CYP2A6). Our proposed methodology provides a swift assortment process for biomarker prioritization that eventually reduces the economic burden of experimental evaluation. Further dedicated validation studies of potential putative biomarkers on HCC patient blood samples are warranted. We hope that the use of such integrative secretome, interactome and miRNAs target filtration approach will accelerate the selection of high-priority biomarkers for other diseases as well, that are more amenable to downstream clinical validation experiments.

OBJECTIVE

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.

METHODS

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.

RESULTS

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).

CONCLUSIONS

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.

OBJECTIVE

In RA, conflicting results have been described on the association between genotypes of the complement factor mannose-binding lectin (MBL) and disease susceptibility and severity. This might be due to underpowerment of previous research work and the fact that no confirmation cohorts were used. Therefore a different approach is warranted.

METHODS

MBL2 gene polymorphisms were determined in two RA cohorts (378 and 261 cases) and 648 controls. Considering MBL polymorphisms, cases and controls were categorized in groups of high, intermediate and low MBL production. The total sample size allows detection of a potential association between RA susceptibility and MBL groups with an odds ratio of 1.37 (alpha < 0.05; 1-beta>> 0.8). Disease severity as defined by the need for anti-TNF therapy was also analysed for possible associations with MBL groups.

RESULTS

There was no difference in the frequencies between MBL genotypes of RA cases and controls that are associated with high (cases 54.4%, controls 57.0%), intermediate (cases 28.9%, controls 27.5%) or low (cases 16.7%, controls 15.5%) MBL production. Furthermore, there was no association between MBL groups and disease severity.

CONCLUSIONS

MBL genotype groups are not associated with RA disease susceptibility or severity in this large study including a confirmation cohort. Compared with previous smaller studies these results add to more definite conclusions.

BACKGROUND

Mannose-binding lectin (MBL) deficiency is associated with susceptibility to respiratory infections. We investigated the impact of MBL2 gene polymorphisms and MBL deficiency on the recurrence of infective exacerbation in patients with COPD.

METHODS

A prospective study was conducted among 215 patients with COPD and 137 healthy subjects. MBL deficiency was determined by the MBL2 gene polymorphisms and serum levels of MBL.

RESULTS

The average frequency of infective exacerbations over 3 years in the 215 patients with COPD was 2.5 ± 1.3 episodes. The COPD group with three or more episodes of infective exacerbation (recurrent exacerbators) included 96 patients, and the remaining 119 patients had two or fewer episodes (less-frequent exacerbators). Among the 96 recurrent exacerbators, 12 (12.50%) had the MBL deficiency genotype compared with 5 (4.20%) among the less-frequent exacerbators (OR, 3.25; 95% CI, 1.01-11.07; P = .0253). In recurrent exacerbators, the frequency of infective exacerbation was significantly higher in patients with MBL-deficient genotypes than in those with non-MBL-deficient genotypes (4.75 ± 1.22 vs 3.52 ± 0.78, respectively; P < .0001). In addition, mortality was significantly increased in recurrent exacerbators with MBL-deficient genotypes compared with those with non-MBL-deficient genotypes (66.7% vs 31.0%, respectively; P = .0153).

CONCLUSIONS

MBL deficiency due to MBL2 polymorphisms increases the risk of recurrent infective exacerbation and worsens its outcome in patients with COPD.

OBJECTIVE

Human mannose-binding lectin, encoded by the MBL2 gene, is an important component of innate immunity and an important regulator of inflammatory processes. MBL2 gene polymorphisms are associated with an increased risk of neonatal infections and some data suggest a relation between the maternal MBL2 genotype and the risk of premature delivery. In this study, we evaluated whether there is an association between the fetal MBL2 genotype and prematurity.

METHODS

A microarray-based on-chip PCR method was used to simultaneously detect five common MBL2 polymorphisms (codon 52, 54, 57; promoter -550, -221) in 204 DNA samples isolated from archival blood cards. MBL2 genotypes of infants born before the 36th week of pregnancy (N = 102) were compared to a control group of infants born at term after the 37th week (N = 102).

RESULTS

The frequency of the codon 52 polymorphism was significantly higher in the pre-term group compared to the term group (10.8% versus 4.9%, P = 0.04), while the frequency of the codon 54 polymorphism was equal in both groups (11.3% versus 11.8%). Interestingly, carriers of genotypes (O/O) likely conferring deficient MBL plasma levels were more common in the group of premature birth (9.8% versus 2.9%, P = 0.05), while the promoter -550 C/C genotype was underrepresented in the pre-term birth group (24.5% versus 39.2%, P = 0.03).

CONCLUSIONS

Our data add to the knowledge about genetic predisposition to prematurity and suggest that the fetal MBL2 genotype might be an additional genetic factor contributing to the risk of premature delivery.

Vasoocclusive crisis (VOC) is the major cause of morbidity and mortality in sickle cell anemia (SCA), which is caused by the occlusion of blood vessels, followed by ischemia or infarct, resulting in progressive damage to organs. However, this clinical manifestation is variable, indicating that this process could be influenced by modifier genes. The gene MBL2 which codes for mannose-binding lectin (MBL) has been associated with modifications in the progression of infectious and inflammatory vascular diseases. The aim of this study was to determine the frequency of the polymorphisms of exon 1 (alleles A/O) and promoter region -221 (alleles Y/X) of MBL2 in children with SCA and to verify their association with VOC. The determination of the polymorphism of exon 1 and the promoter region of MBL2 was performed by SYBR GREEN((R)) and Taqman((R)) system, respectively. In the patients with SCA, the frequency of the genotype related to high production of MBL was 0.46 (YA/YA) and for intermediate/low production was 0.54 (YA/XA, XA/XA, YA/YO, XA/YO, YO/YO). The frequency of the genotypes and haplotypes of MBL2 in patients with SCA did not differ from control individuals. The populations were in Hardy-Weinberg equilibrium. The patients were divided into two groups. The groups were separated by the frequency of VOC, which was defined by the total of VOC episodes divided by the age of the children at the end of this study. Since, we choose a cut point in FVOC <1 (n=48) (which we considered of mild presentation of disease) and FVOC>>or=1 (n=39) (higher severity). In children with SCA, the frequency of the genotypes of MBL2 of intermediate/low expression for MBL was associated with FVOC>>or=1 (p=0.0188 OR=3.15 CI=1.19-8.50). The results suggest that MBL2 polymorphism at promoter and first exon of MBL2 associated with low serum levels and structural alterations of MBL could modify the phenotype of the child with SCA related to VOC.

In Guillain-Barré syndrome (GBS), complement activation plays a crucial role in the induction and extent of the postinfectious immune-mediated peripheral nerve damage. Mannose-binding lectin (MBL) activates the complement system via the lectin pathway after recognition of repetitive sugar groups on pathogens. We investigated whether the MBL2 genotype, serum MBL level, and MBL complex activity are associated with the development and severity of GBS. Single nucleotide polymorphisms in the promoter region (-550 H/L and -221 X/Y) and exon 1 (A/O) of the MBL2 gene were determined in 271 GBS patients and 212 healthy controls. The frequencies of the H allele, HY promoter haplotype, and HYA haplotype, which are related to high MBL activity, were all increased in GBS patients compared with healthy controls (p < or = 0.03), particularly in severely affected GBS patients (MRC-sum score < 40) (p < or = 0.02). Severe weakness was also associated with high MBL concentrations and MBL complex activity in sera from GBS patients (p < 0.01). The MBL2 B allele was associated with functional deficiency and relatively mild weakness. These results support the hypothesis that complement activation mediated by MBL contributes to the extent of nerve damage in GBS, which is codetermined by the MBL2 haplotype.

OBJECTIVE

The incidence of inflammatory bowel disease (IBD) in Europe has increased significantly. At least a fourth of patients are children. Mannan-binding lectin (MBL) is believed to be an important component of innate immunity, acting as an opsonin and activator of the lectin pathway (LP) of complement. The data relating any of the LP factors to IBD are sparse and contradictory and were obtained mainly from adult patients. The aim of this study was to investigate the possible role of MBL in Crohn's disease (CD) and ulcerative colitis (UC) in children.

METHODS

MBL2 gene single nucleotide polymorphisms (PCR-RFLP) and MBL concentrations (ELISA) were determined.

RESULTS

The frequency of MBL2 gene variants responsible for MBL deficiency (LXPA/O and O/O) is significantly higher in CD patients compared with controls or children with UC. A relatively high frequency of the codon 52 mutation (D allele) was noted in these patients. Practically no difference was found between UC and control (C) groups. Similarly, the average MBL levels as well as the number of MBL-deficient (MBL concentrations < 150 ng/ml) individuals differed between CD patients and controls or children suffering from UC. Again, there was no difference between UC and C groups.

CONCLUSIONS

These data suggest that MBL deficiency may be associated with CD but not with UC in pediatric patients. The possible role of MBL in IBD requires confirmation in larger series and further investigation of the mechanisms involved.