BACKGROUND

Oxidative damage to placental DNA can result in negative pregnancy outcomes, including intrauterine growth restriction (IUGR) and low birth weight (LBW).

OBJECTIVE

We investigated associations between the levels of 8-oxo-7,8-dihydro-2´-deoxyguanosine (8-oxodG), a marker of oxidative DNA damage, in placental DNA, exposure to air pollutants during pregnancy, genetic polymorphisms in 94 selected genes, and pregnancy outcomes.

METHODS

We studied 891 newborns who were IUGR- or LBW-affected or normal weight and were born between 1994 and 1999 in the Czech Republic in two districts with different levels of air pollution.

RESULTS

We found nonsignificantly elevated 8-oxodG levels in the IUGR-affected group compared with the non-IUGR group (p = 0.055). Similarly, slightly elevated 8-oxodG levels were found in the LBW-affected group compared with the non-LBW group (p < 0.050). In univariate analyses, we identified single nucleotide polymorphisms associated with 8-oxodG levels, IUGR, and LBW. Exposure to particulate matter < 2.5 µm was associated with increased 8-oxodG levels in placental DNA and LBW. However, multivariate-adjusted logistic regression revealed that above-median 8-oxodG levels were the only factor significantly associated with IUGR [OR = 1.56; 95% confidence interval (CI), 1.07-2.37; p = 0.022]. Above-median levels of 8-oxodG were associated with LBW (OR = 1.88; 95% CI, 1.15-3.06; p = 0.011). Other variables associated with LBW included sex and gestational age of the newborn, maternal smoking, and haplotypes in the promoter region of the gene encoding mannose-binding lectin 2 (MBL2). The role of air pollutants in the risk of adverse pregnancy outcomes seemed to be less important.

CONCLUSIONS

Levels of 8-oxodG in placental DNA were associated with the risk of IUGR as well as LBW. Newborn's sex, gestational age, maternal smoking, and genetic polymorphisms in the promoter region of the MBL2 gene were associated with LBW incidence.

BACKGROUND

Mannan-binding lectin (MBL) and mannan-binding lectin-associated serine protease-2 (MASP-2) represent important arms of the innate immune system, and different deficiencies may result in infections or autoimmune diseases. Both bipolar and panic disorders are associated with increased inflammatory response, infections and mutual comorbidity. However, associations with MBL, MASP-2 or the gene, MBL2, coding for MBL, have not been investigated thoroughly.

METHODS

One hundred patients with bipolar disorder, 100 with panic disorder and 349 controls were included. Serum concentrations of MBL and MASP-2 were measured and seven single nucleotide polymorphisms (SNPs) influencing these concentrations were genotyped. Disease association with genetic markers and serum levels were investigated.

RESULTS

In panic disorder, we observed a large proportion (30%) of MBL deficient (<100ng/ml) individuals and significantly lower levels of MBL and MASP-2 plus association with the MBL2 YA two-marker haplotype. Bipolar disorder was associated with the MBL2 LXPA haplotype and lower MASP-2 levels.

CONCLUSIONS

No information on course or severity of disorders was included, and only MBL and MASP-2 were measured, excluding other components from the complement pathway. Restrictions defined by ethnical committees preclude information of control׳s ethnic origin.

CONCLUSIONS

Significant differences in MBL and MASP-2 concentrations were observed between cohorts, especially an intriguing finding associating panic disorder with MBL deficiency. These differences could not be fully explained by allele or haplotype frequency variations. Since MBL deficiency is highly heterogeneous and associated with both infectious and autoimmune states, more research is needed to identify which complement pathway components could be associated with bipolar respectively panic disorder.

Hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli (STEC HUS) is a worldwide endemic problem, and its pathophysiology is not fully elucidated. Here we tested whether the mannose-binding lectin (MBL2), an initiating factor of lectin complement pathway activation, plays a crucial role in STEC HUS. Using novel human MBL2-expressing mice (MBL2 KI) that lack murine Mbls (MBL2(+/+)Mbl1(-/-)Mbl2(-/-)), a novel STEC HUS model consisted of an intraperitoneal injection with Shiga toxin-2 (Stx-2) with or without anti-MBL2 antibody (3F8, intraperitoneal). Stx-2 induced weight loss, anemia, and thrombocytopenia and increased serum creatinine, free serum hemoglobin, and cystatin C levels, but a significantly decreased glomerular filtration rate compared with control/sham mice. Immunohistochemical staining revealed renal C3d deposition and fibrin deposition in glomeruli in Stx-2-injected mice. Treatment with 3F8 completely inhibited serum MBL2 levels and significantly attenuated Stx-2 induced-renal injury, free serum hemoglobin levels, renal C3d, and fibrin deposition and preserved the glomerular filtration rate. Thus, MBL2 inhibition significantly protected against complement activation and renal injury induced by Stx-2. This novel mouse model can be used to study the role of complement, particularly lectin pathway-mediated complement activation, in Stx-2-induced renal injury.

The tumor microenvironment, including its inflammatory components, regulates tumor progression. Herein, we explore the relationship between inflammation and the progression of T-cell lymphoma in the cutaneous microenvironment. Injection of MBL2 murine T lymphoma cells into ear skin of C57BL/6 and immunodeficient SCID/Beige mice resulted in tumor formation in only the latter group. However, induction of skin inflammation by one topical application of DNFB following MBL2 inoculation in C57BL/6 mice resulted in progressive high-grade lymphoma. The DNFB-regulated tumor formation was blocked by early, but not late, application of a potent topical corticosteroid. At 2 days after implantation, a 10-fold decrease in MBL2 cell apoptosis was detected in DNFB-treated ears compared with vehicle control. After DNFB treatment, Gr-1(high) neutrophils and F4/80(+) macrophages constituted the majority of tumor-infiltrating CD45(+) leukocytes. Depletion of macrophages by clodronate-containing liposomes blocked the tumor-promoting effect of DNFB. Transcriptional profiling of inflammatory cytokines and chemokines after DNFB treatment revealed robust changes in genes that are important in chemotaxis, proliferation, and apoptosis. Activation of oncogenic signal pathways, including NF-κB, was also detected. This work provides insights into the cellular and molecular pathways that mediate lymphoma progression and may have applicability to human cutaneous T-cell lymphomas.

BACKGROUND

Wheezing during early life is a very common disorder, but the reasons underlying the different wheezing phenotypes are still unclear. The aims of this study were to analyse the potential correlations between the risk of developing recurrent wheezing and the presence of specific polymorphisms of some genes regulating immune system function, and to study the relative importance of the associations of different viruses and genetic polymorphisms in causing recurrent episodes.

METHODS

The study involved 119 otherwise healthy infants admitted to hospital for a first episode of wheezing (74 of whom subsequently experienced recurrent episodes) and 119 age- and sex-matched subjects without any history of respiratory problem randomly selected from those attending our outpatient clinic during the study period. All of the study subjects were followed up for two years, and 47 single nucleotide polymorphisms (SNPs) in 33 candidate genes were genotyped on whole blood using an ABI PRISM 7900 HT Fast Real-time instrument.

RESULTS

IL8-rs4073AT, VEGFA-rs833058CT, MBL2-rs1800450CT and IKBKB-rs3747811AT were associated with a significantly increased risk of developing wheezing (p = 0.02, p = 0.03, p = 0.05 and p = 0.0018), whereas CTLA4-rs3087243AG and NFKBIB-rs3136641TT were associated with a significantly reduced risk (p = 0.05 and p = 0.04). IL8-rs4073AT, VEGFA-rs2146323AA and NFKBIA-rs2233419AG were associated with a significantly increased risk of developing recurrent wheezing (p = 0.04, p = 0.04 and p = 0.03), whereas TLR3-rs3775291TC was associated with a significantly reduced risk (p = 0.03). Interestingly, the study of gene-environment interactions showed that rhinovirus was significantly associated with recurrent wheezing in the presence of IL4Ra-rs1801275GG and G (odds ratio [OR] 6.03, 95% confidence interval [CI]: 1.21-30.10, p = 0.03) and MAP3K1-rs702689AA (OR 4.09, 95% CI: 1.14-14.61, p = 0.03).

CONCLUSIONS

This study shows a clear relationship between the risk of wheezing and polymorphisms of some genes involved in the immune response. Although further studies are needed to confirm the results, these findings may be useful for the early identification of children at the highest risk of developing recurrent episodes and possibly subsequent asthma.

DNA biosensors involve molecular recognition of the target sequence by hybridization with specific probes and detection by electrochemical, optical or gravimetric transduction. Disposable, dipstick-type biosensors have been developed recently, which enable visual detection of DNA without using instruments. In this context, we report a multianalyte DNA biosensor for visual genotyping of two single-nucleotide polymorphisms (SNPs). As a model, the biosensor was applied to the simultaneous genotyping of two SNPs, entailing the detection of four alleles. A PCR product that flanks both polymorphic sites is subjected to a single primer extension (PEXT) reaction employing four allele-specific primers, each containing a region complementary to an allele and a characteristic segment that enables subsequent capture on a test zone of the biosensor. The primers are extended with dNTPs and biotin-dUTP only if there is perfect complementarity with the interrogated sequence. The PEXT mixture is applied to the biosensor. As the developing buffer migrates along the strip, all the allele-specific primers are captured by immobilized oligonucleotides at the four test zones of the biosensor and detected by antibiotin-functionalized gold nanoparticles. As a result, the test zones are colored red if extension has occurred denoting the presence of the corresponding allele in the original sample. The excess nanoparticles are captured by immobilized biotinylated albumin at the control zone of the sensor forming another red zone that indicates the proper performance of the system. The assay was applied successfully to the genotyping of twenty clinical samples for two common SNPs of MBL2 gene.

From the dried fruiting bodies of the mushroom Armillaria luteo-virens, a dimeric lectin with a molecular mass of 29.4 kDa has been isolated. The purification procedure involved (NH(4))(2)SO(4) precipitation, ion exchange chromatography on DEAE-cellulose, CM-cellulose, and Q-Sepharose, and gel filtration by fast protein liquid chromatography on Superdex 75. The hemagglutinating activity of the lectin could not be inhibited by simple sugars but was inhibited by the polysaccharide inulin. The activity was stable up to 70 degrees C but was acid- and alkali-labile. Salts including FeCl(3), AlCl(3), and ZnCl(2) inhibited the activity whereas MgCl(2), MnCl(2), and CaCl(2) did not. The lectin stimulated mitogenic response of mouse splenocytes with the maximal response achieved by 1microM lectin. Proliferation of tumor cells including MBL2 cells, HeLa cells, and L1210 cells was inhibited by the lectin with an IC(50) of 2.5, 5, and 10 microM, respectively. However, proliferation of HepG2 cells was not affected. The novel aspects of the isolated lectin include a novel N-terminal sequence, fair thermostability, acid stability, and alkali stability, together with potent mitogenic activity toward spleen cells and antiproliferative activity toward tumor cells.

OBJECTIVE

While genetic risks have been implicated in systemic lupus erythematosus (SLE), the involvement of various genotypes in neuropsychiatric SLE (NPSLE) remains uncertain. The present metaanalysis aimed to combine data from different studies and evaluate the association between each genotype and the risk of developing NPSLE.

METHODS

Studies were searched and retrieved from online databases (PubMed, EMBASE, BIOSIS, and ScienceDirect). Case-control studies were chosen if they reported genotype frequencies of the γ Fc region (FCγR) receptors II-A, III-A, and III-B; tumor necrosis factor-α (TNF-α); mannan-binding lectin (MBL); integrin alpha M (ITGAM); interleukin (IL) 1, IL-1β, and IL-6; IL-10 promoter; and vitamin D genes. The OR were used to assess the strength of this association between patients with NPSLE and SLE.

RESULTS

A total of 33 studies were considered in this metaanalysis. The results suggest that these genotypes demonstrated a significant association with NPSLE: the homozygous FCγR IIIa 158 FF genotype (OR 1.89, p = 0.03 for FF vs VV + FV), heterozygous FCγR IIIb NA1/2 genotype (OR 2.14, p = 0.03 for NA1/2 vs NA1/1; OR 1.81, p = 0.04 for NA1/2 vs NA1/1 + NA2/2), and homozygous ITGAM rs1143679 HH genotype (OR 3.39, p = 0.04 for HH vs RH; OR 3.11, p = 0.048 for HH vs RR + RH). Polymorphisms of the TNF-α, MBL2, IL-1, IL-1β, IL-6, IL-10 promoter, and vitamin D receptor genes did not show a statistically significant association with the risk of developing NPSLE (p>> 0.05).

CONCLUSIONS

This metaanalysis indicates that polymorphisms in the pathways of immune complex clearance, such as the FcγRIIIa, FcγRIIIb, and ITGAM genotypes, are potential susceptibility genes for NPSLE.

Association studies on genetic variation to treatment effect may serve as a predictive marker for effect of treatment and can also uncover biological pathways behind drug effect. Single-nucleotide polymorphisms (SNPs) have been studied in relation to high-dose treatment (HDT), thalidomide- and bortezomib-based therapy, maintenance treatment with interferon-α and in relation to therapy-related adverse effects caused by treatment. Candidate genes for prediction of effect of HDT include DNA repair genes, CYP genes and genes involved in inflammation and apoptosis such as IL1B and RAI. In thalidomide- and bortezomid-based therapy, candidate genes include TNFA and genes involved in the nuclear factor kappa B pathway (NFKB2 and TRAF3), respectively. In maintenance treatment with interferon-α, a polymorphism in gene NFKB1 is a candidate gene for prediction for effect. Adverse effect includes infection, osteonecrosis of the jaw (ONJ), venous thrombotic events (VTE) and peripheral neuropathy (PN). A SNP in MBL2 and MPO gene was associated with septicemia and a SNP in the gene CYP2C8 was strongly associated with ONJ. Several SNPs in genes encoding DNA repair, apoptosis, inflammation and genes involved in function of the nervous system have been associated with VTE induced by thalidomide and with PN induced by bortezomib. SNP analysis is simple and can be performed, e.g., on blood and buccal cells. Further analysis of SNPs in clinical trials is needed, and collaboration between scientific groups will be an advantage because SNP analysis required large number of patients.

To pinpoint true positive single-nucleotide polymorphism (SNP) associations in a genome-wide association study (GWAS) of rheumatoid arthritis (RA), we categorize genetic loci by external knowledge. We test both the 'enrichment of associated loci' in a locus category and the 'combined association' of a locus category. The former is quantified by the odds ratio for the presence of SNP associations at the loci of a category, whereas the latter is quantified by the number of loci in a category that have SNP associations. These measures are compared with their expected values as obtained from the permutation of the affection status. To account for linkage disequilibrium (LD) among SNPs, we view each LD block as a genetic locus. Positional candidates were defined as loci implicated by earlier GWAS results, whereas functional candidates were defined by annotations regarding the molecular roles of genes, such as gene ontology categories. As expected, immune-related categories show the largest enrichment signal, although it is not very strong. The intersection of positional and functional candidate information predicts novel RA loci near the genes TEC/TXK, MBL2 and PIK3R1/CD180. Notably, a combined association signal is not only produced by immune-related categories, but also by most other categories and even randomly defined categories. The unspecific quality of these signals limits the possible conclusions from combined association tests. It also reduces the magnitude of enrichment test results. These unspecific signals might result from common variants of small effect and hardly concentrated in candidate categories, or an inflated size of associated regions from weak LD with infrequent mutations.

BACKGROUND

Over the last five years, there have been numerous reports of association of juvenile idiopathic arthritis with single nucleotide polymorphisms (SNPs) at various loci outside the major histocompatibility complex (MHC) region. However, the majority of these association findings have been generated using a limited number of international cohorts, and thus there is benefit in further independent replication. To address this, we examined a total of 56 SNPs in 42 non-MHC gene regions previously reported to be associated with JIA, in the ChiLdhood Arthritis Risk factor Identification sTudY (CLARITY), a new Australian collection of cases and healthy child controls.

RESULTS

Genotyping was performed on a total of 324 JIA cases (mean age 9.7 years, 67.3% female) and 568 controls (mean age 7.8 years, 40.7% female). We demonstrated clear evidence for replication of association of JIA with SNPs in or around c12orf30, c3orf1, PTPN22, STAT4, and TRAF1-C5, confirming the involvement of these loci in disease risk. Further, we generated evidence supportive of replication of association of JIA with loci containing AFF3, CD226, MBL2, PSTPIP1, and RANTES (CCL5). These results were robust to sensitivity analyses for ethnicity.

CONCLUSIONS

We have provided valuable independent data as to the underlying genetic architecture of this understudied pediatric autoimmune disease, further confirming five loci outside the MHC, and supporting a role for a further five loci in determining disease risk.

Previous studies showed that low expression of mannan-binding lectin C (MBL-C) in pigs was not due to single-nucleotide polymorphisms (SNPs) in the coding region of pig MBL2. In these studies, we compared the 5' flanking regions of porcine MBL1 (1907 bp) and MBL2 (1880 bp) in normal and diseased pigs with low or high hepatic expression of MBL2. Hepatic expression of MBL-C was very low in all pigs submitted for postmortem diagnosis. In various European pig breeds, a G(-1081)A substitution was linked to very low hepatic MBL-C expression, and was more frequent in diseased pigs. A C(-251)T substitution with less influence on MBL-C expression was more common in various breeds but was not associated with disease. MBL2 polymorphisms were associated with some disease groups and with the presence of some etiologic agents. These findings indicate that some promoter polymorphisms impair MBL-C expression in pigs and may increase their susceptibility to disease.

Major infection remains a major barrier to the success of allogeneic hemopoietic stem cell transplantation (SCT). There is growing interest in the importance of innate immunity in host defense, particularly when adaptive immunity is compromised. Furthermore, many host defense genes are polymorphic, and immunogenetic factors are known to influence the risk of other transplant complications, such as graft-versus-host disease. Mannose-binding lectin (MBL) has emerged as an important innate host defense molecule. MBL binds a wide range of pathogens independently of antibody and activates complement leading to lysis and phagocytosis. Genetically determined MBL deficiency is common and results in an increased risk of infection in a variety of clinical settings, especially in individuals already immunocompromised for other reasons. We conducted a retrospective study examining associations between polymorphisms in the gene encoding MBL, MBL2 and risk of major infection post-SCT in 96 related myeloablative transplants. This showed that "low-producing" MBL2 coding alleles, when present in the donor, were significantly associated with increased risk of major infection in the recipient following neutrophil count recovery. Furthermore, a "high-producing" MBL2 haplotype, HYA, when present in the recipient, was protective against infection. As MBL is under development as a therapeutic agent, these findings suggest that administration of MBL may reduce the risk of infection post-transplant. Prior to embarking upon trials of MBL replacement therapy in SCT, further work is required to confirm these results, to examine the kinetics of MBL synthesis peri-transplant, to correlate MBL2 genotype with blood MBL levels, and to examine the role of MBL in other settings, such as transplantation using reduced intensity conditioning regimens, and unrelated donor transplants. These results are the first report of a genetic determinant of risk of infection post-SCT, and highlight the importance of non-HLA genetic factors in determining the risk of transplant complications. Further studies examining other host defence genes are warranted, and are in progress.

BACKGROUND

The complement factor mannose-binding lectin (MBL) is associated with adverse pregnancy outcome. MBL serum concentrations are increased from early pregnancy onwards and depend upon several gene polymorphisms. We investigated whether MBL polymorphisms are associated with term and preterm birth, since preterm birth is the leading cause of neonatal morbidity and mortality.

METHODS

MBL2 gene polymorphisms were determined in 157 nulliparous women. Considering MBL polymorphisms cases were categorized in groups of high (A), intermediate (B) and low (C) MBL production. Kaplan-Meier survival and multiple linear regression analysis were performed.

RESULTS

Women with high MBL genotype group A had a shorter gestational age (274 days+/-S.D. 21) than the women with the intermediate MBL genotype group B (283 days+/-S.D. 12) and the low MBL genotype group C (284 days+/-S.D. 9). This difference in mean gestational age is almost totally attributable to premature births in group A, since 12 of the 14 preterm births were from women with the high MBL genotype group A and only two from the intermediate MBL genotype group B.

CONCLUSIONS

We found an association between the maternal high MBL genotype group A and premature birth, suggesting that during pregnancy MBL-associated inflammation caused by higher MBL activity may contribute to earlier delivery. Furthermore, this finding might explain why so many individuals are MBL deficient in the general population.

During pregnancy, Plasmodium falciparum-infected erythrocytes (IE) sequester in the placenta where they induce pathology and increase the risk of low-birth-weight (LBW) babies. The innate immune mediator, mannose-binding lectin (MBL), enhances phagocytosis of pathogens. Since MBL is reported to bind to IE, we hypothesized that it might aid in clearance of IE from the placenta, thereby reducing the risk of LBW babies. To test this hypothesis, molecular genotyping was used to detect polymorphisms at codon 57 (A/C) in exon 1 of MBL2 in 401 pregnant Cameroonian women, with or without placental malaria, who had LBW and normal-weight babies. Polymorphisms in the promoter region at positions -550 (H/L), -221 (X/Y), and +4 (P/Q) were also determined, and plasma MBL levels were measured during pregnancy and at delivery. The expected correlation between genotype and plasma MBL levels was confirmed. However, asymptomatic infections were not associated with an increase in MBL levels in the peripheral blood, and MBL levels were similar in the placental and cord blood of women with or without placental malaria at delivery. There was no evidence that MBL levels at delivery were associated with malaria-related poor pregnancy outcomes. Women with the LXPA haplotype, however, were more likely to have LBW babies, but the risk was not related to malaria. These results do not support the hypothesis that MBL aids in the clearance of parasites from the placenta but suggest that Cameroonian women with LXPA are at risk of having LBW babies due to other causes.

Podocytes are critical for maintaining the glomerular filtration barrier and are injured in many renal diseases, especially proteinuric kidney diseases. Recently, reports suggested that podocytes are among the renal cells that synthesize complement components that mediate glomerular diseases. Nevertheless, the profile and extent of complement component expression in podocytes remain unclear. This study examined the expression profile of complement in podocytes under physiological conditions and in abnormal podocytes induced by multiple stimuli. In total, 23/32 complement component components were detected in podocyte by conventional RT-PCR. Both primary cultured podocytes and immortalized podocytes expressed the complement factors C1q, C1r, C2, C3, C7, MASP, CFI, DAF, CD59, C4bp, CD46, Protein S, CR2, C1qR, C3aR, C5aR, and Crry (17/32), whereas C4, CFB, CFD, C5, C6, C8, C9, MBL1, and MBL2 (9/32) complement factors were not expressed. C3, Crry, and C1q-binding protein were detected by tandem mass spectrometry. Podocyte complement gene expression was affected by several factors (puromycin aminonucleoside (PAN), angiotensin II (Ang II), interleukin-6 (IL-6), and transforming growth factor-β (TGF-β)). Representative complement components were detected using fluorescence confocal microscopy. In conclusion, primary podocytes express various complement components at the mRNA and protein levels. The complement gene expressions were affected by several podocyte injury factors.

OBJECTIVE

To study the association between polymorphisms in the mannose-binding lectin gene (MBL2) and disease activity, physical disability, and joint erosions in patients with newly diagnosed rheumatoid arthritis (RA).

METHODS

Patients with early RA (n=158) not previously treated with disease modifying antirheumatic drugs, participating in a treatment trial (CIMESTRA study) were examined at inclusion for MBL2 pooled structural genotypes (O/O, A/O, A/A), regulatory MBL2 promoter polymorphism in position -221 (XX, XY, YY), anti-cyclic citrullinated peptide 2 antibodies (anti-CCP2), disease activity by Disease Activity Score-28 (DAS28 score), physical disability by Health Assessment Questionnaire (HAQ) score, and erosive changes in hands and feet (Sharp-van der Heijde score).

RESULTS

Eight patients were homozygous MBL2 defective (O/O), 101 belonged to an intermediate group, and 49 were MBL2 high producers (YA/YA). Anti-CCP was present in 93 patients (59%). High scores of disease activity, C-reactive protein-based DAS28 (p=0.02), and physical disability by HAQ (p=0.01) were associated with high MBL2 expression genotypes in a gene-dose dependent way, but only in anti-CCP-positive patients. At this early stage of the disease there was no association with erosion score from radiographs.

CONCLUSIONS

The results point to a synovitis-enhancing effect of MBL in anti-CCP-positive RA, whereas such an effect was not demonstrated for joint erosions.

Mannose-binding lectin (MBL), a member of the innate immune system, initiates complement deposition on microbial surfaces. MBL deficiency is associated with severe respiratory infections. Polymorphisms in the MBL gene (mbl2) were associated with the susceptibility and severity of autoimmune diseases. This study investigated whether mbl2 polymorphisms at positions -550 and -221 and at codon-54 are associated with asthma phenotypes in Chinese children. Asthmatics aged 5-18 yr and non-allergic controls were eligible, and their plasma total and allergen-specific immunoglobulin E (IgE) concentrations were measured by micro-particle immunoassay and fluorescent enzyme immunoassay. mbl2 polymorphisms were genotyped by restriction fragment length polymorphism. Three hundred and seventeen asthmatic children and 140 controls were recruited, with their mean (s.d.) log-transformed plasma total IgE being 2.61 (0.61) and 1.77 (0.77), respectively (p < 0.0001). Polymorphisms at -550 and codon-54 (p < 0.0001 for both) but not at -221 (p = 0.534) of mbl2 were significantly associated with plasma MBL concentrations. mbl2 genotypes were not associated with asthma, atopy, sensitization to individual aeroallergens or spirometric variable. Subjects with LYB haplotype had the lowest plasma MBL concentrations (p < 0.0001), but two- and three-loci mbl2 haplotypes were also not associated with asthma diagnosis. However, patients with LY and LYB haplotypes were less likely to be atopic (p = 0.006 and 0.031). Subjects with LY and LYA were also less likely to be sensitized to cockroach (p = 0.035 and 0.047). The latter three associations became insignificant when adjusted for multiple comparisons. Despite the importance of MBL in innate immunity, our mbl2 polymorphisms only show weak association with asthma and atopy in children.

The authors systematically reviewed the literature on mannose-binding lectin (MBL) and infections in newborns to determine whether infection risk is increased in MBL-deficient newborns. All original reports on MBL and infections in newborns were retrieved from Embase, Medline and CENTRAL from 1966 to December 2009. Information extracted from each article included study design, definitions of MBL deficiency and neonatal infection, follow-up period and risk factor analysis. The validity of each study was assessed. Eight prospective cohort studies, including 3166 (range 47-1832) premature or term neonates, were assessed. MBL levels were measured in five studies and MBL2 genotype in six studies. Definitions of MBL deficiency and infection varied. In three out of five phenotypic studies low MBL levels were statistically significantly associated with increased culture-confirmed sepsis rates, also after correction for gestational age or birth weight. In the first study, the median MBL level was decreased in newborns with confirmed sepsis (170 μg/l) compared with newborns without sepsis (1450 μg/l). In two other studies, culture-confirmed sepsis was associated with MBL levels ≤700 μg/l (OR 15.0, 95% CI 1.5 to 151.3) and ≤400 μg/l (OR 3.1), respectively. The remaining two studies investigated various non-culture-confirmed infections. Only one study included the timepoint of clinical suspicion of infection in multivariate analysis. Contradicting results were reported in six MBL2 genotypic studies. Newborns with low MBL levels appear to have culture-confirmed sepsis more frequently than MBL-sufficient newborns. However, the influence of confounding factors was analysed insufficiently. Variant MBL2 genotypes appear to have less influence.

BACKGROUND

Mannose-binding lectin (MBL) as a component of innate immunity plays an important role in preterm infants in whom adaptive immunity is not sufficiently developed. Polymorphisms in immunoregulatory genes influence the response to infection and subsequent inflammation. Infection and inflammation have been implicated in the mechanisms responsible for many of the diseases in the preterm newborns.

OBJECTIVE

The aim of the study was to investigate the relationship between MBL gene polymorphism and early neonatal outcome in preterm infants.

METHODS

Codon 54 and 57 polymorphisms in MBL2 gene were genotyped in 99 preterm infants admitted to the Neonatal Intensive Care Unit at Ege University Children's Hospital.

RESULTS

Overall frequencies of sepsis and early-onset sepsis were higher in the group of infants with MBL polymorphism when compared to infants with wild-type MBL genotype (p = 0.008, 0.009, respectively). Maximum Tollner sepsis score in the first 3 days of life was higher for the infants with variant MBL genotype (p = 0.0278). More infants in the variant MBL group had significant patent ductus arteriosus when compared to infants with wild-type MBL (27.8 vs. 9.5% respectively, p = 0.037).

CONCLUSIONS

MBL gene polymorphism was associated with increased frequency of clinical sepsis particularly with early neonatal sepsis and also with higher Tollner sepsis scores and increased frequency of patent ductus arteriosus in infants. Overall mortality and incidence of culture proven sepsis, respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular hemorrhage, periventricular leukomalacia and necrotizing enterocolitis were not found to be related to MBL genotype.

OBJECTIVE

To test the hypothesis that low serum mannose-binding lectin (MBL) levels, as a result of the single-nucleotide polymorphisms in the promoter region (-221 X/Y) and exon 1 (codon 54 A/B) of the MBL2 gene, predispose to infection in Chinese patients with systemic lupus erythematosus (SLE).

METHODS

Two hundred forty-five patients with SLE were prospectively followed for the development of major infective episodes that required hospitalization and antibiotic treatment during 1992-2005. MBL genotypes were determined by polymerase chain reaction and serum MBL levels were measured by ELISA.

RESULTS

In total, 254 major infections developed in 130 patients. Serum MBL levels were shown to correlate inversely with the number of bacterial infections (r = -0.13, p = 0.03). The distribution of MBL genotypes was similar in patients with and without major infection (p = 0.84). Patients with major infection also had more major lupus exacerbations that required daily prednisolone dose>> or = 15 mg. Logistic regression showed that log MBL level (odds ratio 0.516, 95% confidence interval 0.305-0.873; p = 0.01) and major lupus exacerbation (OR 1.382, 95% CI 1.154-1.654; p < 0.001) were independent risk factors to major bacterial infection after adjustment for age and disease duration. Multiple regression analysis showed an increase in risk of bacterial infection by 34.2% for every decrease in serum MBL level by one log, and by 22.8% for each increase in number of major lupus exacerbations.

CONCLUSIONS

Low serum MBL level predisposes Chinese patients with SLE to more major infections, in particular bacterial ones.

OBJECTIVE

Infection during the induction phase of childhood acute lymphoblastic leukemia (ALL) is a major cause of morbidity and mortality. Several studies have indicated that genetically determined low serum levels of mannose-binding lectin (MBL), a component of innate immunity, are associated with increased risk for infections in patients receiving chemotherapy. Thus, these patients have been proposed to be candidates for MBL replacement therapy.

METHODS

In a population-based cohort of 137 children with ALL treated at a single pediatric hematology-oncology center with an almost identical chemotherapy regimen, we studied the relationship between polymorphisms in the MBL gene (MBL2) and the MBL2 promoter and the risk of infections during the first 50 d of induction therapy.

RESULTS

No increased frequency of infection was seen for the children with genotypes encoding serum low levels of MBL. A higher incidence of fever (P < 0.004), infectious events (P = 0.025), days with neutropenia (P < 0.001) and a higher frequency of antimicrobial therapy (P = 0.0007) were seen in the young age group (<2.5 yr) compared with the older age group >> or =2.5 yr), independent of the MBL genotype.

CONCLUSIONS

MBL deficiency did not influence the frequency of infections in children receiving induction chemotherapy for ALL, not even in the youngest children (<2.5 yr) whom we found to have the highest risk for infections.

The aim of this study was to evaluate the association between macrophage migration inhibitory factor (MIF) -173G/C (rs755622), mannose-binding lectin (MBL2) exon 1 codon 54 (rs1800450) gene polymorphisms and rheumatoid arthritis (RA) susceptibility in ethnically different populations. A meta-analysis was conducted (allelic contrast, the additive model, the dominant model and the recessive model) on the MIF-173G/C polymorphism across five studies (four European and one Asian studies), and the MBL2 codon 54 polymorphism with five studies (four Asian and one European studies), respectively. Meta-analysis indicated an association between the MIF-173G/C in all study subjects in allelic contrast (OR=1.19, 95%CI: 1.05-1.35, P=0.001), the additive model (OR=1.68, 95CI: 1.13-2.49, P=0.001), the dominant model (OR=1.17, 95CI: 1.01-1.35, P=0.003), the recessive model (OR=1.63, 95CI: 1.10-2.42, P=0.001). While stratified by ethnicity with European populations, an association was found in allelic contrast (OR=1.20, 95CI: 1.04-1.38, P=0.002), the additive model (OR=1.85, 95CI: 1.19-2.88, P=0.001), the dominant model (OR=1.20, 95CI: 1.02-1.41, P=0.003). With respect to MBL2 codon 54 polymorphism and RA, no association was found in all study subjects in all comparisons, but there was an association while stratified by ethnicity with Asian populations in the dominant model (OR=1.50, 95CI: 1.01-2.23, P=0.007). In conclusion, the present study suggests that the MIF-173G/C polymorphism is associated with RA susceptibility, but the MBL2 codon 54 polymorphism is not associated with RA.