MBL2 genotypes and their associations with MBL levels and NICU morbidity in a cohort of Greek neonates.
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ABSTRACT:
SUBMITTER: Speletas M
PROVIDER: S-EPMC4387979 | biostudies-literature | 2015
REPOSITORIES: biostudies-literature
Publications
MBL2 genotypes and their associations with MBL levels and NICU morbidity in a cohort of Greek neonates.
Speletas Matthaios M Gounaris Antonios A Sevdali Eirini E Kompoti Maria M Konstantinidi Katerina K Sokou Rozeta R Tsitsami Elena E Germenis Anastasios E AE
Journal of immunology research 20150324
The objective of this study was to assess the frequency of MBL2 genotypes and their associations with MBL levels and various morbidities of a neonatal intensive care unit (NICU). One hundred and thirty-four (134) NICU (83 term and 51 preterm) and 150 healthy neonates were enrolled in the study. MBL2 genotype and MBL serum levels at birth were determined prospectively by PCR-RFLP-sequencing and enzyme-linked immunosorbent assay, respectively. NICU neonates displayed significantly lower MBL serum ...[more]
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Project description:INTRODUCTION: Previous studies have provided inconsistent results on whether variants in the MBL2 gene, coding for the complement-activating mannan-binding lectin (MBL) protein, associate with rheumatoid arthritis (RA). We re-evaluated this in context of the main environmental and genetic risk factors (smoking, HLA-DRB1 'shared epitope' (SE), PTPN22*620W), which predispose to rheumatoid factor (RF) and/or anti-citrullinated-protein antibody (ACPA)-positive RA. METHODS: In this population-based EIRA study, rheumatoid factor (RF), ACPA, smoking, SE and PTPN22*620W status was determined in incident RA cases and matched controls. MBL-high (n = 1330) and MBL-low (n = 1257) genotypes predicting MBL levels were constructed from four promoter and exon-1 polymorphisms in the MBL2 gene. Odds ratios with 95% confidence interval (OR, 95% CI) were calculated by logistic regression. In extended families (n = 316), previously reported data were re-analyzed, considering RF and smoking. RESULTS: MBL-high genotypes tended to be associated with RF-negative (OR = 1.20, 95% CI 0.96-1.51) but not RF-positive (OR = 1.00, 95% CI 0.83-1.20) RA. Results divided by ACPA status did not differ. When stratified for smoking, MBL-high genotype was strongly associated with RF-negative RA in never smokers (OR = 1.82, 95% CI 1.24-2.69) but not in ever smokers (OR = 0.96, 95% CI 0.73-1.30). In never smokers, the association was observed in both the RF-negative/ACPA-negative (OR = 1.67, 95% CI 1.10-2.55) and RF-negative/ACPA-positive subgroups (OR = 3.07, 95% CI 1.37-6.89), and remained on an SE/PTPN22*620W negative background. In the extended families, the reported association between high MBL and RA was in fact confined to never smokers. CONCLUSIONS: High MBL may predispose to RF-negative RA but only in individuals who have never smoked. This illustrates the importance of phenotypic subgrouping in genetic studies.
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Project description:OBJECTIVE: Mannose-binding lectin (MBL) is an essential component of the acute-phase immune response and may thus play a role in the pathogenesis of type 1 diabetes and diabetic nephropathy. The serum concentration of MBL is mainly genetically determined, and elevated concentrations have been associated with both type 1 diabetes and diabetic nephropathy. Previous genetic studies have not been conclusive due to the small number of patients and polymorphisms studied. We investigated whether MBL2 polymorphisms are associated with type 1 diabetes or diabetic nephropathy and whether patients with nephropathy have elevated MBL concentrations as indicated previously. Furthermore, we studied the association between MBL2 polymorphisms and MBL concentration. RESEARCH DESIGN AND METHODS: We genotyped 20 MBL2 single nucleotide polymorphisms (SNPs) in a large, well-characterized Finnish case-control sample consisting of 1,297 patients with type 1 diabetes with or without nephropathy and 701 nondiabetic individuals. The serum concentration of MBL was available for 1,064 patients. RESULTS: We found that 19 SNPs were associated with the MBL concentration (P = 3 x 10(-81)-7 x 10(-4)). MBL concentrations were higher in patients with macroalbuminuria compared with patients without nephropathy even when the patients were stratified by the MBL2 genotypic background in accordance with previous studies. However, no evidence of association between any of the SNPs or their haplotype combinations and type 1 diabetes or diabetic nephropathy was observed. CONCLUSIONS: Although most of the MBL2 SNPs studied were associated with the MBL concentration, no common variations (neither single SNPs nor their haplotype combinations) confer risk of type 1 diabetes or diabetic nephropathy.
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Project description:The six types of pattern recognition molecules (PRMs) that initiate complement via the lectin pathway (LP) comprise collectins and ficolins. The importance of having various PRMs to initiate the LP is currently unclear. Mannan-binding lectin (MBL) is a collectin member of the LP PRMs. MBL deficiency is common with mild clinical consequence. Thus, the lack of MBL may be compensated for by the other PRMs. We hypothesized that variants FCN2?+?6424 and FCN3?+?1637delC that cause gene-dose-dependent reduction in ficolin-2 and ficolin-3 levels, respectively, may be rare in MBL-deficient individuals due to the importance of compensation within the LP. The aim of this study was to investigate the distribution and frequency of these variants among MBL2 genotypes in healthy subjects. The allele frequency of FCN2?+?6424 and FCN3?+?1637delC was 0.099 and 0.015, respectively, in the cohort (n?=?498). The frequency of FCN2?+?6424 tended to be lower among MBL-deficient subjects (n?=?53) than among MBL-sufficient subjects (n?=?445) (0.047 versus 0.106, P?=?0.057). In addition, individuals who were homozygous for FCN2?+?6424 were sufficient MBL producers. The frequency of FCN3?+?1637delC did not differ between the groups. The frequency of FCN2?+?6424 was similar in FCN3?+?1637delC carriers (n?=?15) versus wild type (n?=?498). Furthermore, subjects that were heterozygote carriers of both FCN2?+?6424 and FCN3?+?1637delC were sufficient MBL producers. In conclusion, FCN2?+?6424 carriers with MBL deficiency tend to be rare among healthy individuals. MBL-deficient individuals with additional LP PRM defects may be at risk to morbidity.
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Project description:BackgroundMaternal interleukin (IL) single nucleotide polymorphisms (SNPs) are associated with obstetrical outcomes. Conversely, infant SNPs are associated with subsequent neonatal intensive care unit (NICU) outcomes. Little is known about relationships between maternal SNPs and neonatal outcomes.PurposeTo examine the relationships between maternal IL genotypes and neonatal outcomes.MethodsAn ancillary study was conducted among mothers ( N = 63) who delivered very low-birth-weight infants ( N = 74). Maternal DNA was extracted from breast milk and genotyped. Outcomes included fecal calprotectin, length of stay, scores for neonatal acute physiology with perinatal extension (SNAPPE-II), weight gain, oxygen needs, necrotizing enterocolitis, intraventricular hemorrhage, sepsis, retinopathy of prematurity, blood transfusions, and feeding intolerance. Multivariate analyses examined the relationships between maternal IL SNPs and outcomes, controlling for gestational age and the ratio of maternal milk to total milk.ResultsAbsence of a minor allele in 2 IL6 SNPs was associated with fecal calprotectin ( p = .0222, p = .0429), length of stay ( p = .0158), SNAPPE-II ( p = .0497), weight gain ( p = .0272), and days on oxygen ( p = .0316). IL6 genotype GG (rs1800795) was associated with length of stay ( p = .0034) and calprotectin ( p = .0213). Minor-allele absence in 2 IL10 SNPs was associated with days on oxygen ( p = .0320). There were associations between IL10 genotype TT (rs1800871) and calprotectin ( p = .0270) and between IL10 genotypes AA (rs1800872 and rs1800896) and calprotectin ( p = .0158, p = .0045).ConclusionMaternal IL SNPs are associated with NICU outcomes. A potential clinical application includes an antenatal risk profile to identify neonatal needs.
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