Genetic Polymorphisms of Mannose-Binding Lectin Do Not Influence Placental Malaria but Are Associated with Preterm Deliveries

Abstract

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.Women who become infected with Plasmodium falciparum during pregnancy are at an increased risk of anemia and poor pregnancy outcomes (5, 25). One reason for these complications is that P. falciparum-infected erythrocytes (IE) sequester in the intervillous space (IVS) of the placenta (9). As a result, monocytes and macrophages are attracted to the IVS (30, 36), where they stimulate an inflammatory response, produce placental pathology (42), and increase the risk of low-birth-weight (LBW) babies due to intrauterine growth reduction and premature deliveries (reviewed in reference 6). Thus, elimination of IE from the IVS is of great importance.Little is known about the role of innate immune cells and factors in eliminating IE from the IVS. An acute-phase protein that might be important is mannose-binding lectin (MBL), since it promotes opsonophagocytosis and activates the MBL pathway upon binding to oligosaccharides on pathogens (12,17). MBL is reported to bind to the surface of IE and possibly merozoites, although the ligand involved remains undefined (10, 15). In addition, MBL2 genetic deficiencies in children are associated with severe malaria (4, 11). Therefore, it is possible that MBL aids in eliminating IE by enhancing phagocytosis, leading to reduced pathology and risk of LBW babies.Plasma levels of MBL are influenced by three functional single nucleotide polymorphisms (SNPs) in exon 1 of the MBL2 gene at codons 52, 54, and 57 (D, B, and C, respectively) (18,20,21,35). These SNP...

Genetic, Biochemical, and Environmental Factors Associated with Pregnancy Outcomes in Newborns from the Czech Republic

“…The homozygous combination of the most frequent haplotype was inversely associated with LBW. Although the SNPs affecting LBW differed from those identified previously (Thevenon et al 2009), they are also in the promoter region, and thus our results support the data of Thevenon et al (2009). These authors also analyzed MBL concentrations in serum and found that lower levels are associated with polymorphisms that increased the LBW risk.…”

Polymorphisms in host genes encoding NOSII, C-reactive protein, and adhesion molecules thrombospondin and E-selectin are risk factors for Plasmodium falciparum malaria in India

“…NOSII large (CCTTT) n microsatellite repeats are associated with protection from disease manifestation Genotyping of the microsatellite repeat in the promoter of NOSII revealed the presence of ten alleles, (CCTTT) [7][8][9][10][11][12][13][14][15][16][17] , in both the endemic and non-endemic regions. The frequency of each microsatellite allele in the control and patient groups is shown in Fig.…”

“…The number of microsatellite repeats in the NOSII promoter region affects the level of iNOS transcripts and (CCTTT) 14,15,17 microsatellite repeat alleles are strong enhancers of promoter activity, with enhancement being significantly greater than that with (CCTTT) 12, 9 [39]. This would imply higher production of NO when the NOSII promoter carries long repeats.…”

“…4a, b. (CCTTT) 12 was the predominant allele in the controls of both regions. We, thus, categorized the repeats into small repeats of ≤12 (SR, CCTTT 7-12 ) and large repeats of ≥13 (LR, CCTTT [13][14][15][16][17] to analyze the association of the repeat polymorphism with disease susceptibility/resistance. Large repeats CCTTT 13-17 exhibited association with protection from disease manifestation in both the endemic (p < 1 × 10 −5 ) and non-endemic regions (p<1×10 −3 ) (Fig.…”

“…MBL may also directly opsonize the microorganism for phagocytosis and modulate the release of proinflammatory cytokines [16]. During malaria infection, MBL is reported to bind the surface of infected erythrocytes and merozoites [17], thus contributing to consequent innate immune response and parasite clearance. Promoter and exonic SNPs of MBL2 have a major effect on MBL protein structure and serum concentration [18,19].…”