Inflammatory markers and genetic predispositions to Plasmodium falciparum-associated poor pregnancy outcomes
Thévenon, Audrey Davidson.
Thesis (Ph.D.)--Georgetown University, 2009.; Includes bibliographical references.; Text (Electronic thesis) in PDF format. In pregnant women, Plasmodium falciparum infections are an important cause of maternal morbidity and fetal mortality. Malaria-infected erythrocytes sequester in the intervillous space of the placenta where they stimulate a localized inflammatory response that increases the risk of women having low birth weight babies. Since only some malaria-infected women have low birth weight babies, we sought to identify single nucleotide polymorphisms in genes that might predispose women to poor pregnancy outcomes. Mannose Binding Lectin is an innate mediator that may aid in clearance of infected erythrocytes. We demonstrated that polymorphisms in the MBL2 gene were not associated with high parasitemia, but the haplotype LXPA was correlated with increased risk of low birth weight babies. Previously, high levels of the anti-inflammatory cytokine interleulin-10 and the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) were associated with placental malaria and preterm deliveries. Since cytokine levels are genetically influenced, we hypothesized that polymorphisms in the promoter regions of the IL10 and TNFA genes might influence pregnancy outcomes. Women homozygous for the IL10 haplotype -1092G, -819C and -592C (GCC/GCC) had higher levels of interleukine 10 (p=0.005), were more prone to anemia (p=0.045), and had higher risks of preterm delivery when they had placental malaria (p=0.001). While polymorphisms in the TNFA gene did not influence cytokine levels, the promoter genotype -308A/A was more frequent in women who delivered prematurely (p=0.02). Because TNF-α; is involved in malaria-associated pathologies, we investigated the production of soluble tumor necrosis factor receptors (sTNFR) as counter-regulators of the effect of TNF-α. We hypothesize that placental malaria would trigger the shedding of sTNFR, thereby neutralizing TNF-α and lower the risk of low birth weight babies. Despite high levels of sTNF-R1 in the intervillous space, sTNFR levels were not associated with decreased risk of low birth weight babies. However, levels of sTNF-R2 which is a indicator of inflammation, were higher in the peripheral blood of women with placental malaria (p<0.0001) and low birth weight deliveries (p=0.02). Overall, results from this study contribute to the understanding of immune mechanisms involved during placental malaria-associated inflammation and described genetic predispositions for poor pregnancy outcomes.
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