Abstract
BackgroundGenetic polymorphisms in the human immune system modulate susceptibility to malaria. However, there is a paucity of data on the contribution of immunogenetic variants to malaria susceptibility in infants, who present differential biological features related to the immaturity of their adaptive immune system, the protective effect of maternal antibodies and fetal haemoglobin. This study investigated the association between genetic variation in innate immune response genes and malaria susceptibility during the first year of life in 656 infants from a birth cohort survey performed in Nanoro, Burkina Faso.MethodsSeventeen single nucleotide polymorphisms (SNPs) in 11 genes of the immune system previously associated with different malaria phenotypes were genotyped using TaqMan allelic hybridization assays in a Fluidigm platform. Plasmodium falciparum infection and clinical disease were documented by active and passive case detection. Case–control association analyses for both alleles and genotypes were carried out using univariate and multivariate logistic regression. For cytokines showing significant SNP associations in multivariate analyses, cord blood supernatant concentrations were measured by quantitative suspension array technology (Luminex).ResultsGenetic variants in IL-1β (rs1143634) and FcγRIIA/CD32 (rs1801274)—both in allelic, dominant and co-dominant models—were significantly associated with protection from both P. falciparum infection and clinical malaria. Furthermore, heterozygote individuals with rs1801274 SNP in FcγRIIA/CD32 showed higher IL-1RA levels compared to wild-type homozygotes (P = 0.024), a cytokine whose production is promoted by the binding of IgG immune complexes to Fcγ receptors on effector immune cells.ConclusionsThese findings indicate that genetic polymorphisms in genes driving innate immune responses are associated to malaria susceptibility during the first year of life, possibly by modulating production of inflammatory mediators.
Highlights
Genetic polymorphisms in the human immune system modulate susceptibility to malaria
Immuno-genetic variants that have been associated with diverse degrees of malaria susceptibility include: (i) polymorphisms in the Human Leucocyte Antigen (HLA), which may affect recognition of parasite antigens [8,9,10]; (ii) polymorphisms in cytokine related genes, which may affect protein levels and downstream functions, such as production of C-reactive protein and immunoglobulin (Ig) isotype switching [11,12,13,14,15,16]; (iii) polymorphism in toll-like receptors (TLRs), which may impair the ability of individuals to respond adequately to TLR agonists [17,18,19,20,21]; and (iv) polymorphisms in IgG Fcγ receptors, which may affect IgG immune complexes binding and the regulation of the IgG subclass production [22,23,24,25,26]
Association between immune genetic variants and clinical malaria The allelic analysis showed that carriage of the mutant allele A in IL-1β rs1143634 single nucleotide polymorphisms (SNPs) (AOR: 0.66, 95%CI 0.46–0.97; P = 0.032) and mutated allele A in FcγRIIA/ CD32 rs1801274 SNP
Summary
Genetic polymorphisms in the human immune system modulate susceptibility to malaria. there is a paucity of data on the contribution of immunogenetic variants to malaria susceptibility in infants, who pre‐ sent differential biological features related to the immaturity of their adaptive immune system, the protective effect of maternal antibodies and fetal haemoglobin. Immuno-genetic variants that have been associated with diverse degrees of malaria susceptibility include: (i) polymorphisms in the Human Leucocyte Antigen (HLA), which may affect recognition of parasite antigens [8,9,10]; (ii) polymorphisms in cytokine related genes, which may affect protein levels and downstream functions, such as production of C-reactive protein and immunoglobulin (Ig) isotype switching [11,12,13,14,15,16]; (iii) polymorphism in toll-like receptors (TLRs), which may impair the ability of individuals to respond adequately to TLR agonists [17,18,19,20,21]; and (iv) polymorphisms in IgG Fcγ receptors, which may affect IgG immune complexes binding and the regulation of the IgG subclass production [22,23,24,25,26]
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