Abstract
BackgroundPlasmodium falciparum malaria is one of the most widespread and deadliest infectious diseases in children under five years in endemic areas. The disease has been a strong force for evolutionary selection in the human genome, and uncovering the critical host genetic factors that confer resistance to the disease would provide clues to the molecular basis of protective immunity and improve vaccine development initiatives.MethodsThe effect of single nucleotide polymorphisms (SNPs) and plasma transforming growth factor beta (TGF-β) and interleukin 10 (IL-10) levels on malaria pathology was investigated in a case–control study of 1862 individuals from two major ethnic groups in three regions with intense perennial P. falciparum transmission in Cameroon. Thirty-four malaria candidate polymorphisms, including the sickle cell trait (HbS), were assayed on the Sequenom iPLEX platform while plasma TGF-β and IL-10 levels were measured by sandwich ELISA.ResultsThe study confirms the known protective effect of HbS against severe malaria and also reveals a protective effect of SNPs in the nitrogen oxide synthase 2 (NOS2) gene against malaria infection, anaemia and uncomplicated malaria. Furthermore, ADCY9 rs10775349 (additive G) and ABO rs8176746 AC individuals were associated with protection from hyperpyrexia and hyperparasitaemia, respectively. Meanwhile, individuals with the EMR1 rs373533 GT, EMR1 rs461645 CT and RTN3 rs542998 (additive C) genotypes were more susceptible to hyperpyrexia while both females and males with the rs1050828 and rs1050829 SNPs of G6PD, respectively, were more vulnerable to anaemia. Plasma TGF-β levels were strongly correlated with heterozygosity for the ADCY9 rs2230739 and HBB rs334 SNPs while individuals with the ABO rs8176746 AC genotype had lower IL-10 levels.ConclusionTaken together, this study suggests that some rare polymorphisms in candidate genes may have important implications for the susceptibility of Cameroonians to severe malaria. Moreover using the uncomplicated malaria phenotype may permit the identification of novel pathways in the early development of the disease.
Highlights
Plasmodium falciparum malaria is one of the most widespread and deadliest infectious diseases in children under five years in endemic areas
Additional file 1 shows the minimum p-values from allelic/genotypic tests applied to the autosomal Single-nucleotide polymorphisms (SNPs), and confirms that the sickle cell (HbS) polymorphism was significantly associated with protection from malaria infection [AT vs. AA/TT, odds ratio (OR) = 0.29, 95%CI 0.21-0.42, p = 4.95 × 10-13] and from severe malaria anaemia (SMA) [AT vs. AA/TT, OR = 0.34, 95%CI 0.130.93, p = 0.024] (Table 2)
This study suggests that the protective effect of the sickle cell trait may be linked to the raised level of Transforming growth factor (TGF)-ß and provides additional support for a role of ABO and reticulon 3 (RTN3) against severe malaria
Summary
Plasmodium falciparum malaria is one of the most widespread and deadliest infectious diseases in children under five years in endemic areas. Why only a small proportion (1–3%) of Plasmodium falciparum infections comprise a large part of human diversity, and their inheritance may alter susceptibility to disease [4]. There are a number of interesting candidate polymorphisms that have been associated with other infectious diseases and may be linked to malaria pathogenesis. The susceptibility to typhoid fever is associated with a polymorphism in the cystic fibrosis transmembrane conductance regulator (CFTR) [9], while genetic associations of a member of the tripartite motif (TRIM) family with human immunodeficiency virus type 1 infection [10] have been reported. The levels of reticulon 3 (RTN3) is significantly increased in malaria and other infections [11] suggesting that it may be linked to the disease
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