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Background   Plasmodium 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.    Methods  The 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.    Results  The 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.    Conclusion  Taken 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.

Association of candidate gene polymorphisms and TGF-beta/IL-10 levels with malaria in three regions of Cameroon: a case–control study