FOXO3A regulatory polymorphism and susceptibility to severe malaria in Gabonese children

The clinical course of malaria varies between affected individuals and host genetic factors have been shown to influence the outcome of malaria. The role of FOXO3-driven pathway in modulating inflammatory responses, including mediation of distinct functions of regulatory T effector cell populations (Tregs) by the transcription factor FOXO3, has recently been recognized. We aimed to study possible associations of a non-coding polymorphism in intron 2 of the FOXO3A gene (rs12212067T>G) that was shown earlier to modulate the FOXO3 expression and to be associated with the prognosis of distinct inflammatory and infectious diseases. The FOXO3A polymorphism rs12212067T>G was genotyped by direct sequencing in a group of Gabonese children with confirmed Plasmodium falciparum malaria. Severe cases of malaria were compared with asymptomatic/mild cases. The FOXO3A variant rs12212067T>G was associated with the phenotype of severe malaria, but not with asymptomatic/mild malaria (allelic model: OR = 1.54, 95 % CI = 1.15–2.05, P = 0.0028; dominant model: OR = 1.94, 95 % CI = 1.36–2.77, P = 0.0002). The FOXO3A variant rs12212067T>G is associated with increased inflammatory responses to Plasmodium falciparum malaria, indicating a role of the FOXO3-dependent pathway in malaria.