DNA phasing by TA dinucleotide microsatellite length determines in vitro and in vivo expression of the gp91^phox subunit of NADPH oxidase and mediates protection against severe malaria

Reactive oxygen intermediates (ROIs) play a major role in the nonspecific innate immune response to invading microorganisms, such as Plasmodium falciparum. In a search for genetic markers that determine differences in production of ROI, we detected a highly polymorphic region of dinucleotide TA repeats ∼550 bp upstream of the NADPH oxidase gp91^phox subunit promoter. We genotyped 183 matched Gabonese children with severe or mild malaria. Repeat lengths TA₁₁ and TA₁₆ differed significantly in frequency between mild and severe infection, which suggests protection against severe malaria. Both repeat lengths showed lower levels of NADPH oxidase and promoter activities, which can be explained by a cyclic trend in TA repeat length with a period of ∼5, which indicates the necessity of correct DNA phasing between 2 possible control regions in the promoter. We provide a molecular model of how DNA phasing generated by TA dinucleotide polymorphisms may influence the expression level and protect against severe malaria.