Triosephosphate isomerase gene promoter variation: -5G/A and -8G/A polymorphisms in clinical malaria groups in two African populations

- Four SNPs variants of TPI1 were analyzed in malaria patients.
- Two STRs were studied to evaluate haplotype diversity and antiquity of TPI1 promoter variants.
- TPI1 -8A allele was more frequent in non-severe malaria groups.
- The age estimate for -8 variant is within the period of origin of the malaria vector in Africa.
- TPI1 variants could have arisen due to a selective advantage against malaria.

TPI1 promoter polymorphisms occur in high prevalence in individuals from African origin. Malaria-patients from Angola and Mozambique were screened for the TPI1 gene promoter variants rs1800200A > G, (-5G > A), rs1800201G > A, (-8G > A), rs1800202T > G, (-24T > G), and for the intron 5 polymorphism rs2071069G > A, (2262G > A). -5G > A and -8G > A variants occur in 47% and 53% in Angola and Mozambique, respectively while -24T > G was monomorphic for the wild-type T allele. Six haplotypes were identified and -8A occurred in 45% of the individuals, especially associated with the GAG haplotype and more frequent in non-severe malaria groups, although not significantly. The arising and dispersion of -5G > A and -8G > A polymorphisms is controversial. Their age was estimated by analyses of two microsatellite loci, CD4 and ATN1, adjacent to TPI1 gene. The -5G > A is older than -8G > A, with an average estimate of approximately 35,000 years. The -8A variant arose in two different backgrounds, suggesting independent mutational events. The first, on the -5G background, may have occurred in East Africa around 20,800 years ago; the second, on the -5A background, may have occurred in West Africa some 7500 years ago. These estimates are within the period of spread of agriculture and the malaria mosquito vector in Africa, which could has been a possible reason for the selection of -8A polymorphism in malaria endemic countries.