ATP2B4 regulatory genetic variants are associated with mild malaria.

BACKGROUND: Genome-wide association studies have identified ATP2B4 as a severe malaria resistance gene. Recently, 8 potential causal regulatory variants have been shown to be associated with severe malaria. METHODS: Genotyping of rs10900585, rs11240734, rs1541252, rs1541253, rs1541254, rs1541255, rs10751450, rs10751451 and rs10751452 was performed in 154 unrelated individuals (79 controls and 75 mild malaria patients). rs10751450, rs10751451 and rs10751452 were genotyped by Taqman assays, whereas the fragment of the ATP2B4 gene containing the remaining SNPs was sequenced. Logistic regression analysis was used to assess the association between the SNPs and mild malaria. RESULTS: The results showed that mild malaria was associated with rs10900585, rs11240734, rs1541252, rs1541253, rs1541254, rs1541255, rs10751450, rs10751451 and rs10751452. The homozygous genotypes for the major alleles were associated with an increased risk of mild malaria. Furthermore, the haplotype containing the major alleles and that containing the minor alleles were the most frequent haplotypes. Individuals with the major haplotypes had a significantly higher risk of mild malaria compared to the carriers of the minor allele haplotype. CONCLUSIONS: ATP2B4 polymorphisms that have been associated with severe malaria are also associated with mild malaria.

Identification of ATP2B4 Regulatory Element Containing Functional Genetic Variants Associated with Severe Malaria.

Genome-wide association studies for severe malaria (SM) have identified 30 genetic variants mostly located in non-coding regions. Here, we aimed to identify potential causal genetic variants located in these loci and demonstrate their functional activity. We systematically investigated the regulatory effect of the SNPs in linkage disequilibrium (LD) with the malaria-associated genetic variants. Annotating and prioritizing genetic variants led to the identification of a regulatory region containing five ATP2B4 SNPs in LD with rs10900585. We found significant associations between SM and rs10900585 and our candidate SNPs (rs11240734, rs1541252, rs1541253, rs1541254, and rs1541255) in a Senegalese population. Then, we demonstrated that both individual SNPs and the combination of SNPs had regulatory effects. Moreover, CRISPR/Cas9-mediated deletion of this region decreased ATP2B4 transcript and protein levels and increased Ca2+ intracellular concentration in the K562 cell line. Our data demonstrate that severe malaria-associated genetic variants alter the expression of ATP2B4 encoding a plasma membrane calcium-transporting ATPase 4 (PMCA4) expressed on red blood cells. Altering the activity of this regulatory element affects the risk of SM, likely through calcium concentration effect on parasitaemia.

Photoreactivity of NO2 on mineral dusts originating from different locations of the Sahara desert.

The heterogeneous reaction of NO(2) on Saharan sand collected from different locations has been studied at 298 K and 25% relative humidity using a horizontal coated-wall flow tube. The sand samples originated from Mauritania, Algeria, Morocco and Tunisia and were taken as simplified proxies for mineral dust. While the uptake in the dark was always very small, a photo-enhanced uptake of NO(2) was observed on all four samples showing that natural minerals do have a photochemical activity. The uptake coefficient gamma(BET) was measured for all sands. In the dark, the gamma(BET) values are (1.60 +/- 0.24) x 10(-8), (0.43 +/- 0.06) x 10(-8), (0.94 +/- 0.14) x 10(-8) and (0.59 +/- 0.09) x 10(-8) for the samples from Mauritania, Algeria, Morocco and Tunisia, respectively. Under realistic atmospheric conditions, the observed photo-enhancement leads to uptake coefficients of (1.46 +/- 0.21) x 10(-7), (0.35 + 0.05) x 10(-7), (1.30 +/- 0.19) x 10(-7) and (0.89 +/- 0.13) x 10(-7), respectively, i.e. an enhancement factor ranging from 8 to 15. This study shows that the photochemistry of natural minerals will impact significantly on the heterogeneous chemistry of NO(2).

Photochemistry of atmospheric dust: ozone decomposition on illuminated titanium dioxide.

The ozone decomposition onto mineral surfaces prepared with traces of solid TiO2 in a matrix of SiO2 in order to mimic mineral dust particles has been investigated using a coated-wall flow-tube system at room temperature and atmospheric pressure. The ozone uptake coefficients were measured both under dark conditions and irradiation using near UV-light. While uptake in the dark was negligible, a large photoenhanced ozone uptake was observed. For TiO2/SiO2 mixtures under irradiation, the uptake coefficients increased with increasing TiO2 mass fraction (from 1 to 3 wt %), and the corresponding uptake coefficient based on the geometric surfaces ranged from 3 x 10(-6) to 3 x 10(-5). The uptake kinetics was also observed to increase with decreasing ozone concentration between 290 and 50 ppbv. Relative humidity influenced the ozone uptake on the film, and a reduced ozone loss was observed for relative humidity above 30%. The experimental results suggest that under atmospherically relevant conditions the photochemistry of dust can represent an important sink of ozone inside the dust plume.