| Summary: | <p>Abstract</p> <p>Background</p> <p>Severe malaria has been attributed to the expression of a restricted subset of the <it>var</it> multi-gene family, which encodes for <it>Plasmodium falciparum</it> erythrocyte membrane protein 1 (PfEMP1). PfEMP1 mediates cytoadherence and sequestration of infected erythrocytes into the post-capillary venules of vital organs such as the brain, lung or placenta. <it>var</it> genes are highly diverse and can be classified in three major groups (ups A, B and C) and two intermediate groups (B/A and B/C) based on the genomic location, gene orientation and upstream sequences. The genetic diversity of expressed <it>var</it> genes in relation to severity of disease in Tanzanian children was analysed.</p> <p>Methods</p> <p>Children with defined severe (SM) and asymptomatic malaria (AM) were recruited. Full-length <it>var mRNA</it> was isolated and reversed transcribed into <it>var cDNA.</it> Subsequently, the DBL and N-terminal domains, and up-stream sequences were PCR amplified, cloned and sequenced. Sequences derived from SM and AM isolates were compared and analysed.</p> <p>Results</p> <p>The analysis confirmed that the <it>var</it> family is highly diverse in natural <it>Plasmodium falciparum</it> populations. Sequence diversity of amplified <it>var</it> DBL-1α and upstream regions showed minimal overlap among isolates, implying that the <it>var</it> gene repertoire is vast and most probably indefinite in endemic areas. <it>var</it> DBL-1α sequences from AM isolates were more diverse with more singletons found (p<0.05) than those from SM infections. Furthermore, few <it>var</it> DBL-1α sequences from SM patients were rare and restricted suggesting that certain PfEMP1 variants might induce severe disease.</p> <p>Conclusions</p> <p>The genetic sequence diversity of <it>var</it> genes of <it>P. falciparum</it> isolates from Tanzanian children is large and its relationship to disease severity has been studied. Observed differences suggest that different <it>var</it> genes might have fundamentally different roles in the host-parasite interaction. Further research is required to examine clear disease-associations of <it>var</it> gene subsets in different geographical settings. The importance of very strict clinical definitions and appropriate large control groups needs to be emphasized for future studies on disease associations of PfEMP1<it>.</it></p>
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