| Summary: | Malaria has been a major driving force in the evolution of the human genome. In sub-Saharan African populations, two neighbouring polymorphisms in the Complement Receptor One (CR1) gene, named Sl2 and McCb, occur at high frequencies, suggesting selection by malaria. Previous studies have been inconclusive. Using a large case-control study of severe malaria in Kenyan children and statistical models adjusted for confounders, we demonstrate that Sl2 and McCb have opposing malaria associations. The Sl2 polymorphism is associated with markedly reduced odds of cerebral malaria and death, while the McCb polymorphism is associated with increased odds of cerebral malaria. We also identified an unexpected interaction between Sl2 and α+thalassaemia, revealing that the protective association of Sl2 was greatest in children with normal α-globin. The complex relationship between these three mutations may explain previous conflicting findings, and the data highlight the importance of considering genetic interactions in disease-association studies.
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