Two complement receptor one alleles have opposing associations with cerebral malaria and interact with α + thalassaemia

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 ( ) gene, named and , occur at high frequencies, consistent with 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 estimate the relationship between and and malaria phenotypes, and find they have opposing associations. The polymorphism is associated with markedly reduced odds of cerebral malaria and death, while the polymorphism is associated with increased odds of cerebral malaria. We also identify an apparent interaction between and α thalassaemia, with the protective association of greatest in children with normal α-globin. The complex relationship between these three mutations may explain previous conflicting findings, highlighting the importance of considering genetic interactions in disease-association studies.