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

Abstract

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 (<i>CR1</i>) gene, named <i>Sl2</i> and <i>McC^b</i>, 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 <i>Sl2</i> and <i>McC^b</i> and malaria phenotypes, and find they have opposing associations. The <i>Sl2</i> polymorphism is associated with markedly reduced odds of cerebral malaria and death, while the <i>McC^b</i> polymorphism is associated with increased odds of cerebral malaria. We also identify an apparent interaction between <i>Sl2</i> and α⁺thalassaemia, with the protective association of <i>Sl2</i> 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.