TY - JOUR TI - Two complement receptor one alleles have opposing associations with cerebral malaria and interact with α+thalassaemia AU - Opi, D Herbert AU - Swann, Olivia AU - Macharia, Alexander AU - Uyoga, Sophie AU - Band, Gavin AU - Ndila, Carolyne M AU - Harrison, Ewen M AU - Thera, Mahamadou A AU - Kone, Abdoulaye K AU - Diallo, Dapa A AU - Doumbo, Ogobara K AU - Lyke, Kirsten E AU - Plowe, Christopher V AU - Moulds, Joann M AU - Shebbe, Mohammed AU - Mturi, Neema AU - Peshu, Norbert AU - Maitland, Kathryn AU - Raza, Ahmed AU - Kwiatkowski, Dominic P AU - Rockett, Kirk A AU - Williams, Thomas N AU - Rowe, J Alexandra A2 - Pai, Madhukar VL - 7 PY - 2018 DA - 2018/04/25 SP - e31579 C1 - eLife 2018;7:e31579 DO - 10.7554/eLife.31579 UR - https://doi.org/10.7554/eLife.31579 AB - 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, 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 Sl2 and McCb and malaria phenotypes, and find they have opposing 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 identify an apparent interaction between Sl2 and α+thalassaemia, with the protective association of Sl2 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. KW - Complement receptor 1 KW - Knops blood group KW - Cerebral malaria KW - Alpha thalassaemia JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -