Associations between sickle haemoglobin and the <i>Plasmodium falciparum CLAG</i> and <i>FIKK</i> gene families revealed by meta-analysis of 6,289 African samples

Abstract The recent discovery that mutations in the Plasmodium falciparum genome are overrepresented in infections of sickle haemoglobin (HbS)-carriers has highlighted new questions about the underlying biological and evolutionary interaction, yet the full extent of this association is unknown. By meta-analysing host and parasite data from N=6,289 infections, including 831 newly sequenced samples from The Gambia, we implicate several new parasite genome regions in the interaction, including within the CLAG3 nutrient uptake channel and the threonine/serine kinase FIKK3 on chromosome 3. The HbS-associated mutations share unusually strong linkage disequilibrium, and we use a series of analyses to disentangle their complex genetic structure and independent effects. The most prominent signal is observed at a polymorphism shared between two CLAG3 paralogs, estimated to halve the level of protection due to HbS. Alongside previous findings in ACS8 and FIKK4 . 2 , these results now implicate three of the major P. falciparum gene families in host-parasite interactions and open new avenues for functional inquiry.