Associations between sickle haemoglobin and the Plasmodium falciparum CLAG and FIKK 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. Competing Interest Statement The authors have declared no competing interest. Funding Statement Annie J. Forster and Gavin Band were supported by Wellcome (AJF: 218486/Z/19/Z; AJF, GB: 304926/Z/23/Z). HbS genotyping was supported by the John Fell Fund (0013254). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Scientific Coordinating Committee of the London School of Hygiene and Tropical Medicine gave ethical approval for this work. The Oxford Tropical Research Ethics Committee of the University of Oxford gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data availability Short read sequence read data from selective whole-genome amplification and sequencing of 905 P. falciparum genomes and long-read sequence data from genomes in the GAMCC dataset will be deposited on the European Nucleotide Archive (study accession: PRJEB97067). HbS and HbC genotypes are available within an accompanying sample file. A dataset of joint calls made across the GAMCC and CP1 is available from Zenodo (10.5281/zenodo.17056084). Association test summary statistics for a GWAS of severity in the GAMCC (Fig. 1) and the meta-analysis of HbS-associations across multiple datasets (Fig. 2) are also available from Zenodo (10.5281/zenodo.17056194).