title: The IL17F and IL17RA Genetic Variants Increase Risk of Cerebral Malaria in Two African Populations.
abstract: Cerebral malaria (CM) is a neurological complication of infection with Plasmodium falciparum that is partly caused by cytokine-mediated inflammation. It is not known whether interleukin-17 (IL-17) cytokines, which regulate inflammation, control the development of CM. To evaluate the involvement of IL-17 cytokines in CM, we analyzed 46 common polymorphisms in IL17A, IL17F, and IL17RA (which encodes the common receptor chain of the members of the IL-17 family) in two independent African populations. A case-control study involving 115 Nigerian children with CM and 160 controls from the community (CC) showed that IL17F reference single nucleotide polymorphism (SNP) 6913472 (rs6913472) (P = 0.004; odds ratio [OR] = 3.12), IL17F rs4715291 (P = 0.004; OR = 2.82), IL17RA rs12159217 (P = 0.01; OR = 2.27), and IL17RA rs41396547 (P = 0.026; OR = 3.15) were independently associated with CM. A replication study was performed in 240 nuclear Malian family trios (two parents with one CM child). We replicated the association for 3 SNPs, IL17F rs6913472 (P = 0.03; OR = 1.39), IL17RA rs12159217 (P = 0.01; OR = 1.52), and IL17RA rs41396547 (P = 0.04; OR = 3.50). We also found that one additional SNP, IL17RA rs41433045, in linkage disequilibrium (LD) with rs41396547, was associated with CM in both Nigeria and Mali (P = 0.002; OR = 4.12 in the combined sample). We excluded the possibility that SNPs outside IL17F and IL17RA, in strong LD with the associated SNPs, could account for the observed associations. Furthermore, the results of a functional study indicated that the aggravating GA genotype of IL17F rs6913472 was associated with lower IL-17F concentrations. Our findings show for the first time that IL17F and IL17RA polymorphisms modulate susceptibility to CM and provide evidence that IL-17F protects against CM.
authors.affiliation: Aix-Marseille Université, UMR_S 906, Marseille, France Inserm, U906, Marseille, France sandrine.marquet@univ-amu.fr delmiro.fernandez-reyes@ucl.ac.uk.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marquet
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, London, United Kingdom.
authors.forename: Ianina
authors.initials: I
authors.lastname: Conte
authors.affiliation: Malaria Research and Training Center, Department of Epidemiology of Parasitic Disease, Faculty of Medicine, USTTB, Bamako, Mali.
authors.forename: Belco
authors.initials: B
authors.lastname: Poudiougou
authors.affiliation: Aix-Marseille Université, UMR_S 906, Marseille, France Inserm, U906, Marseille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Argiro
authors.affiliation: Aix-Marseille Université, UMR_S 906, Marseille, France Inserm, U906, Marseille, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Cabantous
authors.affiliation: Aix-Marseille Université, UMR_S 906, Marseille, France Inserm, U906, Marseille, France.
authors.forename: Hélia
authors.initials: H
authors.lastname: Dessein
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, London, United Kingdom.
authors.forename: Florence
authors.initials: F
authors.lastname: Burté
authors.affiliation: Centre des Oeuvres Universitaires, University of Bamako, Bamako, Mali.
authors.forename: Aboubacar A
authors.initials: AA
authors.lastname: Oumar
authors.affiliation: Department of Paediatrics, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria Department of Haematology, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria Childhood Malaria Research Group, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria.
authors.forename: Biobele J
authors.initials: BJ
authors.lastname: Brown
authors.affiliation: Malaria Research and Training Center, Department of Epidemiology of Parasitic Disease, Faculty of Medicine, USTTB, Bamako, Mali.
authors.forename: Abdoualye
authors.initials: A
authors.lastname: Traore
authors.affiliation: Department of Paediatrics, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria.
authors.forename: Nathaniel K
authors.initials: NK
authors.lastname: Afolabi
authors.affiliation: Paediatric Wards, Gabriel Toure Hospital, Bamako, Mali.
authors.forename: Abdoulaye
authors.initials: A
authors.lastname: Barry
authors.affiliation: Department of Paediatrics, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria Childhood Malaria Research Group, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria.
authors.forename: Samuel
authors.initials: S
authors.lastname: Omokhodion
authors.affiliation: Aix-Marseille Université, UMR_S 906, Marseille, France Inserm, U906, Marseille, France.
authors.forename: Ursule Ewanda
authors.initials: UE
authors.lastname: Ndoumbe
authors.affiliation: Department of Haematology, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria Childhood Malaria Research Group, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria.
authors.forename: Wuraola A
authors.initials: WA
authors.lastname: Shokunbi
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, London, United Kingdom Department of Paediatrics, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria Department of Haematology, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria Childhood Malaria Research Group, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria Department of Computer Science, University College London, London, United Kingdom.
authors.forename: Olugbemiro
authors.initials: O
authors.lastname: Sodeinde
authors.affiliation: Malaria Research and Training Center, Department of Epidemiology of Parasitic Disease, Faculty of Medicine, USTTB, Bamako, Mali.
authors.forename: Ogobara
authors.initials: O
authors.lastname: Doumbo
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, London, United Kingdom Department of Paediatrics, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria Department of Haematology, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria Childhood Malaria Research Group, College of Medicine, University of Ibadan, University College Hospital, Ibadan, Nigeria Department of Computer Science, University College London, London, United Kingdom sandrine.marquet@univ-amu.fr delmiro.fernandez-reyes@ucl.ac.uk.
authors.forename: Delmiro
authors.initials: D
authors.lastname: Fernandez-Reyes
authors.affiliation: Aix-Marseille Université, UMR_S 906, Marseille, France Inserm, U906, Marseille, France.
authors.forename: Alain J
authors.initials: AJ
authors.lastname: Dessein
mesh_terms: D000293:Adolescent; D000349:Africa / Q000453:epidemiology; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D007223:Infant; D020381:Interleukin-17 / Q000235:genetics* / Q000276:immunology; D015810:Linkage Disequilibrium; D016779:Malaria, Cerebral / Q000453:epidemiology / Q000208:ethnology* / Q000235:genetics* / Q000276:immunology; D008297:Male; D020641:Polymorphism, Single Nucleotide; D053722:Receptors, Interleukin-17 / Q000235:genetics* / Q000276:immunology
chemical_list: C440021:IL17F protein, human; C109985:IL17RA protein, human; D020381:Interleukin-17; D053722:Receptors, Interleukin-17