The IL17F and IL17RA Genetic Variants Increase Risk of Cerebral Malaria in Two African Populations

• Published in: Infection and immunity 2016-02, Vol.84 (2), p.590-597
• Main Authors: Marquet, Sandrine, Conte, Ianina, Poudiougou, Belco, Argiro, Laurent, Cabantous, Sandrine, Dessein, Hélia, Burté, Florence, Oumar, Aboubacar A, Brown, Biobele J, Traore, Abdoualye, Afolabi, Nathaniel K, Barry, Abdoulaye, Omokhodion, Samuel, Ndoumbe, Ursule Ewanda, Shokunbi, Wuraola A, Sodeinde, Olugbemiro, Doumbo, Ogobara, Fernandez-Reyes, Delmiro, Dessein, Alain J
• Format: Article
• Language: English
• Subjects: Adolescent; Africa - epidemiology; Child; Child, Preschool; Computer Simulation; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetics, Population; Genotype; Host Response and Inflammation; Humans; Infant; Interleukin-17 - genetics; Interleukin-17 - immunology; Life Sciences; Linkage Disequilibrium; Malaria, Cerebral - epidemiology; Malaria, Cerebral - ethnology; Malaria, Cerebral - genetics; Malaria, Cerebral - immunology; Male; Plasmodium falciparum; Polymorphism, Single Nucleotide; Receptors, Interleukin-17 - genetics; Receptors, Interleukin-17 - immunology
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.00671-15

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.