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

Abstract

jCerebral 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. C erebral malaria (CM) is one of the most severe complications of infection with Plasmodium falciparum and occurs predominantly in young children under 5 years of age and in "nonimmune" adults. The clinical characteristics of CM are an unarousable coma lasting for at least 1 h, with or without generalized convulsions, and asexual P. falciparum parasitemia with normal cerebrospinal fluid and no other cause of encephalopathy. This reversible encephalopathy is characterized by the sequestration of infected red blood cells (IRBC) in the capillaries of the brain together with the accumulation of leukocytes, platelets, and uninfected red blood cells (URBC) causing mechanical obstruction of microvessels and excessive activation of immune cells. Other pathological consequences are brain edema, alterations of the integrity of the blood-brain barrier (BBB), microhemorrhages, and tissue necrosis (1). However, despite the large number of studies that have investigated CM, the orchestration of the pathogenic mechanisms leading to CM is not well understood.Proinflammatory cytokines are thought to contribute to brain pathology in CM. Interleukin-17A (IL-17A) and IL-17F, the best-studied members of the IL-...

Novel genetic polymorphisms associated with severe malaria and under selective pressure in North-eastern Tanzania

“…Conversely, the IL-23 / IL-17 immune pathway has been implicated in the development of inflammatory reactions in children that develop severe malarial anaemia [ 21 ], in multi-organ dysfunction and acute renal failure in adult P . falciparum cases from India [ 22 ] and with the risk of cerebral malaria in Africa [ 23 ]. IL-23R haplotypes have also been associated with increased susceptibility to severe malarial anaemia in Kenya [ 24 ].…”

Elevated IL-17 levels in semi-immune anaemic mice infected with Plasmodium berghei ANKA

“…Recent reports have also shown IL-17 relationship with SMA [ 26 , 27 ]. Apart from these studies linking IL-17 with haemoglobin (Hb) loss, other studies have shown IL-17 to be involved in multiple organ dysfunction [ 28 ], and also found to be associated with higher risk in developing cerebral malaria (CM) [ 29 ]. Since previous studies have reported the recovery of a group of semi-immune mice at low parasitaemia [ 23 , 24 ], and also for the fact that IL-17 was implicated in one study [ 24 ], it is hypothesized that IL-17 is involved in the recovery/protection of the semi-immune mice at low Hb levels.…”

Evaluation of IL‐17A, IL‐17F, IL‐23R, VDR, CCL2, CCL5, CCR2, and CCR5 gene polymorphisms and expression in Chinese individuals with syphilis

“…Therefore, Th17-related genes were considered as excellent candidate genes for infection diseases. 10 The current study investigated the frequency of IL-17A (rs2275913 and rs3819024), IL-17F (rs763780), and IL-23R (rs11209026 and rs1884444) polymorphisms in a Chinese population with susceptibility to syphilis. 10 The current study investigated the frequency of IL-17A (rs2275913 and rs3819024), IL-17F (rs763780), and IL-23R (rs11209026 and rs1884444) polymorphisms in a Chinese population with susceptibility to syphilis.…”

“…5,6 T-helper type 17 (Th17) cells, a distinct subset of CD4 + T cells, can induce the expression of interleukin (IL)-23R and secrete IL-17 and other cytokines. [10][11][12][13] The vitamin D receptor (VDR) gene encodes a nuclear receptor for the active form of vitamin D, 1,25-dihydroxy vitamin D3 [1,25(OH) 2 D 3 ]. 7 IL-17, a novel family of proinflammatory cytokines comprising six members: IL-17A to 17F is involved in activation of T cells and maturation of macrophages and dendritic cells.…”

“…Mounting evidence shows that the single-nucleotide polymorphism (SNP) of Th17-related cytokines (IL-17A, IL-17F, and IL-23R) was associated with the susceptibility to infectious diseases. [10][11][12][13] The vitamin D receptor (VDR) gene encodes a nuclear receptor for the active form of vitamin D, 1,25-dihydroxy vitamin D3 [1,25(OH) 2 D 3 ]. After binding to its response element on DNA, 1,25(OH) 2 D 3 regulates different genes with different functions.…”