Abstract
Several studies have provided evidence of both helpful and harmful effects of TNF on the outcome of Plasmodium falciparum malaria infection. Several TNF polymorphisms that are located within non-coding regions have been associated with parasitaemia, mild malaria or severe malaria. We investigated the association of TNF1304 (rs3093664), TNF-308 (rs1800629), TNF-238 (rs361525) and TNF-244 (rs673) with mild malaria and symptomatic maximum parasitaemia in a population-based design (n=310). We obtained nominal evidence for an association between symptomatic maximum parasitaemia and TNF-308, TNF-238, and TNF-244 on the one hand, and between the number of mild malaria attacks and TNF-244 on the other hand. After accounting for multiple tests, we confirmed the association of symptomatic maximum parasitaemia with TNF-244. We further provide bioinformatics and experimental evidence that TNF-244 has a cis-regulatory effect. This is the first report that emphasizes the potential role of TNF-244 in malaria.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 digital issues and online access to articles
$119.00 per year
only $19.83 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Kindler V, Sappino AP, Grau GE, Piguet PF, Vassalli P . The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell 1989; 56: 731–740.
Flynn JL, Goldstein MM, Chan J, Triebold KJ, Pfeffer K, Lowenstein CJ et al. Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 1995; 2: 561–572.
Titus RG, Sherry B, Cerami A . Tumor necrosis factor plays a protective role in experimental murine cutaneous leishmaniasis. J Exp Med 1989; 170: 2097–2104.
Liew FY, Parkinson C, Millott S, Severn A, Carrier M . Tumour necrosis factor (TNF alpha) in leishmaniasis. I. TNF alpha mediates host protection against cutaneous leishmaniasis. Immunology 1990; 69: 570–573.
Sibley LD, Adams LB, Fukutomi Y, Krahenbuhl JL . Tumor necrosis factor-alpha triggers antitoxoplasmal activity of IFN-gamma primed macrophages. J Immunol 1991; 147: 2340–2345.
Johnson LL . A protective role for endogenous tumor necrosis factor in Toxoplasma gondii infection. Infect Immun 1992; 60: 1979–1983.
Bouharoun-Tayoun H, Attanath P, Sabchareon A, Chongsuphajaisiddhi T, Druilhe P . Antibodies that protect humans against Plasmodium falciparum blood stages do not on their own inhibit parasite growth and invasion in vitro, but act in cooperation with monocytes. J Exp Med 1990; 172: 1633–1641.
Kremsner PG, Winkler S, Brandts C, Wildling E, Jenne L, Graninger W et al. Prediction of accelerated cure in Plasmodium falciparum malaria by the elevated capacity of tumor necrosis factor production. Am J Trop Med Hyg 1995; 53: 532–538.
Bouharoun-Tayoun H, Oeuvray C, Lunel F, Druilhe P . Mechanisms underlying the monocyte-mediated antibody-dependent killing of Plasmodium falciparum asexual blood stages. J Exp Med 1995; 182: 409–418.
Hernandez-Valladares M, Naessens J, Musoke AJ, Sekikawa K, Rihet P, Ole-Moiyoi OK et al. Pathology of Tnf-deficient mice infected with Plasmodium chabaudi adami 408XZ. Exp Parasitol 2006; 114: 271–278.
Grau GE, Taylor TE, Molyneux ME, Wirima JJ, Vassalli P, Hommel M et al. Tumor necrosis factor and disease severity in children with falciparum malaria. N Engl J Med 1989; 320: 1586–1591.
Kwiatkowski D, Hill AV, Sambou I, Twumasi P, Castracane J, Manogue KR et al. TNF concentration in fatal cerebral, non-fatal cerebral, and uncomplicated Plasmodium falciparum malaria. Lancet 1990; 336: 1201–1204.
Engwerda C, Belnoue E, Gruner AC, Renia L . Experimental models of cerebral malaria. Curr Top Microbiol Immunol 2005; 297: 103–143.
Flori L, Delahaye NF, Iraqi FA, Hernandez-Valladares M, Fumoux F, Rihet P . TNF as a malaria candidate gene: polymorphism-screening and family-based association analysis of mild malaria attack and parasitemia in Burkina Faso. Genes Immun 2005; 6: 472–480.
Aidoo M, McElroy PD, Kolczak MS, Terlouw DJ, ter Kuile FO, Nahlen B et al. Tumor necrosis factor-alpha promoter variant 2 (TNF2) is associated with pre-term delivery, infant mortality, and malaria morbidity in western Kenya: Asembo Bay Cohort Project IX. Genet Epidemiol 2001; 21: 201–211.
McGuire W, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D . Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature 1994; 371: 508–510.
Jepson A, Sisay-Joof F, Banya W, Hassan-King M, Frodsham A, Bennett S et al. Genetic linkage of mild malaria to the major histocompatibility complex in Gambian children: study of affected sibling pairs. BMJ 1997; 315: 96–97.
Brisebarre A, Kumulungui B, Sawadogo S, Atkinson A, Garnier S, Fumoux F et al. A genome scan for Plasmodium falciparum malaria identifies quantitative trait loci on chromosomes 5q31, 6p21.3, 17p12, and 19p13. Malaria J 2014; 13: 198.
Flori L, Sawadogo S, Esnault C, Delahaye NF, Fumoux F, Rihet P . Linkage of mild malaria to the major histocompatibility complex in families living in Burkina Faso. Hum Mol Genet 2003; 12: 375–378.
Koukouikila-Koussounda F, Ntoumi F . Malaria epidemiological research in the Republic of Congo. Malaria J 2016; 15: 598.
Rogier C, Commenges D, Trape JF . Evidence for an age-dependent pyrogenic threshold of Plasmodium falciparum parasitemia in highly endemic populations. Am J Trop Med Hygiene 1996; 54: 613–619.
Wattavidanage J, Carter R, Perera KL, Munasingha A, Bandara S, McGuinness D et al. TNFalpha*2 marks high risk of severe disease during Plasmodium falciparum malaria and other infections in Sri Lankans. Clin Exp Immunol 1999; 115: 350–355.
Kroeger KM, Carville KS, Abraham LJ . The -308 tumor necrosis factor-alpha promoter polymorphism effects transcription. Mol Immunol 1997; 34: 391–399.
Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW . Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci USA 1997; 94: 3195–3199.
Karimi M, Goldie LC, Cruickshank MN, Moses EK, Abraham LJ . A critical assessment of the factors affecting reporter gene assays for promoter SNP function: a reassessment of -308 TNF polymorphism function using a novel integrated reporter system. Eur J Hum Genet 2009; 17: 1454–1462.
McGuire W, Knight JC, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D . Severe malarial anemia and cerebral malaria are associated with different tumor necrosis factor promoter alleles. J Infect Dis 1999; 179: 287–290.
Knight JC, Udalova I, Hill AV, Greenwood BM, Peshu N, Marsh K et al. A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria. Nat Genet 1999; 22: 145–150.
Clark TG, Diakite M, Auburn S, Campino S, Fry AE, Green A et al. Tumor necrosis factor and lymphotoxin-alpha polymorphisms and severe malaria in African populations. J Infect Dis 2009; 199: 569–575.
Kaluza W, Reuss E, Grossmann S, Hug R, Schopf RE, Galle PR et al. Different transcriptional activity and in vitro TNF-alpha production in psoriasis patients carrying the TNF-alpha 238A promoter polymorphism. J Invest Dermatol 2000; 114: 1180–1183.
Koukouikila-Koussounda F, Ntoumi F, Ndounga M, Tong HV, Abena AA, Velavan TP . Genetic evidence of regulatory gene variants of the STAT6, IL10R and FOXP3 locus as a susceptibility factor in uncomplicated malaria and parasitaemia in Congolese children. Malaria J 2013; 12: 9.
Rodriguez S, Gaunt TR, Day IN . Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol 2009; 169: 505–514.
Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.
Sankoh AJ, Huque MF, Dubey SD . Some comments on frequently used multiple endpoint adjustment methods in clinical trials. Stat Med 1997; 16: 2529–2542.
Ritchie GR, Dunham I, Zeggini E, Flicek P . Functional annotation of noncoding sequence variants. Nat Methods 2014; 11: 294–296.
Griffon A, Barbier Q, Dalino J, van Helden J, Spicuglia S, Ballester B . Integrative analysis of public ChIP-seq experiments reveals a complex multi-cell regulatory landscape. Nucleic Acids Res 2015; 43: e27.
Zeng G, Sticky-end PCR . new method for subcloning. BioTechniques 1998; 25: 206–208.
Acknowledgements
We thank all the individuals for participating in the study. We thank Laurence Borge for assistance and the use of the cell culture platform facility (CRCM U1068, Marseille). This work was supported by Institut National de la Santé et de la Recherche Médicale (Inserm) and Aix-Marseille University. TNN and SB were supported by a PhD fellowship from the Vietnamese government and the French ministry, respectively. FKK and FN are members of the Central African Network on Tuberculosis, HIV/AIDS and Malaria, CANTAM) supported by EDCTP.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on Genes and Immunity website
Supplementary information
Rights and permissions
About this article
Cite this article
Nguyen, T., Baaklini, S., Koukouikila-Koussounda, F. et al. Association of a functional TNF variant with Plasmodium falciparum parasitaemia in a congolese population. Genes Immun 18, 152–157 (2017). https://doi.org/10.1038/gene.2017.13
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/gene.2017.13
This article is cited by
-
TNF-α promoter polymorphisms (G-238A and G-308A) are associated with susceptibility to Systemic Lupus Erythematosus (SLE) and P. falciparum malaria: a study in malaria endemic area
Scientific Reports (2019)
-
Cell death pathologies: targeting death pathways and the immune system for cancer therapy
Genes & Immunity (2019)