Interleukin-10 (IL-10) production is under tight genetic control in populations living in affluent environments. However, little is known about the role of IL10 genetics on cytokine production in populations living in environments with high infectious pressure. We have previously reported that, in a rural Ghanaian population, the most common IL10 haplotype associates with a pro-inflammatory response. Here, we aim to replicate these findings in an independent sample of the same population 2 years later. IL-10 and tumour necrosis factor-α (TNF-α) protein concentrations were determined in whole-blood samples ex vivo stimulated with lipopolysaccharide and zymosan in 2006 (n=615) and 2008 (n=647). The association between IL10 single nucleotide polymorphisms and Z-scores of IL-10 and TNF-α levels was analysed in each population subset. The most common IL10 haplotype was associated with a significantly lower IL-10 production and nonsignificantly increased TNF-α levels. The correlation between repeated cytokine assays, based on 111 individuals with measurements in both 2006 and 2008, was r=0.53 (P<0.001) for IL-10 and r=0.36 (P<0.001) for TNF-α. The replication of our previously found effect of variation in the IL10 gene on IL-10 production and the correlation between repeated cytokine stimulation assays provide evidence that IL10 genetics have an important role in regulating the host response under high infectious pressure.
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van Bodegom D, May L, Meij HJ, Westendorp RG . Regulation of human life histories: the role of the inflammatory host response. Ann N Y Acad Sci 2007; 1100: 84–97.
Barreiro LB, Quintana-Murci L . From evolutionary genetics to human immunology: how selection shapes host defence genes. Nat Rev Genet 2010; 11: 17–30.
Le Souef PN, Goldblatt J, Lynch NR . Evolutionary adaptation of inflammatory immune responses in human beings. Lancet 2000; 356: 242–244.
de Craen AJ, Posthuma D, Remarque EJ, van den Biggelaar AH, Westendorp RG, Boomsma DI . Heritability estimates of innate immunity: an extended twin study. Genes Immun 2005; 6: 167–170.
Westendorp RG, Langermans JA, Huizinga TW, Elouali AH, Verweij CL, Boomsma DI et al. Genetic influence on cytokine production and fatal meningococcal disease. Lancet 1997; 349: 170–173.
Reuss E, Fimmers R, Kruger A, Becker C, Rittner C, Hohler T . Differential regulation of interleukin-10 production by genetic and environmental factors—a twin study. Genes Immun 2002; 3: 407–413.
Kuningas M, May L, Tamm R, van Bodegom D, van den Biggelaar AH, Meij JJ et al. Selection for genetic variation inducing pro-inflammatory responses under adverse environmental conditions in a Ghanaian population. PLoS One 2009; 4: e7795.
Daftarian PM, Kumar A, Kryworuchko M, Diaz-Mitoma F . IL-10 production is enhanced in human T cells by IL-12 and IL-6 and in monocytes by tumor necrosis factor-alpha. J Immunol 1996; 157: 12–20.
Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A . Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001; 19: 683–765.
Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG . Replication validity of genetic association studies. Nat Genet 2001; 29: 306–309.
May L, van Bodegom D, Kuningas M, Meij JJ, de Craen AJ, Frolich M et al. Performance of the whole-blood stimulation assay for assessing innate immune activation under field conditions. Cytokine 2009; 45: 184–189.
Smith AJ, Humphries SE . Cytokine and cytokine receptor gene polymorphisms and their functionality. Cytokine Growth Factor Rev 2009; 20: 43–59.
Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV A . An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 1997; 24: 1–8.
Crawley E, Kay R, Sillibourne J, Patel P, Hutchinson I, Woo P . Polymorphic haplotypes of the interleukin-10 5′ flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. Arthritis Rheum 1999; 42: 1101–1108.
Suarez A, Castro P, Alonso R, Mozo L, Gutierrez C . Interindividual variations in constitutive interleukin-10 messenger RNA and protein levels and their association with genetic polymorphisms. Transplantation 2003; 75: 711–717.
Edwards-Smith CJ, Jonsson JR, Purdie DM, Bansal A, Shorthouse C, Powell EE . Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis C to interferon alfa. Hepatology 1999; 30: 526–530.
Koss K, Satsangi J, Fanning GC, Welsh KI, Jewell DP . Cytokine (TNF alpha, LT alpha and IL-10) polymorphisms in inflammatory bowel diseases and normal controls: differential effects on production and allele frequencies. Genes Immun 2000; 1: 185–190.
Schippers EF, van ‘t Veer C, van Voorden S, Martina CA, Huizinga TW, le Cessie S et al. IL-10 and toll-like receptor-4 polymorphisms and the in vivo and ex vivo response to endotoxin. Cytokine 2005; 29: 215–228.
Stanilova SA, Miteva LD, Karakolev ZT, Stefanov CS . Interleukin-10-1082 promoter polymorphism in association with cytokine production and sepsis susceptibility. Intensive Care Med 2006; 32: 260–266.
Hutchings A, Guay-Woodford L, Thomas JM, Young CJ, Purcell WM, Pravica V et al. Association of cytokine single nucleotide polymorphisms with B7 costimulatory molecules in kidney allograft recipients. Pediatr Transplant 2002; 6: 69–77.
Steinke JW, Barekzi E, Huyett P, Borish L . Differential interleukin-10 production stratified by -571 promoter polymorphism in purified human immune cells. Cell Immunol 2007; 249: 101–107.
Luik A, Knapp S, Thursz M, Thomas HC, Schlaak JF . Autoregulatory role of interleukin-10 in hepatitis C patients treated with IFN-alpha. J Interferon Cytokine Res 2004; 24: 585–593.
Warle MC, Farhan A, Metselaar HJ, Hop WC, Perrey C, Zondervan PE et al. Are cytokine gene polymorphisms related to in vitro cytokine production profiles? Liver Transpl 2003; 9: 170–181.
Huizinga TW, Keijsers V, Yanni G, Hall M, Ramage W, Lanchbury J et al. Are differences in interleukin 10 production associated with joint damage? Rheumatology (Oxford) 2000; 39: 1180–1188.
van den Biggelaar AH, Hua TD, Rodrigues LC, Kremsner PG, Yazdanbakhsh M, Kube D . Genetic variation in IL-10 is associated with atopic reactivity in Gabonese schoolchildren. J Allergy Clin Immunol 2007; 120: 973–975.
Akira S, Uematsu S, Takeuchi O . Pathogen recognition and innate immunity. Cell 2006; 124: 783–801.
Ghana Health Service. Upper East Regional Health Administration Annual Report 2004.
World Health Organization. Mortality Country Fact Sheet. Ghana 2006.
Ghana Statistical Service (GSS), Noguchi Memorial Institute for Medical Research (NMIMR), ORC Macro. Ghana Demographic and Health Survey 2003. GSS, NMIMR and ORC Macro: Calverton, Maryland, 2004.
Rutstein SO, Johnson K . The DHS Wealth Index. DHS Comparative Reports No. 6. ORC Macro: Calverton, Maryland, 2004.
May L, Kuningas M, van Bodegom D, Meij HJ, Frolich M, Slagboom PE et al. Genetic variation in pentraxin (PTX) 3 gene associates with PTX3 production and fertility in women. Biol Reprod 2010; 82: 299–304.
Bio-Rad Laboratories. Bulletin 2902: Bio-Plex Cytokine Assays 2011.
This research was supported by the Netherlands Foundation for the advancements of Tropical Research (WOTRO 93-467), the Netherlands Organisation for Scientific Research (grants NWO 051-14-050 and 050-60810), the EU funded Network of Excellence LifeSpan (EU FP6 036894), an unrestricted grant of the Board of the Leiden University Medical Center and the Association Dioraphte. None of these organisations had any role in the design, analysis, interpretation or report of the study.
We want to thank Margo van Schie-Troost and Marja Kersbergen-van Oostrom for their work on the cytokine assays.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on Genes and Immunity website
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Boef, A., May, L., van Bodegom, D. et al. The influence of genetic variation on innate immune activation in an environment with high infectious pressure. Genes Immun 13, 103–108 (2012). https://doi.org/10.1038/gene.2011.57
- tumour necrosis factor-α
- genetic variation
- innate immunity
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