Advertisement

Immunogenetics

, Volume 64, Issue 5, pp 351–359 | Cite as

Genome-wide associated loci influencing interleukin (IL)-10, IL-1Ra, and IL-6 levels in African Americans

  • Fasil Tekola Ayele
  • Ayo Doumatey
  • Hanxia Huang
  • Jie Zhou
  • Bashira Charles
  • Michael Erdos
  • Jokotade Adeleye
  • Williams Balogun
  • Olufemi Fasanmade
  • Thomas Johnson
  • Johnnie Oli
  • Godfrey Okafor
  • Albert Amoah
  • Benjamin A. EghanJr.
  • Kofi Agyenim-Boateng
  • Joseph Acheampong
  • Clement A. Adebamowo
  • Alan Herbert
  • Norman Gerry
  • Michael Christman
  • Guanjie Chen
  • Daniel Shriner
  • Adebowale Adeyemo
  • Charles N. Rotimi
Original Paper

Abstract

Interleukins (ILs) are key mediators of the immune response and inflammatory process. Plasma levels of IL-10, IL-1Ra, and IL-6 are associated with metabolic conditions, show large inter-individual variations, and are under strong genetic control. Therefore, elucidation of the genetic variants that influence levels of these ILs provides useful insights into mechanisms of immune response and pathogenesis of diseases. We conducted a genome-wide association study (GWAS) of IL-10, IL-1Ra, and IL-6 levels in 707 non-diabetic African Americans using 5,396,780 imputed and directly genotyped single nucleotide polymorphisms (SNPs) with adjustment for gender, age, and body mass index. IL-10 levels showed genome-wide significant associations (p < 5 × 10−8) with eight SNPs, the most significant of which was rs5743185 in the PMS1 gene (p = 2.30 × 10−10). We tested replication of SNPs that showed genome-wide significance in 425 non-diabetic individuals from West Africa, and successfully replicated rs17365948 in the YWHAZ gene (p = 0.02). IL-1Ra levels showed suggestive associations with two SNPs in the ASB3 gene (p = 2.55 × 10−7), ten SNPs in the IL-1 gene family (IL1F5, IL1F8, IL1F10, and IL1Ra, p = 1.04 × 10−6 to 1.75 × 10−6), and 23 SNPs near the IL1A gene (p = 1.22 × 10−6 to 1.63 × 10−6). We also successfully replicated rs4251961 (p = 0.009); this SNP was reported to be associated with IL-1Ra levels in a candidate gene study of Europeans. IL-6 levels showed genome-wide significant association with one SNP (RP11-314E23.1; chr6:133397598; p = 8.63 × 10−9). To our knowledge, this is the first GWAS on IL-10, IL-1Ra, and IL-6 levels. Follow-up of these findings may provide valuable insight into the pathobiology of IL actions and dysregulations in inflammation and human diseases.

Keywords

Interleukin Interleukin-10 Interleukin-1Ra Interleukin-6 Genome-wide association study African American 

Notes

Acknowledgements

The study was supported by grants S06GM008016-320107 to CR and S06GM008016-380111 to AA, both from the NIGMS/MBRS/SCORE Program. Participant enrollment was carried out at the Howard University General Clinical Research Center (GCRC), which is supported by grant number 2M01RR010284 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). Additional support was provided by the Coriell Institute for Biomedical Sciences. This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, in the Center for Research in Genomics and Global Health (Z01HG200362). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Supplementary material

251_2011_596_MOESM1_ESM.doc (8.2 mb)
ESM 1 (DOC 8418 kb)
251_2011_596_MOESM2_ESM.doc (179 kb)
ESM 2 (DOC 179 kb)

References

  1. Adeyemo A, Gerry N, Chen G et al (2009) A genome-wide association study of hypertension and blood pressure in African Americans. PLoS Genet 5:e1000564PubMedCrossRefGoogle Scholar
  2. Baltrus PT, Shim RS, Ye J, Watson L, Davis SK (2010) Socioeconomic position, stress, and cortisol in relation to waist circumference in African American and white women. Ethn Dis 20:376–382PubMedGoogle Scholar
  3. Bluher M, Fasshauer M, Tonjes A, Kratzsch J, Schon MR, Paschke R (2005) Association of interleukin-6, C-reactive protein, interleukin-10 and adiponectin plasma concentrations with measures of obesity, insulin sensitivity and glucose metabolism. Exp Clin Endocrinol Diabetes 113:534–537PubMedCrossRefGoogle Scholar
  4. Bros M, Dexheimer N, Besche V, Masri J, Trojandt S, Hövelmeyer N, Reissig S, Massoumi R, Grabbe S, Waisman A, Reske-Kunz AB (2010) Mutated cylindromatosis gene affects the functional state of dendritic cells. Eur J Immunol 40:2848–2857PubMedCrossRefGoogle Scholar
  5. Cannavo E, Gerrits B, Marra G, Schlapbach R, Jiricny J (2007) Characterization of the interactome of the human MutL homologues MLH1, PMS1, and PMS2. J Biol Chem 282:2976–2986PubMedCrossRefGoogle Scholar
  6. Cartier A, Bergeron J, Poirier P et al (2009) Increased plasma interleukin-1 receptor antagonist levels in men with visceral obesity. Ann Med 41:471–478PubMedCrossRefGoogle Scholar
  7. Charles BA, Doumatey A, Huang H, Zhou J, Chen G, Shriner D, Adeyemo A, Rotimi CN (2011) The roles of IL-6, IL-10, and IL-1RA in obesity and insulin resistance in African-Americans. J Clin Endocrinol Metab epub 1945-7197Google Scholar
  8. Crawford AG, Cote C, Couto J, Daskiran M, Gunnarsson C, Haas K, Haas S, Nigam SC, Schuette R (2010) Prevalence of obesity, type II diabetes mellitus, hyperlipidemia, and hypertension in the United States: findings from the GE Centricity Electronic Medical Record database. Popul Health Manag 13:151–161PubMedCrossRefGoogle Scholar
  9. de Craen AJ, Posthuma D, Remarque EJ, van den Biggelaar AH, Westendorp RG, Boomsma DI (2005) Heritability estimates of innate immunity: an extended twin study. Genes Immun 6:167–170PubMedCrossRefGoogle Scholar
  10. Di Renzo L, Bigioni M, Del Gobbo V et al (2007) Interleukin-1 (IL-1) receptor antagonist gene polymorphism in normal weight obese syndrome: relationship to body composition and IL-1 alpha and beta plasma levels. Pharmacol Res 55:131–138PubMedCrossRefGoogle Scholar
  11. Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11:98–107PubMedCrossRefGoogle Scholar
  12. Doumatey AP, Lashley KS, Huang H et al (2010) Relationships among obesity, inflammation, and insulin resistance in African Americans and West Africans. Obesity (Silver Spring) 18:598–603CrossRefGoogle Scholar
  13. Feairheller DL, Park JY, Rizzo V, Kim B, Brown MD (2011) Racial differences in the responses to shear stress in human umbilical vein endothelial cells. Vasc Health Risk Manag 7:425–431PubMedCrossRefGoogle Scholar
  14. Sims JE, Smith DE (2010) The IL-1 family: regulators of immunity. Nat Rev Immunol 10:89–102PubMedCrossRefGoogle Scholar
  15. Feng S, Wang S, Chen CC, Lan L (2011) GWAPower: a statistical power calculation software for genome-wide association studies with quantitative traits. BMC Genet 12:12PubMedCrossRefGoogle Scholar
  16. Ferrari SL, Ahn-Luong L, Garnero P, Humphries SE, Greenspan SL (2003) Two promoter polymorphisms regulating interleukin-6 gene expression are associated with circulating levels of C-reactive protein and markers of bone resorption in postmenopausal women. J Clin Endocrinol Metab 88:255–259PubMedCrossRefGoogle Scholar
  17. Ferrari SL, Karasik D, Liu J et al (2004) Interactions of interleukin-6 promoter polymorphisms with dietary and lifestyle factors and their association with bone mass in men and women from the Framingham Osteoporosis Study. J Bone Miner Res 19:552–559PubMedCrossRefGoogle Scholar
  18. Fishman D, Faulds G, Jeffery R et al (1998) The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 102:1369–1376PubMedCrossRefGoogle Scholar
  19. Fisman EZ, Tenenbaum A (2010) The ubiquitous interleukin-6: a time for reappraisal. Cardiovasc Diabetol 9:62PubMedCrossRefGoogle Scholar
  20. Fumagalli M, Pozzoli U, Cagliani R, Comi GP, Riva S, Clerici M, Bresolin N, Sironi M (2009) Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions. J Exp Med 206:1395–1408PubMedCrossRefGoogle Scholar
  21. Gao X, Starmer JD (2008) AWclust: point-and-click software for non-parametric population structure analysis. BMC Bioinforma 9:77CrossRefGoogle Scholar
  22. Ge D, Zhang K, Need AC et al (2008) WGAViewer: software for genomic annotation of whole genome association studies. Genome Res 18:640–643PubMedCrossRefGoogle Scholar
  23. Gibson AW, Edberg JC, Wu J, Westendorp RG, Huizinga TW, Kimberly RP (2001) Novel single nucleotide polymorphisms in the distal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus. J Immunol 166:3915–3922PubMedGoogle Scholar
  24. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560PubMedCrossRefGoogle Scholar
  25. Hohaus S, Giachelia M, Massini G et al (2009) Clinical significance of interleukin-10 gene polymorphisms and plasma levels in Hodgkin lymphoma. Leuk Res 33:1352–1356PubMedCrossRefGoogle Scholar
  26. Hurme M, Santtila S (1998) IL-1 receptor antagonist (IL-1Ra) plasma levels are co-ordinately regulated by both IL-1Ra and IL-1beta genes. Eur J Immunol 28:2598–2602PubMedCrossRefGoogle Scholar
  27. Juge-Aubry CE, Somm E, Giusti V et al (2003) Adipose tissue is a major source of interleukin-1 receptor antagonist: upregulation in obesity and inflammation. Diabetes 52:1104–1110PubMedCrossRefGoogle Scholar
  28. Juge-Aubry CE, Henrichot E, Meier CA (2005) Adipose tissue: a regulator of inflammation. Best Pract Res Clin Endocrinol Metab 19:547–566PubMedCrossRefGoogle Scholar
  29. Kile BT, Nicola NA, Alexander WS (2001) Negative regulators of cytokine signaling. Int J Hematol 73:292–298PubMedCrossRefGoogle Scholar
  30. King GL (2008) The role of inflammatory cytokines in diabetes and its complications. J Periodontol 79:1527–1534PubMedCrossRefGoogle Scholar
  31. Lai S, Fishman EK, Lai H, Pannu H, Detrick B (2009) Serum IL-6 levels are associated with significant coronary stenosis in cardiovascularly asymptomatic inner-city black adults in the US. Inflamm Res 58:15–21PubMedCrossRefGoogle Scholar
  32. Lai Z, Kalkunte S, Sharma S (2011) A critical role of interleukin-10 in modulating hypoxia-induced preeclampsia-like disease in mice. Hypertension 57:505–514PubMedCrossRefGoogle Scholar
  33. Levy D, Ehret GB, Rice K et al (2009) Genome-wide association study of blood pressure and hypertension. Nat Genet 41:677–687PubMedCrossRefGoogle Scholar
  34. Li Y, Willer CJ, Ding J, Scheet P, Abecasis GR (2010) MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 34:816–834PubMedCrossRefGoogle Scholar
  35. McCarroll SA, Kuruvilla FG, Korn JM et al (2008) Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet 40:1166–1174PubMedCrossRefGoogle Scholar
  36. Mulero JJ, Pace AM, Nelken ST et al (1999) IL1HY1: a novel interleukin-1 receptor antagonist gene. Biochem Biophys Res Commun 263:702–706PubMedCrossRefGoogle Scholar
  37. Nicklin MJ, Barton JL, Nguyen M, FitzGerald MG, Duff GW, Kornman K (2002) A sequence-based map of the nine genes of the human interleukin-1 cluster. Genomics 79:718–725PubMedCrossRefGoogle Scholar
  38. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38:904–909PubMedCrossRefGoogle Scholar
  39. Purcell S, Neale B, Todd-Brown K et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575PubMedCrossRefGoogle Scholar
  40. Rafiq S, Stevens K, Hurst AJ et al (2007) Common genetic variation in the gene encoding interleukin-1-receptor antagonist (IL-1RA) is associated with altered circulating IL-1RA levels. Genes Immun 8:344–351PubMedCrossRefGoogle Scholar
  41. Reiner AP, Wurfel MM, Lange LA et al (2008) Polymorphisms of the IL1-receptor antagonist gene (IL1RN) are associated with multiple markers of systemic inflammation. Arterioscler Thromb Vasc Biol 28:1407–1412PubMedCrossRefGoogle Scholar
  42. Reuss E, Fimmers R, Kruger A, Becker C, Rittner C, Hohler T (2002) Differential regulation of interleukin-10 production by genetic and environmental factors–a twin study. Genes Immun 3:407–413PubMedCrossRefGoogle Scholar
  43. Rotimi CN, Chen G, Adeyemo AA et al (2004) A genome-wide search for type 2 diabetes susceptibility genes in West Africans: the Africa America Diabetes Mellitus (AADM) Study. Diabetes 53:838–841PubMedCrossRefGoogle Scholar
  44. Ruchat SM, Despres JP, Weisnagel SJ, Chagnon YC, Bouchard C, Perusse L (2008) Genome-wide linkage analysis for circulating levels of adipokines and C-reactive protein in the Quebec family study (QFS). J Hum Genet 53:629–636PubMedCrossRefGoogle Scholar
  45. Shoelson SE, Lee J, Goldfine AB (2006) Inflammation and insulin resistance. J Clin Invest 116:1793–1801PubMedCrossRefGoogle Scholar
  46. Shriner D, Adeyemo A, Chen G, Rotimi CN (2010) Practical considerations for imputation of untyped markers in admixed populations. Genet Epidemiol 34:258–265PubMedGoogle Scholar
  47. Smith AJ, Humphries SE (2009) Cytokine and cytokine receptor gene polymorphisms and their functionality. Cytokine Growth Factor Rev 20:43–59PubMedCrossRefGoogle Scholar
  48. Tinsley JH, South S, Chiasson VL, Mitchell BM (2010) Interleukin-10 reduces inflammation, endothelial dysfunction, and blood pressure in hypertensive pregnant rats. Am J Physiol Regul Integr Comp Physiol 298:R713–R719PubMedCrossRefGoogle Scholar
  49. Walston JD, Fallin MD, Cushman M et al (2007) IL-6 gene variation is associated with IL-6 and C-reactive protein levels but not cardiovascular outcomes in the Cardiovascular Health Study. Hum Genet 122:485–494PubMedCrossRefGoogle Scholar
  50. Wellen KE, Hotamisligil GS (2005) Inflammation, stress, and diabetes. J Clin Invest 115:1111–1119PubMedGoogle Scholar
  51. Westendorp RG, Langermans JA, Huizinga TW, Verweij CL, Sturk A (1997) Genetic influence on cytokine production in meningococcal disease. Lancet 349:1912–1913PubMedCrossRefGoogle Scholar
  52. Willer CJ, Li Y, Abecasis GR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26:2190–2191PubMedCrossRefGoogle Scholar
  53. Yang W, Shen N, Ye DQ et al (2010) Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. PLoS Genet 6:e1000841PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag (outside the USA) 2011

Authors and Affiliations

  • Fasil Tekola Ayele
    • 1
  • Ayo Doumatey
    • 1
  • Hanxia Huang
    • 1
  • Jie Zhou
    • 1
  • Bashira Charles
    • 1
  • Michael Erdos
    • 2
  • Jokotade Adeleye
    • 3
  • Williams Balogun
    • 3
  • Olufemi Fasanmade
    • 4
  • Thomas Johnson
    • 4
  • Johnnie Oli
    • 5
  • Godfrey Okafor
    • 5
  • Albert Amoah
    • 6
  • Benjamin A. EghanJr.
    • 7
  • Kofi Agyenim-Boateng
    • 7
  • Joseph Acheampong
    • 7
  • Clement A. Adebamowo
    • 8
  • Alan Herbert
    • 9
  • Norman Gerry
    • 10
  • Michael Christman
    • 10
  • Guanjie Chen
    • 1
  • Daniel Shriner
    • 1
  • Adebowale Adeyemo
    • 1
  • Charles N. Rotimi
    • 1
  1. 1.Center for Research on Genomics and Global Health, National Human Genome Research InstituteNational Institutes of HealthBethesdaUSA
  2. 2.Genome Technology Branch, Molecular Genetics Section, National Human Genome Research InstituteNational Institutes of HealthBethesdaUSA
  3. 3.Department of MedicineUniversity of IbadanIbadanNigeria
  4. 4.University of LagosLagosNigeria
  5. 5.University of Nigeria Teaching HospitalEnuguNigeria
  6. 6.Department of MedicineUniversity of Ghana Medical SchoolAccraGhana
  7. 7.Department of MedicineUniversity of Science and TechnologyKumasiGhana
  8. 8.Department of Epidemiology and Public Health, School of MedicineUniversity of MarylandBaltimoreUSA
  9. 9.Department of Genetics and GenomicsBoston UniversityBostonUSA
  10. 10.Coriell Institute for Medical ResearchCamdenUSA

Personalised recommendations