Behavior Genetics

, Volume 44, Issue 4, pp 368–382 | Cite as

The Contribution of the Functional IL6R Polymorphism rs2228145, eQTLs and Other Genome-Wide SNPs to the Heritability of Plasma sIL-6R Levels

  • Jenny van Dongen
  • Rick Jansen
  • Dirk Smit
  • Jouke-Jan Hottenga
  • Hamdi Mbarek
  • Gonneke Willemsen
  • Cornelis Kluft
  • AAGC Collaborators
  • Brenda W. J. Penninx
  • Manuel A. Ferreira
  • Dorret I. Boomsma
  • Eco J. C. de Geus
Original Research

Abstract

The non-synonymous SNP rs2228145 in the IL6R gene on chromosome 1q21.3 is associated with a wide range of common diseases, including asthma, rheumatoid arthritis, type 1 diabetes and coronary heart disease. We examined the contribution of this functional IL6R gene polymorphism rs2228145 versus other genome-wide SNPs to the variance of sIL-6R levels in blood plasma in a large population-based sample (N ~5,000), and conducted an expression QTL analysis to identify SNPs associated with IL6R gene expression. Based on data from 2,360 twin families, the broad heritability of sIL-6R was estimated at 72 and 51 % of the total variance was explained by the functional SNP rs2228145. Converging findings from GWAS, linkage, and GCTA analyses indicate that additional variance of sIL-6R levels can be explained by other variants in the IL6R region, including variants at the 3′-end of IL6R tagged by rs60760897 that are associated with IL6R RNA expression.

Keywords

Soluble interleukin-6 receptor Inflammation Heritability GWAS Gene expression eQTL 

Supplementary material

10519_2014_9656_MOESM1_ESM.pdf (4.8 mb)
Supplementary material 1 (PDF 4919 kb)

References

  1. Abecasis GR, Wigginton JE (2005) Handling marker–marker linkage disequilibrium: pedigree analysis with clustered markers. Am J Hum Genet 77(5):754–767PubMedCentralPubMedCrossRefGoogle Scholar
  2. Abecasis GR, Cardon LR, Cookson WO (2000) A general test of association for quantitative traits in nuclear families. Am J Hum Genet 66(1):279–292PubMedCentralPubMedCrossRefGoogle Scholar
  3. Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2002) Merlin-rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30(1):97–101PubMedCrossRefGoogle Scholar
  4. Atreya R, Mudter J, Finotto S, Mullberg J, Jostock T, Wirtz S, Schutz M, Bartsch B, Holtmann M, Becker C, Strand D, Czaja J, Schlaak JF, Lehr HA, Autschbach F, Schurmann G, Nishimoto N, Yoshizaki K, Ito H, Kishimoto T, Galle PR, Rose-John S, Neurath MF (2000) Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo. Nat Med 6(5):583–588PubMedGoogle Scholar
  5. Becker C, Fantini MC, Schramm C, Lehr HA, Wirtz S, Nikolaev A, Burg J, Strand S, Kiesslich R, Huber S, Ito H, Nishimoto N, Yoshizaki K, Kishimoto T, Galle PR, Blessing M, Rose-John S, Neurath MF (2004) TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity 21(4):491–501PubMedCrossRefGoogle Scholar
  6. Boomsma DI, de Geus EJ, Vink JM, Stubbe JH, Distel MA, Hottenga JJ, Posthuma D, van Beijsterveldt TC, Hudziak JJ, Bartels M, Willemsen G (2006) Netherlands twin register: from twins to twin families. Twin Res Hum Genet 9(6):849–857PubMedCrossRefGoogle Scholar
  7. Boomsma DI, Willemsen G, Sullivan PF, Heutink P, Meijer P, Sondervan D, Kluft C, Smit G, Nolen WA, Zitman FG, Smit JH, Hoogendijk WJ, van Dyck R, de Geus EJ, Penninx BW (2008) Genome-wide association of major depression: description of samples for the GAIN Major Depressive Disorder Study: NTR and NESDA biobank projects. Eur J Hum Genet 16(3):335–342PubMedCrossRefGoogle Scholar
  8. de la Rica L, Urquiza JM, Gomez-Cabrero D, Islam AB, Lopez-Bigas N, Tegner J, Toes RE, Ballestar E (2013) Identification of novel markers in rheumatoid arthritis through integrated analysis of DNA methylation and microRNA expression. J Autoimmun 41:6–16PubMedCrossRefGoogle Scholar
  9. Dobson A (2002) An introduction to generalized linear models. Chapman & Hall/CRC, LondonGoogle Scholar
  10. Doganci A, Eigenbrod T, Krug N, De Sanctis GT, Hausding M, Erpenbeck VJ, Haddad E, Lehr HA, Schmitt E, Bopp T, Kallen KJ, Herz U, Schmitt S, Luft C, Hecht O, Hohlfeld JM, Ito H, Nishimoto N, Yoshizaki K, Kishimoto T, Rose-John S, Renz H, Neurath MF, Galle PR, Finotto S (2005) The IL-6R alpha chain controls lung CD4+ CD25+ Treg development and function during allergic airway inflammation in vivo. J Clin Invest 115(2):313–325PubMedCentralPubMedCrossRefGoogle Scholar
  11. Eyre S, Bowes J, Diogo D, Lee A, Barton A, Martin P, Zhernakova A, Stahl E, Viatte S, McAllister K, Amos CI, Padyukov L, Toes RE, Huizinga TW, Wijmenga C, Trynka G, Franke L, Westra HJ, Alfredsson L, Hu X, Sandor C, de Bakker PI, Davila S, Khor CC, Heng KK, Andrews R, Edkins S, Hunt SE, Langford C, Symmons D, Concannon P, Onengut-Gumuscu S, Rich SS, Deloukas P, Gonzalez-Gay MA, Rodriguez-Rodriguez L, Arlsetig L, Martin J, Rantapaa-Dahlqvist S, Plenge RM, Raychaudhuri S, Klareskog L, Gregersen PK, Worthington J (2012) High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat Genet 44(12):1336–1340PubMedCentralPubMedCrossRefGoogle Scholar
  12. Falconer DS (1960) Introduction to quantitative genetics. Ronald Press Co, New YorkGoogle Scholar
  13. Fehrmann RS, Jansen RC, Veldink JH, Westra HJ, Arends D, Bonder MJ, Fu J, Deelen P, Groen HJ, Smolonska A, Weersma RK, Hofstra RM, Buurman WA, Rensen S, Wolfs MG, Platteel M, Zhernakova A, Elbers CC, Festen EM, Trynka G, Hofker MH, Saris CG, Ophoff RA, van den Berg LH, van Heel DA, Wijmenga C, Te Meerman GJ, Franke L (2011) Trans-eQTLs reveal that independent genetic variants associated with a complex phenotype converge on intermediate genes, with a major role for the HLA. PLoS Genet 7(8):e1002197PubMedCentralPubMedCrossRefGoogle Scholar
  14. Ferreira MA, Matheson MC, Duffy DL, Marks GB, Hui J, Le SP, Danoy P, Baltic S, Nyholt DR, Jenkins M, Hayden C, Willemsen G, Ang W, Kuokkanen M, Beilby J, Cheah F, de Geus EJ, Ramasamy A, Vedantam S, Salomaa V, Madden PA, Heath AC, Hopper JL, Visscher PM, Musk B, Leeder SR, Jarvelin MR, Pennell C, Boomsma DI, Hirschhorn JN, Walters H, Martin NG, James A, Jones G, Abramson MJ, Robertson CF, Dharmage SC, Brown MA, Montgomery GW, Thompson PJ (2011) Identification of IL6R and chromosome 11q13.5 as risk loci for asthma. Lancet 378(9795):1006–1014PubMedCentralPubMedCrossRefGoogle Scholar
  15. Ferreira RC, Freitag DF, Cutler AJ, Howson JM, Rainbow DB, Smyth DJ, Kaptoge S, Clarke P, Boreham C, Coulson RM, Pekalski ML, Chen WM, Onengut-Gumuscu S, Rich SS, Butterworth AS, Malarstig A, Danesh J, Todd JA (2013) Functional IL6R 358ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases. PLoS Genet 9(4):e1003444PubMedCentralPubMedCrossRefGoogle Scholar
  16. Fulker DW, Cherny SS, Sham PC, Hewitt JK (1999) Combined linkage and association sib-pair analysis for quantitative traits. Am J Hum Genet 64(1):259–267PubMedCentralPubMedCrossRefGoogle Scholar
  17. Galicia JC, Tai H, Komatsu Y, Shimada Y, Akazawa K, Yoshie H (2004) Polymorphisms in the IL-6 receptor (IL-6R) gene: strong evidence that serum levels of soluble IL-6R are genetically influenced. Genes Immun 5(6):513–516PubMedCrossRefGoogle Scholar
  18. Gong J, Zhang JP, Li B, Zeng C, You K, Chen MX, Yuan Y, Zhuang SM (2012) MicroRNA-125b promotes apoptosis by regulating the expression of Mcl-1, Bcl-w and IL-6R. Oncogene 32(25):3071–3079. doi:10.1038/onc.2012.318 PubMedCrossRefGoogle Scholar
  19. Hatziapostolou M, Polytarchou C, Aggelidou E, Drakaki A, Poultsides GA, Jaeger SA, Ogata H, Karin M, Struhl K, Hadzopoulou-Cladaras M, Iliopoulos D (2011) An HNF4α-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis. Cell 147(6):1233–1247PubMedCentralPubMedCrossRefGoogle Scholar
  20. Horiuchi S, Koyanagi Y, Zhou Y, Miyamoto H, Tanaka Y, Waki M, Matsumoto A, Yamamoto M, Yamamoto N (1994) Soluble interleukin-6 receptors released from T cell or granulocyte/macrophage cell lines and human peripheral blood mononuclear cells are generated through an alternative splicing mechanism. Eur J Immunol 24(8):1945–1948PubMedCrossRefGoogle Scholar
  21. Hurst SM, Wilkinson TS, McLoughlin RM, Jones S, Horiuchi S, Yamamoto N, Rose-John S, Fuller GM, Topley N, Jones SA (2001) Il-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation. Immunity 14(6):705–714PubMedCrossRefGoogle Scholar
  22. IL6R Genetics Consortium and Emerging Risk Factors Collaboration (2012) Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet 379(9822):1205–1213CrossRefGoogle Scholar
  23. Jansen R, Batista S, Brooks AI, Tischfield JA, Willemsen G, van Grootheest G, Hottenga JJ, Milaneschi Y, Mbarek H, Madar V, Peyrot W, Vink JM, Verweij CL, de Geus EJ, Smit JH, Wright FA, Sullivan PF, Boomsma DI, Penninx BW (2014) Sex differences in the human peripheral blood transcriptome. BMC Genom 15(1):33CrossRefGoogle Scholar
  24. Jia HY, Wang YX, Yan WT, Li HY, Tian YZ, Wang SM, Zhao HL (2012) MicroRNA-125b functions as a tumor suppressor in hepatocellular carcinoma cells. Int J Mol Sci 13(7):8762–8774PubMedCentralPubMedCrossRefGoogle Scholar
  25. Jones SA, Horiuchi S, Topley N, Yamamoto N, Fuller GM (2001) The soluble interleukin 6 receptor: mechanisms of production and implications in disease. FASEB J. 15(1):43–58PubMedCrossRefGoogle Scholar
  26. Kotake S, Sato K, Kim KJ, Takahashi N, Udagawa N, Nakamura I, Yamaguchi A, Kishimoto T, Suda T, Kashiwazaki S (1996) Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Miner Res 11(1):88–95PubMedCrossRefGoogle Scholar
  27. Kwan T, Benovoy D, Dias C, Gurd S, Provencher C, Beaulieu P, Hudson TJ, Sladek R, Majewski J (2008) Genome-wide analysis of transcript isoform variation in humans. Nat Genet 40(2):225–231PubMedCrossRefGoogle Scholar
  28. Lourdusamy A, Newhouse S, Lunnon K, Proitsi P, Powell J, Hodges A, Nelson SK, Stewart A, Williams S, Kloszewska I, Mecocci P, Soininen H, Tsolaki M, Vellas B, Lovestone S, Dobson R (2012) Identification of cis-regulatory variation influencing protein abundance levels in human plasma. Hum Mol Genet 21(16):3719–3726PubMedCrossRefGoogle Scholar
  29. Lust JA, Donovan KA, Kline MP, Greipp PR, Kyle RA, Maihle NJ (1992) Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor. Cytokine 4(2):96–100PubMedCrossRefGoogle Scholar
  30. Mackiewicz A, Schooltink H, Heinrich PC, Rose-John S (1992) Complex of soluble human IL-6-receptor/IL-6 up-regulates expression of acute-phase proteins. J Immunol 149(6):2021–2027PubMedGoogle Scholar
  31. McPeek MS, Wu X, Ober C (2004) Best linear unbiased allele-frequency estimation in complex pedigrees. Biometrics 60(2):359–367PubMedCrossRefGoogle Scholar
  32. Melzer D, Perry JR, Hernandez D, Corsi AM, Stevens K, Rafferty I, Lauretani F, Murray A, Gibbs JR, Paolisso G, Rafiq S, Simon-Sanchez J, Lango H, Scholz S, Weedon MN, Arepalli S, Rice N, Washecka N, Hurst A, Britton A, Henley W, van de Leemput J, Li R, Newman AB, Tranah G, Harris T, Panicker V, Dayan C, Bennett A, McCarthy MI, Ruokonen A, Jarvelin MR, Guralnik J, Bandinelli S, Frayling TM, Singleton A, Ferrucci L (2008) A genome-wide association study identifies protein quantitative trait loci (pQTLs). PLoS Genet 4(5):e1000072PubMedCentralPubMedCrossRefGoogle Scholar
  33. Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, von ME, Farrall M, Lathrop M, Cookson WO (2010) A large-scale, consortium-based genome wide association study of asthma. N Engl J Med 363(13):1211–1221PubMedCrossRefGoogle Scholar
  34. Müllberg J, Schooltink H, Stoyan T, Gunther M, Graeve L, Buse G, Mackiewicz A, Heinrich PC, Rose-John S (1993) The soluble interleukin-6 receptor is generated by shedding. Eur J Immunol 23(2):473–480PubMedCrossRefGoogle Scholar
  35. Müllberg J, Oberthur W, Lottspeich F, Mehl E, Dittrich E, Graeve L, Heinrich PC, Rose-John S (1994) The soluble human IL-6 receptor. Mutational characterization of the proteolytic cleavage site. J Immunol 152(10):4958–4968PubMedGoogle Scholar
  36. Muller-Newen G, Kohne C, Keul R, Hemmann U, Muller-Esterl W, Wijdenes J, Brakenhoff JP, Hart MH, Heinrich PC (1996) Purification and characterization of the soluble interleukin-6 receptor from human plasma and identification of an isoform generated through alternative splicing. Eur J Biochem 236(3):837–842PubMedCrossRefGoogle Scholar
  37. Neale MC, Boker SM, Xie G, Maes HH (2006) Mx: statistical modeling. Department of Psychiatry, Virginia Commonwealth University, RichmondGoogle Scholar
  38. Penninx BW, Beekman AT, Smit JH, Zitman FG, Nolen WA, Spinhoven P, Cuijpers P, De Jong PJ, Van Marwijk HW, Assendelft WJ, Van Der MK, Verhaak P, Wensing M, De GR, Hoogendijk WJ, Ormel J, van Dyck R (2008) The Netherlands Study of Depression and Anxiety (NESDA): rationale, objectives and methods. Int J Methods Psychiatr Res 17(3):121–140PubMedCrossRefGoogle Scholar
  39. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575PubMedCentralPubMedCrossRefGoogle Scholar
  40. Rafiq S, Frayling TM, Murray A, Hurst A, Stevens K, Weedon MN, Henley W, Ferrucci L, Bandinelli S, Corsi AM, Guralnik JM, Melzer D (2007) A common variant of the interleukin 6 receptor (IL-6r) gene increases IL-6r and IL-6 levels, without other inflammatory effects. Genes Immun 8(7):552–559PubMedCentralPubMedCrossRefGoogle Scholar
  41. Raggi P, Su S, Karohl C, Veledar E, Rojas-Campos E, Vaccarino V (2010) Heritability of renal function and inflammatory markers in adult male twins. Am J Nephrol 32(4):317–323PubMedCentralPubMedCrossRefGoogle Scholar
  42. Reich D, Patterson N, Ramesh V, De Jager PL, McDonald GJ, Tandon A, Choy E, Hu D, Tamraz B, Pawlikowska L, Wassel-Fyr C, Huntsman S, Waliszewska A, Rossin E, Li R, Garcia M, Reiner A, Ferrell R, Cummings S, Kwok PY, Harris T, Zmuda JM, Ziv E (2007) Admixture mapping of an allele affecting interleukin 6 soluble receptor and interleukin 6 levels. Am J Hum Genet 80(4):716–726PubMedCentralPubMedCrossRefGoogle Scholar
  43. Revez JA, Bain L, Chapman B, Powell JE, Jansen R, Duffy DL, Tung JY, Penninx PM, Visscher PM, de Geus EJ, Boomsma DI, Hinds DA, Martin NG, Montgomery GW, Ferreira MA (2013) A new regulatory variant in the interleukin-6 receptor gene associates with asthma risk. Genes Immun 14(7):441–446PubMedCrossRefGoogle Scholar
  44. Rose-John S, Scheller J, Elson G, Jones SA (2006) Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol 80(2):227–236PubMedGoogle Scholar
  45. Saito M, Yoshida K, Hibi M, Taga T, Kishimoto T (1992) Molecular cloning of a murine IL-6 receptor-associated signal transducer, gp130, and its regulated expression in vivo. J. Immunol. 148(12):4066–4071PubMedGoogle Scholar
  46. Scheller J, Garbers C, Rose-John S (2013) Interleukin-6: From basic biology to selective blockade of pro-inflammatory activities. Semin, ImmunolGoogle Scholar
  47. Spijker S, van de Leemput JC, Hoekstra C, Boomsma DI, Smit AB (2004) Profiling gene expression in whole blood samples following an in vitro challenge. Twin Res. 7(6):564–570PubMedCrossRefGoogle Scholar
  48. Stephens OW, Zhang Q, Qu P, Zhou Y, Chavan S, Tian E, Williams DR, Epstein J, Barlogie B, Shaughnessy JD Jr (2012) An intermediate-risk multiple myeloma subgroup is defined by sIL-6r: levels synergistically increase with incidence of SNP rs2228145 and 1q21 amplification. Blood 119(2):503–512PubMedCentralPubMedCrossRefGoogle Scholar
  49. Taga T, Kishimoto T (1997) Gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol 15:797–819PubMedCrossRefGoogle Scholar
  50. Taga T, Hibi M, Hirata Y, Yamasaki K, Yasukawa K, Matsuda T, Hirano T, Kishimoto T (1989) Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell 58(3):573–581PubMedCrossRefGoogle Scholar
  51. The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium (2012) The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet 379(9822):1214–1224CrossRefGoogle Scholar
  52. Visscher PM, Benyamin B, White I (2004) The use of linear mixed models to estimate variance components from data on twin pairs by maximum likelihood. Twin. Res. 7(6):670–674PubMedCrossRefGoogle Scholar
  53. Willemsen G, de Geus EJ, Bartels M, van Beijsterveldt CE, Brooks AI, Estourgie-van Burk GF, Fugman DA, Hoekstra C, Hottenga JJ, Kluft K, Meijer P, Montgomery GW, Rizzu P, Sondervan D, Smit AB, Spijker S, Suchiman HE, Tischfield JA, Lehner T, Slagboom PE, Boomsma DI (2010) The Netherlands Twin Register biobank: a resource for genetic epidemiological studies. Twin Res. Hum. Genet. 13(3):231–245PubMedCrossRefGoogle Scholar
  54. Williams RL (2000) A note on robust variance estimation for cluster-correlated data. Biometrics 56(2):645–646PubMedCrossRefGoogle Scholar
  55. Yang J, Lee SH, Goddard ME, Visscher PM (2011a) GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet 88(1):76–82PubMedCentralPubMedCrossRefGoogle Scholar
  56. Yang J, Manolio TA, Pasquale LR, Boerwinkle E, Caporaso N, Cunningham JM, de Andrade M, Feenstra B, Feingold E, Hayes MG, Hill WG, Landi MT, Alonso A, Lettre G, Lin P, Ling H, Lowe W, Mathias RA, Melbye M, Pugh E, Cornelis MC, Weir BS, Goddard ME, Visscher PM (2011b) Genome partitioning of genetic variation for complex traits using common SNPs. Nat Genet 43(6):519–525PubMedCrossRefGoogle Scholar
  57. Zhang W, Duan S, Bleibel WK, Wisel SA, Huang RS, Wu X, He L, Clark TA, Chen TX, Schweitzer AC, Blume JE, Dolan ME, Cox NJ (2009) Identification of common genetic variants that account for transcript isoform variation between human populations. Hum Genet 125(1):81–93PubMedCentralPubMedCrossRefGoogle Scholar
  58. Zhu LH, Liu T, Tang H, Tian RQ, Su C, Liu M, Li X (2010) MicroRNA-23a promotes the growth of gastric adenocarcinoma cell line MGC803 and downregulates interleukin-6 receptor. FEBS J 277(18):3726–3734PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Jenny van Dongen
    • 1
    • 2
  • Rick Jansen
    • 3
    • 4
  • Dirk Smit
    • 1
    • 4
  • Jouke-Jan Hottenga
    • 1
    • 2
  • Hamdi Mbarek
    • 1
    • 2
  • Gonneke Willemsen
    • 1
    • 2
  • Cornelis Kluft
    • 5
  • AAGC Collaborators
  • Brenda W. J. Penninx
    • 2
    • 3
    • 4
  • Manuel A. Ferreira
    • 6
  • Dorret I. Boomsma
    • 1
    • 2
    • 4
  • Eco J. C. de Geus
    • 1
    • 2
  1. 1.Department of Biological PsychologyVU University AmsterdamAmsterdamThe Netherlands
  2. 2.EMGO Institute for Health and Care ResearchVU University Medical CenterAmsterdamThe Netherlands
  3. 3.Department of PsychiatryVU University Medical CenterAmsterdamThe Netherlands
  4. 4.Neuroscience Campus AmsterdamAmsterdamThe Netherlands
  5. 5.Good Biomarker SciencesLeidenThe Netherlands
  6. 6.Queensland Institute of Medical ResearchHerstonAustralia

Personalised recommendations