Genome-wide association study of circulating interleukin 6 levels identifies novel loci

Author:

Ahluwalia Tarunveer S12ORCID,Prins Bram P3,Abdollahi Mohammadreza3,Armstrong Nicola J4,Aslibekyan Stella5,Bain Lisa6,Jefferis Barbara7,Baumert Jens8,Beekman Marian9,Ben-Shlomo Yoav10,Bis Joshua C11,Mitchell Braxton D12,de Geus Eco1314,Delgado Graciela E15,Marek Diana16,Eriksson Joel17,Kajantie Eero1819,Kanoni Stavroula20,Kemp John P2122,Lu Chen23,Marioni Riccardo E2425,McLachlan Stela26,Milaneschi Yuri27,Nolte Ilja M3,Petrelis Alexandros M28,Porcu Eleonora29,Sabater-Lleal Maria3031,Naderi Elnaz3,Seppälä Ilkka32,Shah Tina33,Singhal Gaurav34,Standl Marie8,Teumer Alexander35ORCID,Thalamuthu Anbupalam36,Thiering Elisabeth837,Trompet Stella3839,Ballantyne Christie M40,Benjamin Emelia J4142,Casas Juan P43,Toben Catherine34,Dedoussis George44,Deelen Joris945,Durda Peter46,Engmann Jorgen33,Feitosa Mary F47,Grallert Harald848,Hammarstedt Ann49,Harris Sarah E2550,Homuth Georg51,Hottenga Jouke-Jan1314,Jalkanen Sirpa5253,Jamshidi Yalda54,Jawahar Magdalene C34,Jess Tine55,Kivimaki Mika56,Kleber Marcus E15,Lahti Jari5758,Liu Yongmei59,Marques-Vidal Pedro6061,Mellström Dan17,Mooijaart Simon P39,Müller-Nurasyid Martina6263ORCID,Penninx Brenda27,Revez Joana A6ORCID,Rossing Peter164,Räikkönen Katri58,Sattar Naveed65,Scharnagl Hubert66,Sennblad Bengt3067,Silveira Angela30,Pourcain Beate St226869,Timpson Nicholas J22,Trollor Julian3670,van Dongen Jenny1314,Van Heemst Diana40,Visvikis-Siest Sophie28,Vollenweider Peter6061,Völker Uwe52,Waldenberger Melanie8,Willemsen Gonneke1314,Zabaneh Delilah71,Morris Richard W72,Arnett Donna K73,Baune Bernhard T747576,Boomsma Dorret I1314,Chang Yen-Pei C12,Deary Ian J2550,Deloukas Panos2077,Eriksson Johan G7879,Evans David M2122,Ferreira Manuel A6,Gaunt Tom8081,Gudnason Vilmundur8283,Hamsten Anders30,Heinrich Joachim88485,Hingorani Aroon33,Humphries Steve E33,Jukema J Wouter3986,Koenig Wolfgang878889,Kumari Meena5690,Kutalik Zoltan1691,Lawlor Deborah A8081,Lehtimäki Terho32,März Winfried156692,Mather Karen A3693,Naitza Silvia29,Nauck Matthias9495,Ohlsson Claes17,Price Jackie F26,Raitakari Olli969798,Rice Ken99,Sachdev Perminder S36100,Slagboom Eline945,Sørensen Thorkild I A101102,Spector Tim103,Stacey David104,Stathopoulou Maria G28,Tanaka Toshiko105,Wannamethee S Goya7,Whincup Peter106,Rotter Jerome I107,Dehghan Abbas108,Boerwinkle Eric109110,Psaty Bruce M11111,Snieder Harold3,Alizadeh Behrooz Z3,

Affiliation:

1. Steno Diabetes Center Copenhagen, Gentofte DK2820, Denmark

2. Department of Biology, The Bioinformatics Center, University of Copenhagen, Copenhagen DK2200, Denmark

3. Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, The Netherlands

4. Mathematics and Statistics, Murdoch University, Perth 6150, Australia

5. Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, Alabama 35233, USA

6. QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia

7. Department of Primary Care & Population Health, UCL Institute of Epidemiology & Health Care, University College London, London NW3 2PF, UK

8. Institute of Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health, Neuherberg 85764, Germany

9. Department of Biomedical Data Sciences, Section of Molecular Epidemiology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands

10. Population Health Sciences, University of Bristol, Bristol BS8 2PS, UK

11. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA

12. Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21202, USA

13. Department of Biological Psychology, Behaviour and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam 1081 BT, The Netherlands

14. Amsterdam Public Health Research Institute, Amsterdam University Medical Center, Amsterdam 1105 AZ, The Netherlands

15. Vth Department of Medicine (Nephrology, Hypertensiology, Rheumatology, Endocrinology, Diabetology), Medical Faculty Mannheim, University of Heidelberg, Mannheim 68167, Germany

16. SIB Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland

17. Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, Centre for Bone and Arthritis Research (CBAR), University of Gothenburg, Gothenburg 41345, Sweden

18. Chronic Disease Prevention Unit, National Institute for Health and Welfare, PO Box 30, Helsinki 00271, Finland

19. Hospital for Children and Adolescents, Helsinki University Central Hospital and University of Helsinki, Helsinki 00014, Finland

20. William Harvey Research Institute, Barts & the London Medical School, Queen Mary University of London, London EC1M 6BQ, UK

21. The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Queensland 4102, Australia

22. MRC Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, Bristol BS8 2BN, UK

23. Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA

24. Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK

25. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH8 9JZ, UK

26. Usher Institute, University of Edinburgh, Edinburgh EH8 9AG, UK

27. Department of Psychiatry, Amsterdam UMC, Vrije Universiteit, Amsterdam 1081 HJ, The Netherlands

28. Université de Lorraine, Inserm, IGE-PCV, Nancy 54000, France

29. Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato (CA) 09042, Italy

30. Cardiovascular Medicine, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm 17176, Sweden

31. Unit of Genomics of Complex Diseases, Institut d'Investigació Biomèdica Sant Pau (IIB-Sant Pau), Barcelona 08041, Spain

32. Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center—Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33520, Finland

33. Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK

34. Discipline of Psychiatry, Adelaide Medical School, University of Adelaide, Adelaide 5005, Australia

35. Institute for Community Medicine, University Medicine Greifswald, Greifswald 17475, Germany

36. Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney 2052, Australia

37. Division of Metabolic Diseases and Nutritional Medicine, Ludwig-Maximilians-University of Munich, Dr. von Hauner Children's Hospital, Munich 80337, Germany

38. Department of Cardiology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands

39. Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands

40. Baylor College of Medicine, Houston, TX 77030, USA

41. National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA 01702, USA

42. Section of Cardiovascular Medicine and Preventive Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA

43. Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA 02130, USA

44. 44Department of Nutrition-Dietetics, Harokopio University, Athens 17671, Greece

45. Max Planck Institute for Biology of Ageing, Cologne 50931, Germany

46. Department of Pathology and Laboratory Medicine, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA

47. Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110-1093, USA

48. German Center for Diabetes Research (DZD), Neuherberg 85764, Germany

49. The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg SE-41345, Sweden

50. Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK

51. Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald 17475, Germany

52. MediCity Research Laboratory, University of Turku, Turku 20520, Finland

53. Department of Medical Microbiology and Immunology, University of Turku, Turku 20520, Finland

54. Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's University of London, London SW17 0RE, UK

55. 55Department of Epidemiology Research, Statens Serum Institute, Copenhagen DK2300, Denmark

56. Department of Epidemiology & Public Health, UCL Institute of Epidemiology & Health Care, University College London, London WC1E 7HB, UK

57. Turku Institute for Advanced Studies, University of Turku, Turku 20014, Finland

58. Department of Psychology and Logopedics, University of Helsinki, Helsinki 00014, Finland

59. Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA

60. Department of Internal Medicine, Lausanne University Hospital (CHUV), Lausanne 1011, Switzerland

61. University of Lausanne, Lausanne 1011, Switzerland

62. IBE, Faculty of Medicine, Ludwig Maximilians University (LMU) Munich, Munich 81377, Germany

63. Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center, Johhanes Gutenberg University, Mainz 55101, Germany

64. Department of Clinical Medicine, University of Copenhagen, Copenhagen DK2200, Denmark

65. BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, Glasgow G12 8TA, UK

66. 66Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz 8036, Austria

67. Department of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala 75124, Sweden

68. Max Planck Institute for Psycholinguistics, Nijmegen XD 6525, The Netherlands

69. Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen 6525 AJ, The Netherlands

70. Department of Developmental Disability Neuropsychiatry, School of Psychiatry, University of New South Wales, Sydney 2031, Australia

71. Department of Genetics, Environment and Evolution, University College London Genetics Institute, London WC1E 6BT, UK

72. Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1UD, UK

73. Dean’s Office, College of Public Health, University of Kentucky, Lexington, KY 40536, USA

74. Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Parkville 3000, Australia

75. Department of Psychiatry and Psychotherapy, University of Muenster, Muenster 48149, Germany

76. The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville 3000, Australia

77. 77Centre for Genomic Health, Queen Mary University of London, London EC1M 6BQ, UK

78. National Institute for Health and Welfare, University of Helsinki, Helsinki 00014, Finland

79. Department of General Practice and Primary Health Care, University of Helsinki, Helsinki 00014, Finland

80. MRC Integrative Epidemiology Unit at the University of Bristol, Bristol BS6 2BN, UK

81. Population Health Science, Bristol Medical School, University of Bristol, Bristol BS8 2BN, UK

82. Icelandic Heart Association, Kópavogur 201, Iceland

83. Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland

84. Institute and Clinic for Occupational, Social and Environmental Medicine, University Hospital, LMU Munich, Munich 81377, Germany

85. Allergy and Lung Health Unit, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne 3010, Australia

86. Durrer Center for Cardiogenetic Research, Amsterdam 1105 AZ, The Netherlands

87. Deutsches Herzzentrum München, Technische Universität München, Munich 80636, Germany

88. 88DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich 80336, Germany

89. Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm 89081, Germany

90. Institute for Social and Economic Research, University of Essex, Colchester CO4 3SQ, Germany

91. University Center for Primary Care and Public Health, University of Lausanne, Lausanne 1010, Switzerland

92. SYNLAB Academy, SYNALB Holding Deutschland GmbH, Mannheim 68163, Germany

93. Neuroscience Research Australia, Sydney 2031, Australia

94. Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald 17475, Germany

95. DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald 17475, Germany

96. Centre for Population Health Research, University of Turku, Turku University Hospital, Turku 20520, Finland

97. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20520, Finland

98. Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku 20014, Finland

99. Department of Biostatistics, University of Washington, Seattle, WA 98195, USA

100. Neuropsychiatric Institute, Prince of Wales Hospital, Sydney 2031, Australia

101. Novo Nordisk Foundation Center For Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK2200, Denmark

102. Department of Public Health, Section on Epidemiology, University of Copenhagen, Copenhagen DK1014, Denmark

103. Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK

104. MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK

105. Longitudinal Study Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, MD 21224, USA

106. Population Health Research Institute, St George’s, University of London, London SW17 0RE, UK

107. Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA 90502, USA

108. Department of Epidemiology, Erasmus MC, Rotterdam 3000 CA, The Netherlands

109. Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA

110. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA

111. Departments of Epidemiology and Health Services, University of Washington, Seattle, WA 98101, USA

Abstract

Abstract Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10−11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10−10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10−122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

Funder

Novo Nordisk Foundation

Publisher

Oxford University Press (OUP)

Subject

Genetics (clinical),Genetics,Molecular Biology,General Medicine

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