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Original article
Genome-wide association study identifies seven novel loci associating with circulating cytokines and cell adhesion molecules in Finns
  1. Eeva Sliz1,2,3,
  2. Marita Kalaoja1,2,3,
  3. Ari Ahola-Olli4,5,
  4. Olli Raitakari5,6,
  5. Markus Perola7,8,9,
  6. Veikko Salomaa7,
  7. Terho Lehtimäki10,
  8. Toni Karhu3,11,
  9. Heimo Viinamäki12,
  10. Marko Salmi13,
  11. Kristiina Santalahti13,
  12. Sirpa Jalkanen13,
  13. Jari Jokelainen2,14,
  14. Sirkka Keinänen-Kiukaanniemi2,14,15,
  15. Minna Männikkö16,
  16. Karl-Heinz Herzig3,11,17,18,
  17. Marjo-Riitta Järvelin2,3,19,20,
  18. Sylvain Sebert2,3,21,
  19. Johannes Kettunen1,2,3
  1. 1 Computational Medicine, Faculty of Medicine, University of Oulu, Oulu, Finland
  2. 2 Center for Life Course Health Research, University of Oulu, Oulu, Finland
  3. 3 Biocenter Oulu, Oulu, Finland
  4. 4 Department of Internal Medicine, Satakunta Central Hospital, Pori, Finland
  5. 5 Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
  6. 6 Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
  7. 7 National Institute for Health and Welfare, Helsinki, Finland
  8. 8 Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
  9. 9 University of Tartu, Estonian Genome Center, Tartu, Estonia
  10. 10 Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center - Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
  11. 11 Institute of Biomedicine, University of Oulu, Oulu, Finland
  12. 12 Department of Psychiatry, University of Eastern Finland, and Kuopio University Hospital, Kuopio, Finland
  13. 13 Medicity Research Laboratory and Institute of Biomedicine, University of Turku, Turku, Finland
  14. 14 Unit of General Practice, Oulu University Hospital, Oulu, Finland
  15. 15 Oulu Deaconess Institute/Diapolis Oy Research Unit, Oulu, Finland
  16. 16 Northern Finland Birth Cohorts, Faculty of Medicine, University of Oulu, Oulu, Finland
  17. 17 Medical Research Center (MRC), University of Oulu, and Oulu University Hospital, Oulu, Finland
  18. 18 Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, Poznan, Poland
  19. 19 Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, Imperial College London, London, UK
  20. 20 Unit of Primary Care, Oulu University Hospital, Oulu, Finland
  21. 21 Department of Genomics and Complex Diseases, School of Public Health, Imperial College, London, UK
  1. Correspondence to Dr Johannes Kettunen, Center for Life Course Health Research, Oulun Yliopisto, Oulu 90014, Finland; johannes.kettunen{at}oulu.fi

Abstract

Background Inflammatory processes contribute to the pathophysiology of multiple chronic conditions. Genetic factors play a crucial role in modulating the inflammatory load, but the exact mechanisms are incompletely understood.

Objective To assess genetic determinants of 16 circulating cytokines and cell adhesion molecules (inflammatory phenotypes) in Finns.

Methods Genome-wide associations of the inflammatory phenotypes were studied in Northern Finland Birth Cohort 1966 (N=5284). A subsequent meta-analysis was completed for 10 phenotypes available in a previous genome-wide association study, adding up to 13 577 individuals in the study. Complementary association tests were performed to study the effect of the ABO blood types on soluble adhesion molecule levels.

Results We identified seven novel and six previously reported genetic associations (p<3.1×10−9). Three loci were associated with soluble vascular cell adhesion molecule-1 (sVCAM-1) level, one of which was the ABO locus that has been previously associated with soluble E-selectin (sE-selectin) and intercellular adhesion molecule-1 (sICAM-1) levels. Our findings suggest that the blood type B associates primarily with sVCAM-1 level, while the A1 subtype shows a robust effect on sE-selectin and sICAM-1 levels. The genotypes in the ABO locus associating with higher soluble adhesion molecule levels tend to associate with lower circulating cholesterol levels and lower cardiovascular disease risk.

Conclusion The present results extend the knowledge about genetic factors contributing to the inflammatory load. Our findings suggest that two distinct mechanisms contribute to the soluble adhesion molecule levels in the ABO locus and that elevated soluble adhesion molecule levels per se may not increase risk for cardiovascular disease.

  • genome-wide association
  • inflammatory load
  • svcam-1
  • abo blood type

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Footnotes

  • SS and JK contributed equally.

  • Correction notice This article has been corrected since it was published Online First. Values in table 2 have been amended.

  • Contributors ES, SS and JK conceptualised the study. ES, MK and AA-O performed the statistical analyses. TK, K-HH, MS, KS and SJ performed the quantifications of the inflammatory markers. OR, MP, VS, TL, HV, MS, SJ, JJ, SK-K, MM, K-HH, M-RJ, SS and JK provided funding or other resources to conduct the study. SS and JK supervised the study. ES, SS and JK wrote the original manuscript. All authors contributed to revising the content and approved the final version.

  • Funding This work was supported by the University of Oulu Graduate School (ES, MK), the Finnish Foundation for Cardiovascular Research (VS), Biocenter Oulu (SS), European Commission (DynaHEALTH – H2020 – 633595; SS), Academy of Finland (297338 and 307247; JK) and Novo Nordisk Foundation (NNF17OC0026062; JK). NFBC1966 received financial support from University of Oulu (Grant No 65354), Oulu University Hospital (Grant No 2/97 and 8/97), Ministry of Health and Social Affairs (Grant No 23/251/97, 160/97 and 190/97), National Institute for Health and Welfare, Helsinki (Grant No 54121), and Regional Institute of Occupational Health, Oulu, Finland (Grant No 50621 and 54231). The Young Finns Study has been financially supported by the Academy of Finland (grants 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi) and 41071 (Skidi)); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; Sigrid Juselius Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; Diabetes Research Foundation of Finnish Diabetes Association; EU Horizon 2020 (grant 755320 for TAXINOMISIS); European Research Council (grant 742927 for MULTIEPIGEN project); and Tampere University Hospital Supporting Foundation.

  • Competing interests VS has participated in a conference trip sponsored by Novo Nordisk and received a honorarium from the same source for participating in and advisory board meeting. He also has ongoing research collaboration with Bayer.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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