Genome-wide Association Study Identifies 27 Loci Influencing Concentrations of Circulating Cytokines and Growth Factors

Ari V Ahola-Olli; Peter Würtz; Aki S Havulinna; Kristiina Aalto; Niina Pitkänen; Terho Lehtimäki; Mika Kähönen; Leo-Pekka Lyytikäinen; Emma Raitoharju; Ilkka Seppälä; Antti-Pekka Sarin; Samuli Ripatti; Aarne Palotie; Markus Perola; Jorma S Viikari; Sirpa Jalkanen; Mikael Maksimow; Veikko Salomaa; Marko Salmi; Johannes Kettunen; Olli T Raitakari

doi:10.1016/j.ajhg.2016.11.007

Genome-wide Association Study Identifies 27 Loci Influencing Concentrations of Circulating Cytokines and Growth Factors

Am J Hum Genet. 2017 Jan 5;100(1):40-50. doi: 10.1016/j.ajhg.2016.11.007. Epub 2016 Dec 15.

Authors

Ari V Ahola-Olli¹, Peter Würtz², Aki S Havulinna³, Kristiina Aalto⁴, Niina Pitkänen⁵, Terho Lehtimäki⁶, Mika Kähönen⁷, Leo-Pekka Lyytikäinen⁶, Emma Raitoharju⁶, Ilkka Seppälä⁶, Antti-Pekka Sarin⁸, Samuli Ripatti⁹, Aarne Palotie¹⁰, Markus Perola⁸, Jorma S Viikari¹¹, Sirpa Jalkanen⁴, Mikael Maksimow⁴, Veikko Salomaa³, Marko Salmi⁴, Johannes Kettunen¹², Olli T Raitakari¹³

Affiliations

¹ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, 20520 Turku, Finland. Electronic address: avahol@utu.fi.
² Computational Medicine, Center for Life Course Health Research, University of Oulu, 90014 Oulu, Finland.
³ National Institute of Health and Welfare, 00271 Helsinki, Finland.
⁴ Medicity Research Laboratory, Department of Medical Microbiology and Immunology, University of Turku, 20520 Turku, Finland.
⁵ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, 20520 Turku, Finland.
⁶ The Department of Clinical Chemistry, Fimlab Laboratories, Pirkanmaa Hospital District, School of Medicine, University of Tampere, 33014 Tampere, Finland.
⁷ The Department of Clinical Physiology, Tampere University Hospital, 33521 Tampere, Finland.
⁸ National Institute of Health and Welfare, 00271 Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014 Helsinki, Finland.
⁹ National Institute of Health and Welfare, 00271 Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014 Helsinki, Finland; The Department of Public Health, University of Helsinki, 00271 Helsinki, Finland.
¹⁰ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014 Helsinki, Finland; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
¹¹ The Department of Medicine, University of Turku, 20520 Turku, Finland; Division of Medicine, Turku University Hospital, 20520 Turku, Finland.
¹² Computational Medicine, Center for Life Course Health Research, University of Oulu, 90014 Oulu, Finland; National Institute of Health and Welfare, 00271 Helsinki, Finland; NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, 70211 Kuopio, Finland; Biocenter Oulu, University of Oulu, 90014 Oulu, Finland.
¹³ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, 20520 Turku, Finland; Biocenter Oulu, University of Oulu, 90014 Oulu, Finland; The Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, 20520 Turku, Finland.

Abstract

Circulating cytokines and growth factors are regulators of inflammation and have been implicated in autoimmune and metabolic diseases. In this genome-wide association study (GWAS) of up to 8,293 Finns we identified 27 genome-widely significant loci (p < 1.2 × 10^-9) for one or more cytokines. Fifteen of the associated variants had expression quantitative trait loci in whole blood. We provide genetic instruments to clarify the causal roles of cytokine signaling and upstream inflammation in immune-related and other chronic diseases. We further link inflammatory markers with variants previously associated with autoimmune diseases such as Crohn disease, multiple sclerosis, and ulcerative colitis and hereby elucidate the molecular mechanisms underpinning these diseases and suggest potential drug targets.

MeSH terms

Autoimmune Diseases / genetics
Colitis, Ulcerative / genetics
Crohn Disease / genetics
Cytokines / blood*
Female
Genome-Wide Association Study*
Humans
Inflammation / genetics
Intercellular Signaling Peptides and Proteins / blood*
Male
Multiple Sclerosis / genetics
Quantitative Trait Loci / genetics*

Substances

Cytokines
Intercellular Signaling Peptides and Proteins