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
- abo blood type
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
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.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.