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Genome-wide association study identifies seven novel loci associating with circulating cytokines and cell adhesion molecules in Finns

By Eeva Sliz, Marita Kalaoja, Ari Ahola-Olli, Olli Raitakari, Markus Perola, Veikko Salomaa, Terho Lehtimaki, Toni Karhu, Heimo Viinamäki, Marko Salmi, Kristiina Santalahti, Sirpa Jalkanen, Jari Jokelainen, Sirkka Keinänen-Kiukaanniemi, Minna Männikkö, Karl-Heinz Herzig, Marjo-Riitta Järvelin, Sylvain Sebert, Johannes Kettunen

Posted 10 Dec 2018
bioRxiv DOI: 10.1101/491852 (published DOI: 10.1136/jmedgenet-2018-105965)

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. Methods: To add understanding to the molecular mechanisms in inflammation, we performed a genome-wide association study (GWAS) on 16 circulating cytokines and cell adhesion molecules (inflammatory phenotypes) in Northern Finland Birth Cohort 1966 (NFBC1966, N=5,284). A subsequent meta-analysis was completed for 10 phenotypes available in a GWAS of three other Finnish population cohorts 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 confirmed six previously reported loci associating with at least one of the studied inflammatory phenotypes (p<3.1x10-9). We observed three loci associating with the concentration of soluble vascular cell adhesion molecule-1 (sVCAM-1), one of which is the ABO locus that has been previously associated with soluble E-selectin (sE-selectin) and intercellular adhesion molecule-1 (sICAM-1) levels. Results from the complementary analyses suggest that the blood type B associates primarily with the concentration of sVCAM-1 while the A1 subtype shows a robust effect on sE-selectin and sICAM-1 levels. Furthermore, the genotypes in the ABO locus associating with higher soluble adhesion molecule levels tend to associate with lower low-density lipoprotein cholesterol level 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 at the ABO locus. The negative correlation between the genetic effects on soluble adhesion molecule levels and cardiovascular traits in this locus further suggests that increased soluble adhesion molecule levels per se may not be a risk factor for cardiovascular disease.

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