RT Journal Article
SR Electronic
T1 Genome-wide association study identifies seven novel loci associating with circulating cytokines and cell adhesion molecules in Finns
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 491852
DO 10.1101/491852
A1 Eeva Sliz
A1 Marita Kalaoja
A1 Ari Ahola-Olli
A1 Olli Raitakari
A1 Markus Perola
A1 Veikko Salomaa
A1 Terho Lehtimäki
A1 Toni Karhu
A1 Heimo Viinamäki
A1 Marko Salmi
A1 Kristiina Santalahti
A1 Sirpa Jalkanen
A1 Jari Jokelainen
A1 Sirkka Keinänen-Kiukaanniemi
A1 Minna Männikkö
A1 Karl-Heinz Herzig
A1 Marjo-Riitta Järvelin
A1 Sylvain Sebert
A1 Johannes Kettunen
YR 2018
UL http://biorxiv.org/content/early/2018/12/10/491852.abstract
AB 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<3.1×10−9). 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.AbbreviationsGWASgenome-wide association studyIL1αinterleukin 1-alphaIL1βinterleukin 1-betaIL1rainterleukin 1 receptor antagonistIL4interleukin 4IL6interleukin 6IL8interleukin 8IL17interleukin 17IP10interferon gamma-induced protein 10MAFminor allele frequencyMCP1monocyte chemoattractant protein 1NFBC1966Northern Finland Birth Cohort 1966PAI-1plasminogen activator inhibitor 1sCD40Lsoluble CD40 ligandsE-selectinsoluble E-selectinsICAM-1soluble intercellular cell adhesion molecule 1sVCAM-1soluble vascular cell adhesion molecule 1TNFαtumor necrosis factor alphaVEGFvascular endothelial growth factor