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

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.

Keywords: abo blood type; genome-wide association; inflammatory load; svcam-1.

Figure 1

The combined Manhattan plots for significant associations with inflammatory markers studied in (A) Northern Finland Birth Cohort 1966 and in (B) meta-analyses with three other Finnish population cohorts. Significance threshold p<3.1×10⁻⁹ derives from the standard p value limit for genome-wide significance p<5×10⁻⁸ corrected for 16 markers examined in the present study. Novel association signals are highlighted with red font and replicated loci are marked with black font. sE-selectin, soluble E-selectin; IL1b, interleukin 1-beta; IP10, interferon gamma-induced protein 10; MCP1, monocyte chemoattractant protein 1; sICAM-1, soluble intercellular adhesion molecule-1; sVCAM-1, soluble vascular cell adhesion molecule-1; TNFa, tumour necrosis factor alpha; VEGF, vascular endothelial growth factor.

Figure 2

The effects of the ABO blood types and the A1 subtype on soluble adhesion molecule levels. The effects of the ABO blood types on sE-selectin, sICAM-1 and sVCAM-1 levels were evaluated in linear models, where adjusted (sex, age, body mass index and the 10 first genetic principal components) and transformed soluble adhesion molecule concentrations were used as outcomes and the ABO blood type served as categorical variable (A vs non-A, and so on). Corresponding models were fitted for the ABO blood types stratified by the rs507666-A allele count (0, 1 or 2), where the A allele tags the ABO subtype A1 having enhanced glycosyltransferase activity. No individuals were found to have B or O blood type and one or more copies of the rs507666-A allele, and thus it was not possible to perform stratification within these blood types. sE-selectin, soluble E-selectin; sICAM-1, soluble intercellular adhesion molecule-1; sVCAM-1, soluble vascular cell adhesion molecule-1.

Figure 3

SNP effects on soluble adhesion molecule levels versus other cardiovascular health-related traits in the ABO locus. The Pearson’s r of the genetic effects (Z-scores) were estimated using a set of SNPs that located in the ABO locus (defined as the LD block containing ABO gene in the gwas-pw analyses) and that were available in both the present study and open-access data sets. Positive correlations are indicated with red color, negative correlations are indicated with blue color, and correlations with p≥0.05 are left blank. The scatter plot representations as well as correlations in the other loci are shown in online supplementary figure S3. CAD, coronary artery disease; HDL-C, high-density lipoprotein cholesterol; LD, linkage disequilibrium; LDL-C, low-density lipoprotein cholesterol; sE-selectin; soluble E-selectin; sICAM-1, soluble intercellular adhesion molecule-1; sVCAM-1, soluble vascular cell adhesion molecule-1; TG, total triglycerides; TotC, total cholesterol.