Genetic study of circulating cytokines offers insight into the determinants, cascades and effects of systemic inflammation

Abstract

Cytokines are the signalling molecules that underlie inflammatory processes. Here, we performed genome-wide association study (GWAS) analyses of 47 circulating cytokines in up to 13,365 individuals to identify protein quantitative trait loci (pQTL). Applying a novel approach, we incorporated pQTL and expression quantitative trait loci (eQTL) data of 10,361 tissue samples in 635 individuals to identify biologically plausible genetic instruments to proxy the effect of cytokines. Using Mendelian randomization analysis, we explored the causal determinants of inflammatory cytokines, investigated inflammatory cascades and evaluated their effects on 20 diseases. We show evidence of body mass index (BMI), smoking and systolic blood pressure (SBP) being associated with inflammation, and specifically BMI affecting levels of active PAI-1, HGF, MCP1, sE-Selectin, sICAM1, TRAIL, IL6 and CRP. Our analysis highlights a key role of VEGF in influencing the levels of eight other inflammatory cytokines. Finally, we report evidence of sICAM affecting waist circumference and risk of major depressive disorder, evidence for TRAIL affecting the risk of cardiovascular diseases, breast and prostate cancer, and evidence for MIG affecting the risk of stroke. Overall, our results offer insight into inflammatory mediators of BMI, smoking and SBP, pleiotropic effects of VEGF, and circulating cytokines that increase the risk of cancer, cardiovascular, metabolic and neuropsychiatric diseases. All the studied cytokines represent pharmacological targets and therefore offer opportunities for clinical translation in diseases with inflammatory components.

Inflammatory Diseases, Inflammatory Biomarkers, and Alzheimer Disease

“…We previously found that circulating MIG causally affects the IP10 level. 16 MIG ( CXCL9 ), IP10 ( CXCL10 ), and IP9 ( CXCL11 ) share the same receptor, C-X-C chemokine receptor 3 (CXCR3), 38 but colocalization in our study did not support common causal SNPs for IP10 and Crohn disease. This may suggest a more prominent role of MIG in Crohn disease.…”

“…We also took advantage of two additional GWAS to increase the sample size of 20 biomarkers (the maximum sample size was increased from 8,293 to 13,365). 16 Our MR findings suggested a link between MIG and higher risk of AD, but lower risk of Crohn's disease. MIG belongs to the CXC chemokine family and is also known as chemokine (C-X-C motif) ligand 9 (CXCL9).…”

“…We also took advantage of 2 additional GWASs to increase the sample size of 20 biomarkers (the maximum sample size was increased from 8,293 to 13,365). 16 …”

“…We selected circulating inflammatory biomarkers of which meta-analyses of a genome-wide association study (GWAS) were available based on 3 Finnish cohorts, namely Northern Finland Birth Cohort 1966, the Cardiovascular Risk in Young Finns, and FINRISK. 16 To increase the power of our analysis, we further incorporated the Finnish meta-analysis with summary statistics from GWAS on proteins in the INTERVAL study 17 and SCALLOP consortium. 18 Details of the meta-analysis are described in eMethods ( links.lww.com/WNL/C487 ) and eTable 7 ( links.lww.com/WNL/C486 ).…”

The Protective Effect of Interleukin-1 Receptor Antagonist on Kidney Function: A Mendelian Randomization Study

“…The genetic instruments were identi ed from a previous GWAS meta-analysis study 18 including genetic information of 47 in ammatory cytokines from three sources: a GWAS of up to 21,758 individuals of European ancestry from the SCALLOP consortium, 23 3301 individuals of European ancestry from the INTERVAL study, 24 and 13,365 Finnish individuals from the Northern Finland Birth Cohort 1966, 25 the Cardiovascular Risk in Young Finns study, and FINRISK 1997 and 2002. 17,26 Using these genetic instruments, a total of 80 cis-instruments (60 as cis-pQTL and 20 as cis-eQTL) that are strongly associated with the effect of circulating IL concentration were developed (Supplemental Table 1,2). 18 Two cis-instrumental selection criteria were used to identify variants that re ected the effect of circulating cytokine levels are described in Supplemental Data 1.…”