Genome-wide Association Study Identifies 27 Loci Influencing Concentrations of Circulating Cytokines and Growth Factors

Abstract

Circulating cytokines and growth factors are regulators of inflammation and have been implicated in autoimmune and metabolic diseases. In this genome-wide association study (GWAS) of up to 8,293 Finns we identified 27 genome-widely significant loci (p < 1.2 × 10^-9) for one or more cytokines. Fifteen of the associated variants had expression quantitative trait loci in whole blood. We provide genetic instruments to clarify the causal roles of cytokine signaling and upstream inflammation in immune-related and other chronic diseases. We further link inflammatory markers with variants previously associated with autoimmune diseases such as Crohn disease, multiple sclerosis, and ulcerative colitis and hereby elucidate the molecular mechanisms underpinning these diseases and suggest potential drug targets.

Figure 1

Combined Manhattan Plot of Meta-analysis Results from the GWAS of 41 Circulating Cytokines Loci not previously associated with cytokine concentration in the GWAS are bolded. The horizontal dashed line indicates the genome-wide significance threshold (p < 1.2 × 10⁻⁹) accounting for the number of cytokines tested in the study.

Figure 2

Variants Genome-widely Associated with More than One Cytokine Variant rs12075-A is associated with increased concentrations of eotaxin, monocyte chemotactic protein-1 (MCP1), and growth regulated oncogene-α (GROa). In addition, rs12075-A is associated with increased ACKR1 mRNA. Since ACKR1 is a cell surface receptor, the cluster effect on the three cytokines is unlikely to be mediated (in a cascade) through any of the three cytokines associated with rs12075 (A). Similarly, effect of rs2228467 is mediated through a cell surface receptor (ACKR2) (B). Variant rs6921438 in 6p21.1 is located near VEGFA. This suggests that VEGF is causally regulating the concentrations of IL-7, IL-10, IL-12p70, and IL-13 (C). Instrumental variable analyses indicate that the inter-correlations between the cytokines match the causal effect estimates; this suggests a causal role of VEGF in mediating a cascade effect on IL-7, IL-10, IL-12p70, and IL-13 (D).

Figure 3

Boxplots of Interleukin-16 Cytokine and IL16 mRNA Concentrations The mRNA and circulating cytokine concentration are depicted by the dark gray and white boxes, respectively. Variant rs4778636 is located within IL16. The asterisk indicates undetectable concentration of circulating IL-16. The A allele of rs4778636 leads to nonsense-mediated decay of IL16 mRNA and thus circulating concentration of IL-16 is undetectable in rs4778636-AA homozygotes. The box indicates the 25^th and 75^th percentile. The black horizontal lines within the boxes represent median. The whiskers indicate the least and the maximum value excluding outliers, indicated by dots.