Genetic determinants of cytokine production in activated human monocytes

Abstract

Monocyte function plays a central role in human health and mapping the genetic determinants of monocyte gene expression has provided insights into numerous disease processes. The relationship between genetic variation and functional cytokine secretion in response to immune stimuli remains poorly characterised however. To address this, we have quantified the production of 28 cytokines by monocytes from 366 healthy, European-ancestry donors following activation with lipopolysaccharide (LPS) and interferon gamma (IFN{gamma}). By integrating these data with genomic and transcriptomic data from the same cells we robustly define the regulatory determinants of monocyte cytokine secretion. We identify four genome-wide significant loci affecting monocyte cytokine release, observing both cis and trans regulatory effects on cytokine release. These loci include multi-cytokine trans regulatory activity of the CCR5-{Delta}32 deletion on secretion of the CCR5-binding cytokines, MIP-1{beta} and RANTES, and a cis regulator of PDGF-BB secretion, which colocalises with GWAS risk loci for ulcerative colitis and primary biliary cirrhosis. We further map the genetics of co-expression to establish relationships between RNA transcription and cytokine protein secretion. In doing so we identify marked enrichment of genes related to lipid metabolism in gene regulatory networks linked to cytokine secretion and identify that the COVID-19 risk locus at OAS1 uncouples OAS1 RNA expression from the secretion of 10 cytokines in response to LPS stimulation.