A Functional Genomics Approach to Understand Variation in Cytokine Production in Humans

作者：Li Yang; Oosting Marije; Smeekens Sanne P; Jaeger Martin; Aguirre Gamboa Raul; Le Kieu T T; Deelen Patrick; Ricano Ponce Isis; Schoffelen Teske; Jansen Anne F M; Swertz Morris A; Withoff Sebo; van de Vosse Esther; van Deuren Marcel; van de Veerdonk Frank; Zhernakova Alexandra; van der Meer Jos W M; Xavier Ramnik J; Franke Lude; Joosten Leo A B; Wijmenga Cisca; Kumar Vinod; Netea Mihai G

来源：Cell, 2016, 167(4): 1099-+.

DOI：10.1016/j.cell.2016.10.017

As part of the Human Functional Genomics Project, which aims to understand the factors that determine the variability of immune responses, we investigated genetic variants affecting cytokine production in response to ex vivo stimulation in two independent cohorts of 500 and 200 healthy individuals. We demonstrate a strong impact of genetic heritability on cytokine production capacity after challenge with bacterial, fungal, viral, and non-microbial stimuli. In addition to 17 novel genome-wide significant cytokine QTLs (cQTLs), our study provides a comprehensive picture of the genetic variants that influence six different cytokines in whole blood, blood mononuclear cells, and macrophages. Important biological pathways that contain cytokine QTLs map to pattern recognition receptors (TLR1-6-10 cluster), cytokine and complement inhibitors, and the kallikrein system. The cytokine QTLs show enrichment for monocyte-specific enhancers, are more often located in regions under positive selection, and are significantly enriched among SNPs associated with infections and immune-mediated diseases.

• 出版日期2016-11-3