TY - JOUR T1 - The autoimmune disease risk allele rs6897932 modulates monocyte IL7R surface and soluble receptor levels in a context-specific manner JF - bioRxiv DO - 10.1101/262410 SP - 262410 AU - Hussein Al-Mossawi AU - Evelyn Lau AU - Sara Danielli AU - Nicole Yager AU - Jelle de Wit AU - Seiko Makino AU - James Gilchrist AU - Wanseon Lee AU - Isar Nassiri AU - Elise A Mahe AU - Laila Rizvi AU - Jane Cheeseman AU - Matt Neville AU - Julian C Knight AU - Paul Bowness AU - Benjamin P Fairfax Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/02/10/262410.abstract N2 - IL-7 is a key factor in T-cell immunity and IL7R polymorphisms are implicated in autoimmune pathogenesis. We previously reported an expression quantitative trait locus (eQTL) at rs931555, 5’ to IL7R, associated with stimulated monocyte IL7R mRNA expression. Unlike in T-cells, a role for IL7R in monocyte biology is poorly described. Here we detail replication and characterization of this eQTL at protein level across cell subsets and conditions in a separate cohort. We find rs6897932, a non-synonymous IL7R polymorphism associated with susceptibility to Multiple Sclerosis, Ankylosing Spondylitis and Primary Biliary Cirrhosis, is the key determinant of monocyte IL7R surface expression and soluble IL7R (sIL7R) and functions in a context-specific manner. Monocyte surface IL7R is markedly induced by LPS and TNF stimulation under the genotypic regulation of rs6897932, whereas no effect of this allele was observed on CD4+, CD8+ or CD56+ cell surface IL7R or in unstimulated monocytes. LPS-induced monocyte release of sIL7R was strongly associated with both rs6897932 genotype and expression of the splicing factor gene DDX39A. After induction of IL7R expression, human monocytes display a robust and pleiotropic transcriptional response to exogenous IL-7. Monocytes from the synovial fluid of patients with Spondyloarthritis were similarly found to express high levels of surface IL7R. These data demonstrate that disease-associated genetic variants in the IL7R gene critically impact monocyte IL7R and sIL7R expression following innate immune stimulation, suggesting a previously unappreciated key role for monocytes in IL-7 pathway biology and IL7R-associated diseases. ER -