Neutrophil GM-CSF signaling in inflammatory bowel disease patients is influenced by non-coding genetic variants

• Type of Material: Article
• Authors: Suresh Venkateswaran, Emory University; Lee A. Denson, University of Cincinnati; Ingrid Jurickova, University of Cincinnati; Anne Dodd, Emory University; Michael Zwick, Emory University; David J Cutler, Emory University; Subramaniam Kugathasan, Emory University; David T. Okou, Emory University
• Language: English
• Date: 2019-06-24
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2019, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-019-45701-2
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 9
• Issue: 1
• Start Page: 9168
• End Page: 9168
• Grant/Funding Information: Additional support was provided by the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378.; This study was supported by grants R01 DK098231 (L.A.D. and S.K.) and P30 DK078392 (L.A.D.) from the National Institutes of Health.; This study was also supported in part by the Emory Integrated Genomics Core (EIGC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities.
• Keywords: CROHNS-DISEASE; CELL; Science & Technology; EXPRESSION; ASSOCIATION; RISK; BETA; Multidisciplinary Sciences; LOCI; RESOURCE; Science & Technology - Other Topics
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Genetics

Abstract

Neutrophil dysfunction and GM-CSF auto-antibodies are observed in pediatric and adult patients with Crohn’s disease (CD). We associated damaging coding variants with low GM-CSF induced STAT5 stimulation index (GMSI) in pediatric CD patients and implicated variation of neutrophil GM-CSF signaling in cell function and disease complications. Because many CD patients with low GMSI do not carry damaging coding mutations, we sought to test the hypothesis that non-coding variants contribute to this phenotype. We enrolled, performed whole genome sequencing, and measured the GMSI in 77 CD and ulcerative colitis (UC) patients (24 low and 53 normal GMSI). We identified 4 non-coding variants (rs3808851, rs10974787, rs10974788 and rs10974789) in RCL1 significantly associated with variation of GMSI level (p < 0.011). They were validated in two independent cohorts with: RNAseq data (n = 50) and blood eQTL dataset (n = 31,684). These variants are in LD and affect expression of JAK2 (p 0.005 to 0.013), RCL1 (p 8.17E-13 to 2.98E-11) and AK3 (p 2.00E-68 to 3.03E-55) genes. Additionally, they influence proteins involved in differentiation of gut epithelium, inflammation, and immune system regulation. In summary, our study outlines the contribution of non-coding variants in neutrophil GM-CSF signaling and the potential importance of RCL1 and AK3 in CD pathogenesis.