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

• 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
• Journal Title: Scientific Reports
• Volume: Volume 9, Number 1
• Publisher: Nature Research (part of Springer Nature): Fully open access journals | 2019-06-24, Pages 9168-9168
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/s41598-019-45701-2
• Subjects: Health Sciences, Medicine and Surgery; Biology, Genetics
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; CROHNS-DISEASE; CELL; ASSOCIATION; EXPRESSION; RESOURCE; RISK; LOCI; BETA

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.