Genetic studies of type 1 diabetes (T1D) have identified more than 40 risk loci, yet the causative genes in each locus is widely unknown. Here, we investigated a candidate gene in the 10q23.31 risk locus—FAD-dependent amine oxidase (RNLS). Variants in RNLS gene are associated with T1D risk in both European and African ancestry populations, indicating common genetic contributions to T1D. Currently, our understanding of the function of RNLS is very limited and primarily within the context of a few human diseases, most notably hypertension, kidney disease, cardiovascular disease, and cancer. In previous studies a positive RNLS-STAT3 feedback loop has been suggested. With consideration to these reports, and the importance of JAK-STAT signalling in immune-mediated diseases we evaluated if RNLS functions in activation of STAT3. An IFN-β time course was conducted to understand if overexpression of RNLS affects STAT3 levels and phosphorylation levels of STAT3. While we observed no difference in steady-state levels of STAT3 in cells overexpressing RNLS, we did observe increased levels of phospho-STAT3 upon IFN-β stimulation (p: 0.0051). In addition, to understand the function of RNLS in the immune system, we used RNAseq to compare transcriptomes of Jurkat cells expressing endogenous RNLS vs. ones overexpressing RNLS. RNAseq analysis identified 390 genes that were differentially expressed, by more than two-fold, of which 74.1 (289/390) of genes were up-regulated and 25.9 (101/390) were down-regulated in cells overexpressing RNLS. Tissue specific gene network analysis revealed that genes that were up-regulated mainly functioned in pathways related to chromosome segregation and cell division while genes that were down-regulated by RNLS were involved in IFN and NF-kappa B signaling pathways. Overall our results established a role for RNLS in cell-cycle related pathways and immune signaling pathways, providing new mechanistic insights of the role of RNLS in T1D.


S. Onengut-Gumuscu: None. N. Vogler: None. M. Faidas: None. R.R. Pickin: None. E. Gersz: None. S.S. Rich: None.

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