1465-P: The C1858T Polymorphism in PTPN22 Modulates the Human Pancreatic Islet Transcriptome

Introduction & Objective: PTPN22 encodes for a lymphoid-specific intracellular phosphatase involved in T-cell receptor signaling. The C1858T PTPN22 polymorphism induces gain of function of the encoded Lyp phosphatase and associates with T1D. Since PTPN22 is expressed in human pancreatic islets (HI), we assessed whether the C1858T variant affects HI function and molecular features.

Methods: Genomic DNA of 105 nondiabetic (ND) donors was analyzed and HI were isolated from the same subjects. Islet insulin release was assessed in response to 16.7 mM glucose (G), glyburide (Glyb) and arginine (Arg). RNA-sequencing was performed in hand-picked HI. Islet functional and transcriptomic data of 8 carriers of the polymorphism and 11 wild type (WT) matched donors were compared.

Results: Insulin stimulation indexes in response to G, Glyb and Arg did not differ significantly between C1858T and WT islets (respectively 3.17±1.18 vs 2.80±0.94, 3.85±1.41 vs 3.75±1.30, and 3.20±1.14 vs 2.16±1.13). Comparison between the mutated vs WT islet transcriptomes evidenced 21 differentially expressed genes (FDR<0.05, absolute fold-change>1.5): 3 were up-regulated (DCD, MIR205HG, SNORA72) and 18 down-regulated (the top 5 being H2BC17, RRM2, IQGAP3, CYBB and FN1). GSEA retrieved 34 gene sets significant at FDR < 25% threshold. At nominal p value of < 1%, 6 of them were positively enriched in C1858T islets (Myc target_V1 and Myc target_V2, Unfolded protein response, Pancreas beta cells, DNA repair, E2F targets) and 18 were negatively enriched (including IFN-gamma response, IFN-alpha response, TNFA signaling via NFKB, Complement, Inflammatory response).

Conclusion: These results suggest that the C1858T PTPN22 polymorphism affects the islet transcriptome, including cellular stress, inflammation, and innate immunity pathways, without a major impact on insulin secretion. The ultimate mechanism(s) behind the role for the C1858T PTPN22 polymorphism in T1D-mediated beta cell damage remains to be clarified.