Dysfunction of FOXP3‐positive regulatory T cells (Tregs) likely plays a major role in the pathogenesis of multiple autoimmune diseases including type 1 diabetes (T1D). Whether genetic polymorphisms associated with the risk of autoimmune diseases affect Treg frequency or function is currently unclear. Here, we analysed the effect of T1D‐associated major HLA class II haplotypes and seven single nucleotide polymorphisms in six non‐HLA genes [INS (rs689), PTPN22 (rs2476601), IL2RA (rs12722495 and rs2104286), PTPN2 (rs45450798), CTLA4 (rs3087243), and ERBB3 (rs2292239)] on peripheral blood Treg frequencies. These were determined by flow cytometry in 65 subjects who had progressed to T1D, 86 islet autoantibody‐positive at‐risk subjects, and 215 islet autoantibody‐negative healthy controls. The PTPN22 rs2476601 risk allele A was associated with an increase in total (p = 6 × 10−6) and naïve (p = 4 × 10−5) CD4+CD25+CD127lowFOXP3+ Treg frequencies. These findings were validated in a separate cohort comprising ten trios of healthy islet autoantibody‐negative children carrying each of the three PTPN22 rs2476601 genotypes AA, AG, and GG (p = 0.005 for total and p = 0.03 for naïve Tregs, respectively). In conclusion, our analysis implicates the autoimmune PTPN22 rs2476601 risk allele A in controlling the frequency of Tregs in human peripheral blood.

The non-HLA loci conferring susceptibility to type 1 diabetes determine approximately half of the genetic disease risk, and several of them have been shown to affect immune-cell or pancreatic β-cell functions. A number of these loci have shown associations with the appearance of autoantibodies or with progression from seroconversion to clinical type 1 diabetes. In the current study, we have re-analyzed 21 of our loci with prior association evidence using an expanded DIPP follow-up cohort of 976 autoantibody positive cases and 1,910 matched controls. Survival analysis using Cox regression was applied for time periods from birth to seroconversion and from seroconversion to type 1 diabetes. The appearance of autoantibodies was also analyzed in endotypes, which are defined by the first appearing autoantibody, either IAA or GADA. Analyzing the time period from birth to seroconversion, we were able to replicate our previous association findings at PTPN22, INS, and NRP1. Novel findings included associations with ERBB3, UBASH3A, PTPN2, and FUT2. In the time period from seroconversion to clinical type 1 diabetes, prior associations with PTPN2, CD226, and PTPN22 were replicated, and a novel association with STAT4 was observed. Analyzing the appearance of autoantibodies in endotypes, the PTPN22 association was specific for IAA-first. In the progression phase, STAT4 was specific for IAA-first and ERBB3 to GADA-first. In conclusion, our results further the knowledge of the function of non-HLA risk polymorphisms in detailing endotype specificity and timing of disease development.

Objective: The pathogenesis of type 1 diabetes (T1D) is associated with genetic predisposition and immunological changes during presymptomatic disease. Differences in immune cell subset numbers and phenotypes between T1D patients and healthy controls have been described; however, the role and function of these changes in the pathogenesis is still unclear. Here we aimed to analyze the transcriptomic landscapes of peripheral blood mononuclear cells (PBMCs) during presymptomatic disease.Methods: Transcriptomic differences in PBMCs were compared between cases positive for islet autoantibodies and autoantibody negative controls (9 case-control pairs) and further in monocytes and lymphocytes separately in autoantibody positive subjects and control subjects (25 case-control pairs).Results: No significant differential expression was found in either data set. However, when gene set enrichment analysis was performed, the gene sets "defence response to virus" (FDR <0.001, ranking 2), "response to virus" (FDR <0.001, ranking 3) and "response to type I interferon" (FDR = 0.002, ranking 12) were enriched in the upregulated genes among PBMCs in cases. Upon further analysis, this was also seen

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