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  • As in our earlier observations the PTPN

    2021-03-03

    As in our earlier observations, the PTPN22 SNP affected the appearance of β-cell autoimmunity, but in contrast to our earlier report, only a borderline effect of the PTPN22 SNP on the progression to clinical disease was observed in the current analysis [22], [27]. The finding of an effect of the PTPN22 SNP on autoimmunity initiation is in line with three other reports [17], [19], [23] whereas no effect of a PTPN22 SNP in close linkage disequilibrium with the one used in the current analysis was observed on the type 1 diabetes pathogenesis in the German cohort [28]. The main difference, which might explain the discrepant findings between the studies is the number of subjects in the analysis. The higher number of autoantibody-positive subjects in the current analysis enables us to detect smaller effects and this is even reinforced with the fact that the frequency of the minor T allele varies strongly between different populations, and the frequency of the risk allele is higher in Northern Europe and in Finland, in particular [29]. The PTPN22 risk allele has multiple effects in immune INNO-406 and effects on different phases of the autoimmune process have been hypothesized [30]. In our cohort IFIH1 exerted its effect on the INNO-406 early phase of the development of β-cell autoimmunity which is in contrast to the finding from the cohorts from Germany and Colorado showing IFIH1 to be associated with enhanced progression rate after the appearance of autoantibodies but not with the appearance of autoantibodies [23], [28]. In the recent multi-center TEDDY cohort no effect was observed on the appearance of β-cell autoimmunity [17]. IFIH1 serves as an intracellular receptor for enteroviruses and transmits the intracellular signal to activate defense mechanisms in virus-infected cells [31]. The differences observed may be related to the varying size of the two follow-up cohorts, but also to possible gene–environmental interactions that might affect the findings. Enterovirus infections have been repeatedly associated with the initiation of autoimmunity in Finnish observational cohorts but no increased number of infections has been reported at the presentation of clinical diabetes whereas in many other populations increased signs of an enterovirus infection have been observed in association with disease manifestation [32], [33], [34], [35], [36]. Moreover, the IFIH1 risk effect on the progression of autoimmunity has been reported to be influenced by the mode of delivery suggesting gene–environmental interaction that might explain the variable observations [37]. The analysis of progression from autoantibody positivity to clinical disease is in essence measuring the rate of this progression as long-term follow-up results indicate that close to all of the children testing positive for two or more autoantibodies progress to clinical disease within 15–20 years [38]. This also implies that it may be difficult to identify these genes in case–control studies accumulating diabetic patients diagnosed at variable ages although some enrichment in cohorts diagnosed at young age may be expected. The PTPN2 gene was most conspicuously affecting this rate in our study, in which homozygosity for the rs45450798C allele was strongly associated with rapid disease progression, although no effect on autoantibody seroconversion was seen. Homozygosity for the minor allele is relatively rare but it was clearly associated with the highest risk for type 1 diabetes also by Smyth et al. [39], and in our family trio transmission study [40]. In contrast, the recent report by Steck et al. did not observe any effect of a PTPN2 SNP in tight linkage disequilibrium with the one in our analysis during the progression from β-cell autoimmunity to clinical disease but the number of subjects with islet autoimmunity in their study was too low to detect a minor allele homozygosity effect [23]. In experimental models PTPN2 knockdown was shown to exacerbate interferon induced β-cell apoptosis in rodent and human β cells pointing to a possible mechanism how genetic polymorphism might affect the rate of β-cell destruction in autoimmunity associated with human diabetes [41]. PTPN2 was recently shown to be a molecule regulating the activity of cytotoxic CD8 T cells recognizing β-cell autoantigens in a mouse model [42].