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    • Polymorphism of the CD gene also

    2019-10-21

    Polymorphism of the CD226 gene also affected the progression rate without any significant effect on autoantibody formation. This gene has been reported to be a common genetic factor in multiple autoimmune diseases such as SLE, systemic sclerosis and type 1 diabetes [43]. CD226 is an immunoglobulin supergene family receptor, is expressed in NKT cells, CD4+ and CD8+ cells, monocytes and in a subset of B cells. The rs763361 polymorphism is shown to alter the splicing of the CD226 transcript, affect down-stream signaling and increase the activations of T and NK Nicotine Difartrate mg [44], phenomena that may possibly be involved in β-cell destruction. The SNP in the CTLA4 gene has been reported to affect the progression rate of β-cell autoimmunity in German and Colorado cohorts [19], [45] although in the expanded Colorado cohort it was no more significant. In our analysis, the CTLA4 polymorphism was not significantly associated with either of the phases in the disease process or even the development of diabetes when observed from birth on although its role in diabetes susceptibility in the Finnish population has been demonstrated [46]. We could not detect any significant effect of the ERBB3-IKZF4 region on the disease pathogenesis in the whole cohort analyzed although it was highly significant in the Finnish type 1 diabetes trio family analysis [40]. However, after the primary analyses we proceeded to see whether the effect of the diabetes risk-associated SNPs is related to the triggering autoantigen. For this purpose case subjects from whom the first biochemical autoantibody could be defined together with control subjects selected for them were divided into subgroups according to the first biochemical autoantibody. Here, the effect of the polymorphisms in the IKZF4 and the nearby ERBB3 genes revealed a significant effect on the development of type 1 diabetes and specifically on the progression rate of disease process after the initiation of β-cell autoimmunity. The effect of these two SNPs on disease development could be observed only when analyzing subjects with GADA as the first autoantibody and corresponding controls whereas no effect of the polymorphisms among subjects with IAA as the first autoantibody could be seen. This finding is in line with our previous findings of decreased IAA positivity among subjects carrying the IKZF4 or ERBB3 risk-associated C allele at the time of diagnosis among children with type 1 diabetes [16]. There is a strong linkage (r2 = 0.84) between these two polymorphisms. When comparing the two polymorphisms among Finnish children affected by type 1 diabetes the IKZF4 effect size was larger [40] and similarly in the current study the effect of the IKZF4 polymorphism on diabetes development was stronger. The IKZF4 gene encodes Eos, which is a zinc-finger factor of the Ikaros family and is suggested to mediate Foxp3-dependent signaling of regulatory T cells indicating that the IKZF4 SNP may affect the programming of regulatory T cells [47]. In conclusion, the major new findings of the study were the observation that PTPN2 gene polymorphism affected the progression rate of already-established beta-cell autoimmunity among children with HLA class II conferred risk for T1D as well as the finding that IKZF4-ERBB3 SNPs locus altered the progression rate of the disease process among subjects with GADA as their first autoantibody. This primary autoantigen dependent finding supports the model of various pathways involved in disease pathogenesis and heterogeneity of T1D. The INS gene polymorphism was associated with the appearance of humoral beta-cell autoantibodies and this effect was restricted to subjects with IAA as the first autoantibody. The effect of PTPN22 and IFIH1 gene polymorphisms on the initiation of beta-cell autoimmunity was also detected. These findings indicate that genetic associations of various pathways include also later phases in the process than just different initial factors inducing autoimmunity and that the general disease pathogenesis constitutes of several different pathways between which individual subjects differ.