Type 1 diabetes mellitus. Comparison between the association with PTPN22 genotype and the association with ACP1-ADA1joint genotype

Aims: T1D has been found associated with PTPN22 and with ACP1-ADA1joint genotype. In the present note we have collected further data to evaluate the relative importance of the two systems and to search for possible interaction of PTPN22 with ACP1-ADA1joint genotype. Methods: We have studied 314 children with T1D and 770 controls from the White population of Central Italy. ACP1, ADA1and PTPN22 genotypes were determined by DNA analysis. Chi square test of independence was performed by SPSS program and three way contingency analysis by a log-linear model. Results: Both carriers of *T allele of PTPN22 and subjects with ACP1*A/*A and *A/*B genotypes carrying ADA1*2 allele show an increase of susceptibility to T1D. There is evidence of additive effect (p=0.0002) but not of epistatic interaction. The association of T1D with ACP1-ADA1joint genotype is stronger (OR=2.494, 95% C.I. 1.509-4.122) as compared to that with PTPN22 (OR=1.825, 95% C.I. 1.951-2.859). Conclusions: It has been suggested that the *T variant of PTPN22 inhibits T cell receptor signaling leading to failure to delete autoreactive T cells during intrathymic selection resulting in increased susceptibility to autoimmune disorders. The joint genotype ACP1*A/*A and *A/*B carrying the ADA1*2 allele shows a decreased activity of ACP1resulting in a lowering of Zap70 activity that may decrease T cell receptor signaling with an additive effects to the inhibition due to the *T variant of PTPN22.