| 總結: | <h4>Aims/hypothesis</h4> <p>The genetic risk of type 1 diabetes has been extensively studied. However, the genetic determinants of age at diagnosis (AAD) of type 1 diabetes remain relatively unexplained. Identification of AAD genes and pathways could provide insight into the earliest events in the disease process.</p> <h4>Methods</h4> <p>Using ImmunoChip data from 15,696 cases, we aimed to identify regions in the genome associated with AAD.</p> <h4>Results</h4> <p>Two regions were convincingly associated with AAD (p < 5 × 10^−8): the MHC on 6p21, and 6q22.33. Fine-mapping of 6q22.33 identified two AAD-associated haplotypes in the region nearest to the genes encoding protein tyrosine phosphatase receptor kappa (PTPRK) and thymocyte-expressed molecule involved in selection (THEMIS).We examined the susceptibility to type 1 diabetes at these SNPs by performing a metaanalysis including 19,510 control participants. Although these SNPs were not associated with type 1 diabetes overall (p > 0.001), the SNP most associated with AAD, rs72975913, was associated with susceptibility to type 1 diabetes in those individuals diagnosed at less than 5 years old (p = 2.3 × 10^−9).</p> <h4>Conclusion/interpretation</h4> <p>PTPRK and its neighbour THEMIS are required for early development of the thymus, which we can assume influences the initiation of autoimmunity. Non-HLA genes may only be detectable as risk factors for the disease in individuals diagnosed under the age 5 years because, after that period of immune development, their role in disease susceptibility has become redundant.</p>
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