The chromosome 6q22.33 region is associated with age at diagnosis of type 1 diabetes and disease risk in those diagnosed ... View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-01

AUTHORS

Jamie R. J. Inshaw, Neil M. Walker, Chris Wallace, Leonardo Bottolo, John A. Todd

ABSTRACT

AIMS/HYPOTHESIS: 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. METHODS: Using ImmunoChip data from 15,696 cases, we aimed to identify regions in the genome associated with AAD. RESULTS: 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 meta-analysis 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). CONCLUSION/INTERPRETATION: 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. More... »

PAGES

147-157

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00125-017-4440-y

DOI

http://dx.doi.org/10.1007/s00125-017-4440-y

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1092101001

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28983737


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