The chromosome 6q22.33 region is associated with age at diagnosis of type 1 diabetes and disease risk in those diagnosed under 5 years of age
Journal Title
Diabetologia
ISSN
0012-186X
Publisher
Springer
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Inshaw, J., Walker, N., Wallace, C., Bottolo, L., & Todd, J. (2017). The chromosome 6q22.33 region is associated with age at diagnosis of type 1 diabetes and disease risk in those diagnosed under 5 years of age. Diabetologia https://doi.org/10.1007/s00125-017-4440-y
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.
Keywords
age at diagnosis, early diagnosis, genetic risk, type 1 diabetes
Sponsorship
CW is funded by the Wellcome Trust (WT107881) and the Medical Research Council (MC_UP_1302/5). LB was supported by the Alan Turing Institute under the EPSRC grant EP/N510129/1.
Funder references
Wellcome Trust (089989/Z/09/Z)
Wellcome Trust (091157/Z/10/Z)
WELLCOME TRUST (107881/Z/15/Z)
Alan Turing Institute (unknown)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (U01DK062418)
WELLCOME TRUST (107212/Z/15/Z)
Wellcome Trust (091157/Z/10/B)
Medical Research Council (MC_UU_00002/4)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1007/s00125-017-4440-y
This record's URL: https://www.repository.cam.ac.uk/handle/1810/268096
Rights
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International
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