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dc.contributor.authorInshaw, JRJen
dc.contributor.authorWalker, NMen
dc.contributor.authorWallace, Chrisen
dc.contributor.authorBottolo, Leonardoen
dc.contributor.authorTodd, JAen
dc.date.accessioned2017-11-06T09:55:56Z
dc.date.available2017-11-06T09:55:56Z
dc.identifier.issn0012-186X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/268096
dc.description.abstractAIMS/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.
dc.description.sponsorshipCW 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.
dc.languageengen
dc.publisherSpringer
dc.rightsAttribution 4.0 International*
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectage at diagnosisen
dc.subjectearly diagnosisen
dc.subjectgenetic risken
dc.subjecttype 1 diabetesen
dc.titleThe chromosome 6q22.33 region is associated with age at diagnosis of type 1 diabetes and disease risk in those diagnosed under 5 years of ageen
dc.typeArticle
prism.publicationNameDiabetologiaen
dc.identifier.doi10.17863/CAM.14320
dcterms.dateAccepted2017-07-28en
rioxxterms.versionofrecord10.1007/s00125-017-4440-yen
rioxxterms.versionVoR*
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2017-07-28en
dc.contributor.orcidWallace, Chris [0000-0001-9755-1703]
dc.contributor.orcidBottolo, Leonardo [0000-0002-6381-2327]
dc.identifier.eissn1432-0428
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (089989/Z/09/Z)
pubs.funder-project-idWellcome Trust (091157/Z/10/Z)
pubs.funder-project-idWELLCOME TRUST (107881/Z/15/Z)
pubs.funder-project-idAlan Turing Institute (unknown)
pubs.funder-project-idNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (U01DK062418)
pubs.funder-project-idWELLCOME TRUST (107212/Z/15/Z)
pubs.funder-project-idWellcome Trust (091157/Z/10/B)
pubs.funder-project-idMedical Research Council (MC_UU_00002/4)
cam.issuedOnline2017-10-05en
cam.orpheus.successThu Jan 30 12:59:14 GMT 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2100-01-01


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International