{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T15:47:52Z","timestamp":1787759272146,"version":"build-2784847793"},"reference-count":80,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2023,9,29]],"date-time":"2023-09-29T00:00:00Z","timestamp":1695945600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK106130"],"award-info":[{"award-number":["DK106130"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007249","name":"University of Minnesota","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007249","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunology"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The aetiology of type 1 diabetes (T1D) is considered multifactorial with the contribution of the MHC on chromosome 6 being most important. Multiple factors also contribute to the aetiology of colorectal neoplasia, but the final event causing the change from normal mucosa to polyp and from polyp to cancer is due to a single somatic mutation event. Repeated formation of colorectal neoplasia within an at\u2010risk population results in a predictable, tapering, exponential neoplasia distribution. Critical mutations driving colorectal neoplasia formation occur in mutation\u2010prone DNA. These observations led to three hypotheses related to T1D. First, a single somatic mutation within the MHC of antigen presenting cells results in a change in phenotype from normal to T1D. Second, the distribution of additional autoimmune diseases (AAIDs) among persons with T1D adheres to a predictable, tapering, exponential distribution. And third, critical mutations driving development of T1D occur in mutation\u2010prone DNA. To address the hypotheses in an orderly fashion, a new analytical method called genome\u2010wide aetiology analysis (GWEA) consisting of nine steps is presented. All data required for GWEA of T1D are obtained from peer\u2010reviewed publications or publicly available genome and proteome databases. Critical GWEA steps include AAID distribution among persons with T1D, analysis of at\u2010risk HLA loci for mutation\u2010prone DNA, determination of the role of non\u2010MHC genes on GWAS, and verification of human data by cell culture or animal experiments. GWEA results show that distribution of AAID among persons with T1D adheres to a predictable, tapering, exponential distribution. A single, critical, somatic mutation within the epitope\u2010binding groove of at\u2010risk HLA loci alters HLA\u2010insulin\u2010peptide\u2010T\u2010cell\u2010receptor (TCR) complex binding affinity and creates a new pathway that leads to loss of self\u2010tolerance. The at\u2010risk HLA loci, in particular binding pockets P1, P4 and P9, are encoded by mutation\u2010prone DNA: GC\u2010rich DNA sequence and somatic hypermutation hotspots. All other genes on GWAS can but do not have to amplify the new autoimmune pathway by facilitating DNA mutations, changing peptide binding affinity, reducing signal inhibition or augmenting signal intensity. Animal experiments agree with human studies. In conclusion, T1D is caused by a somatic mutation within the epitope\u2010binding groove of an at\u2010risk HLA gene that affects HLA\u2010insulin\u2010peptide\u2010TCR complex binding affinity and initiates an autoimmune pathway. The nature of the peptide that binds to a mutated epitope\u2010binding groove of an at\u2010risk HLA gene determines the type of autoimmune disease that develops, that is, one at\u2010risk HLA locus, multiple autoimmune diseases. Thus, T1D and AAIDs, and therefore common autoimmune diseases, share a similar somatic mutation\u2010based aetiology.<\/jats:p>","DOI":"10.1111\/imm.13700","type":"journal-article","created":{"date-parts":[[2023,9,29]],"date-time":"2023-09-29T11:46:58Z","timestamp":1695988018000},"page":"77-91","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A new, all\u2010encompassing aetiology of type 1 diabetes"],"prefix":"10.1111","volume":"171","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2560-1254","authenticated-orcid":false,"given":"Piet C.","family":"de Groen","sequence":"first","affiliation":[{"name":"Division of Gastroenterology, Hepatology &amp; Nutrition University of Minnesota  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,9,29]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.16"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02221682"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/mp.56.1.1"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.381"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc19-2429"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra0804588"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.122612899"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2016-312232"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2008.070724"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2014.20"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gie.2020.03.3321"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.3389\/fspas.2022.1067491"},{"key":"e_1_2_8_14_1","unstructured":"Type 1 diabetes wide definition.https:\/\/genetics.opentargets.org\/study\/FINNGEN_R5_T1D_WIDE(2021). Accessed May 18 2022."},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05473-8"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0952-7915(95)80010-7"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.6.2385"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2020.10.003"},{"key":"e_1_2_8_19_1","first-page":"D948","article-title":"IPD\u2010IMGT\/HLA database","volume":"48","author":"Robinson J","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1383-5742(03)00032-2"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(22)61241-1"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20084"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/28.1.235"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab225"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf9011"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.14309\/01.ajg.0000702940.86539.b9"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.14309\/01.ajg.0000702408.16429.14"},{"key":"e_1_2_8_28_1","first-page":"67","volume-title":"Congress program and abstract book; the 28th world congress on Controversies in Obstetrics, Gynecology & Infertility (COGI)","author":"Groen PC","year":"2020"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1159\/000322936"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc10-1756"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/1753-0407.12856"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-18-0515"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11892-011-0223-x"},{"key":"e_1_2_8_34_1","unstructured":"Allele Query Tool.https:\/\/www.ebi.ac.uk\/ipd\/imgt\/hla\/alleles\/(2022). Accessed 14 Dec 2022."},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/368215a0"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780301102"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2021.103431"},{"key":"e_1_2_8_38_1","volume-title":"Endotext [Internet]","author":"Sperling MA","year":"2000"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-0262-8"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13148-021-01057-x"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.636618"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/2609737"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2016.07.003"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1111\/cei.12997"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2021.669298"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2100454"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2021.101280"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0225021"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.154.10.5567"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1039\/c3cs60436e"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.2337\/db06-0058"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.24.5.838"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad2197"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2021.101316"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2026834"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.2337\/diacare.26.8.2345"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamadermatol.2023.0002"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.152.4.2042"},{"key":"e_1_2_8_59_1","article-title":"Accelerated type 1 diabetes induction in mice by adoptive transfer of diabetogenic CD4+ T cells","author":"Berry G","year":"2013","journal-title":"J Vis Exp"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature18959"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature19768"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.652487"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2202348"},{"key":"e_1_2_8_64_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-018-0604-8"},{"key":"e_1_2_8_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(23)02818-4"},{"key":"e_1_2_8_66_1","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1212\/WNL.0000000000201976","article-title":"The mechanism of disease of tri\u2010nucleotide repeat expansion diseases (P9\u201011.002)","volume":"100","author":"Groen PC","year":"2023","journal-title":"Neurology"},{"key":"e_1_2_8_67_1","doi-asserted-by":"crossref","first-page":"3388","DOI":"10.1212\/WNL.0000000000203234","article-title":"The mechanism of disease of Alzheimer's and Parkinson disease (P3\u20106.001)","volume":"100","author":"Groen PC","year":"2023","journal-title":"Neurology"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1896"},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.12678"},{"key":"e_1_2_8_70_1","doi-asserted-by":"publisher","DOI":"10.21037\/atm.2018.07.32"},{"key":"e_1_2_8_71_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.11.5042"},{"key":"e_1_2_8_72_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.75263"},{"key":"e_1_2_8_73_1","doi-asserted-by":"publisher","DOI":"10.1006\/clim.2002.5220"},{"key":"e_1_2_8_74_1","doi-asserted-by":"publisher","DOI":"10.3803\/EnM.2018.33.2.175"},{"key":"e_1_2_8_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.det.2016.11.013"},{"key":"e_1_2_8_76_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41439-018-0033-7"},{"key":"e_1_2_8_77_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(19)30799-5"},{"key":"e_1_2_8_78_1","doi-asserted-by":"publisher","DOI":"10.14309\/01.ajg.0000862836.39307.32"},{"key":"e_1_2_8_79_1","first-page":"S1493","article-title":"The etiology of PBC: an immune reaction to an external antigen due to somatic mutation of an at\u2010risk HLA gene","volume":"76","author":"Groen PC","year":"2022","journal-title":"Hepatology"},{"key":"e_1_2_8_80_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2305032"},{"key":"e_1_2_8_81_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.13239"}],"container-title":["Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/imm.13700","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,20]],"date-time":"2023-12-20T03:57:41Z","timestamp":1703044661000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/imm.13700"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,29]]},"references-count":80,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2024,1]]}},"alternative-id":["10.1111\/imm.13700"],"URL":"https:\/\/doi.org\/10.1111\/imm.13700","archive":["Portico"],"relation":{},"ISSN":["0019-2805","1365-2567"],"issn-type":[{"value":"0019-2805","type":"print"},{"value":"1365-2567","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,29]]},"assertion":[{"value":"2023-04-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-10","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-29","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}