{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T16:04:08Z","timestamp":1775664248916,"version":"3.50.1"},"reference-count":43,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T00:00:00Z","timestamp":1686700800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007397","name":"Univerzita Karlova v Praze","doi-asserted-by":"publisher","award":["COOPERATIO 39"],"award-info":[{"award-number":["COOPERATIO 39"]}],"id":[{"id":"10.13039\/100007397","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007397","name":"Univerzita Karlova v Praze","doi-asserted-by":"publisher","award":["260646\/SVV\/2023"],"award-info":[{"award-number":["260646\/SVV\/2023"]}],"id":[{"id":"10.13039\/100007397","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Protein tyrosine phosphatase, nonreceptor type 22 (<jats:italic>PTPN22<\/jats:italic>), is an archetypal non-HLA autoimmunity gene. It is one of the most prominent genetic contributors to type 1 diabetes mellitus outside the HLA region, and prevalence of its risk variants is subject to enormous geographic variability. Here, we address the genetic background of patients with type 1 diabetes mellitus of Armenian descent. Armenia has a population that has been genetically isolated for 3000 years. We hypothesized that two <jats:italic>PTPN22<\/jats:italic> polymorphisms, rs2476601 and rs1310182, are associated with type 1 diabetes mellitus in persons of Armenian descent. In this association study, we genotyped the allelic frequencies of two risk-associated <jats:italic>PTPN22<\/jats:italic> variants in 96 patients with type 1 diabetes mellitus and 100 controls of Armenian descent. We subsequently examined the associations of <jats:italic>PTPN22<\/jats:italic> variants with the manifestation of type 1 diabetes mellitus and its clinical characteristics. We found that the rs2476601 minor allele (c.1858T) frequency in the control population was very low (q = 0.015), and the trend toward increased frequency of c.1858CT heterozygotes among patients with type 1 diabetes mellitus was not significant (OR 3.34, 95% CI 0.88\u201312.75; \u03c7<jats:sup>2<\/jats:sup> test <jats:italic>p<\/jats:italic> &gt; 0.05). The control population had a high frequency of the minor allele of rs1310182 (q = 0.375). The frequency of c.2054-852TC heterozygotes was significantly higher among the patients with type 1 diabetes mellitus (OR 2.39, 95% CI 1.35\u20134.24; \u03c7<jats:sup>2<\/jats:sup> test <jats:italic>p<\/jats:italic> &lt; 0.001), as was the frequency of the T allele (OR 4.82, 95% CI 2.38\u20139.76; \u03c7<jats:sup>2<\/jats:sup> test <jats:italic>p<\/jats:italic> &lt; 0.001). The rs2476601 c.1858CT genotype and the T allele correlated negatively with the insulin dose needed three to six months after diagnosis. The rs1310182 c.2054-852CC genotype was positively associated with higher HbA<jats:sub>1c<\/jats:sub> at diagnosis and 12 months after diagnosis. We have provided the first information on diabetes-associated polymorphisms in <jats:italic>PTPN22<\/jats:italic> in a genetically isolated Armenian population. We found only a limited contribution of the prototypic gain-of-function <jats:italic>PTPN22<\/jats:italic> polymorphism rs2476601. In contrast, we found an unexpectedly close association of type 1 diabetes mellitus with rs1310182.<\/jats:p>","DOI":"10.1371\/journal.pone.0286743","type":"journal-article","created":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T17:35:52Z","timestamp":1686764152000},"page":"e0286743","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["PTPN22 intron polymorphism rs1310182 (c.2054-852T&gt;C) is associated with type 1 diabetes mellitus in patients of Armenian descent"],"prefix":"10.1371","volume":"18","author":[{"given":"Robert","family":"\u017dak","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lusine","family":"Navasardyan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00e1n","family":"Hun\u00e1k","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji\u0159ina","family":"Martin\u016f","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0703-951X","authenticated-orcid":true,"given":"Petr","family":"Heneberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,6,14]]},"reference":[{"key":"pone.0286743.ref001","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1038\/ejhg.2015.206","article-title":"Genetic evidence for an origin of the Armenians from Bronze Age mixing of multiple populations","volume":"24","author":"M Haber","year":"2016","journal-title":"Eur J Hum Genet"},{"key":"pone.0286743.ref002","article-title":"IDF Diabetes Atlas, 10th Edition. Brussels","author":"EJ Boyko","year":"2022","journal-title":"International Diabetes Federation"},{"key":"pone.0286743.ref003","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1038\/nrrheum.2014.109","article-title":"PTPN22: the archetypal non-HLA autoimmunity gene","volume":"10","author":"SM Stanford","year":"2014","journal-title":"Nat Rev Rheumatol"},{"key":"pone.0286743.ref004","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/nchembio.916","article-title":"LYP inhibits T cells activation when dissociated from CSK","volume":"8","author":"T Vang","year":"2012","journal-title":"Nat Chem Biol"},{"key":"pone.0286743.ref005","doi-asserted-by":"crossref","first-page":"ra87","DOI":"10.1126\/scisignal.2003365","article-title":"Lack of the phosphatase PTPN22 increases adhesion of murine regulatory T cells to improve their immunosuppressive function","volume":"5","author":"RJ Brownlie","year":"2012","journal-title":"Sci 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Dullin","year":"2015","journal-title":"Transplantation"},{"key":"pone.0286743.ref033","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1111\/tan.13706","article-title":"Protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene polymorphisms in liver transplant donors and impact on acute cellular liver transplant rejection","volume":"95","author":"H Thude","year":"2020","journal-title":"HLA"},{"key":"pone.0286743.ref034","doi-asserted-by":"crossref","first-page":"S19","DOI":"10.2337\/dc23-S002","article-title":"2. Classification and diagnosis of diabetes: Standards of care in diabetes 2023","volume":"46","author":"NA ElSayed","year":"2023","journal-title":"Diabetes Care"},{"key":"pone.0286743.ref035","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1111\/dme.12004","article-title":"Area-under-the-HbA1c curve above the normal range and the prediction of microvascular outcomes: an analysis of data from the Diabetes Control and Complications Trial","volume":"30","author":"LJ Maple-Brown","year":"2013","journal-title":"Diabet Med"},{"key":"pone.0286743.ref036","doi-asserted-by":"crossref","first-page":"e115","DOI":"10.1093\/nar\/gks596","article-title":"Primer3 \u2013new capabilities and interfaces","volume":"40","author":"A Untergasser","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"pone.0286743.ref037","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/ng1323","article-title":"A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes","volume":"36","author":"N Bottini","year":"2004","journal-title":"Nat Genet"},{"key":"pone.0286743.ref038","doi-asserted-by":"crossref","first-page":"2731","DOI":"10.1093\/molbev\/msr121","article-title":"MEGA5: Molecular Evolutionary Genetics Analysis using Maximum Likelihood, Evolutionary Distance, and Maximum Parsimony Methods","volume":"28","author":"K Tamura","year":"2011","journal-title":"Mol Biol Evol"},{"key":"pone.0286743.ref039","doi-asserted-by":"crossref","first-page":"3689","DOI":"10.1016\/j.febslet.2011.04.032","article-title":"Why is PTPN22 a good candidate susceptibility gene for autoimmune disease?","volume":"585","author":"GL Burn","year":"2011","journal-title":"FEBS Lett"},{"key":"pone.0286743.ref040","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1530\/eje.1.02035","article-title":"Sex-specific association of PTPN22 1858T with type 1 diabetes but not with Hashimoto\u2019s thyroiditis or Addison\u2019s disease in the German population","volume":"153","author":"H Kahles","year":"2005","journal-title":"Eur J Endocrinol"},{"key":"pone.0286743.ref041","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.diabres.2006.09.009","article-title":"No independent role of the -1123G>C and +2740A>G variants in the association of PTPN22 with type 1 diabetes and juvenile idiopathic arthritis in two Caucasian populations","volume":"76","author":"O Cinek","year":"2007","journal-title":"Diabet Res Clin Pract"},{"key":"pone.0286743.ref042","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1038\/tpj.2016.6","article-title":"Role of the C1858T polymorphism of protein tyrosine phosphatase non-receptor type 22 (PTPN22) in children and adolescents with type 1 diabetes","volume":"17","author":"A Blasetti","year":"2017","journal-title":"Pharmacogenomics J"},{"key":"pone.0286743.ref043","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1111\/pedi.12429","article-title":"Coincidence of PTPN22 c.1858CC and FCRL3 -169CC genotypes as a biomarker of preserved residual \u03b2-cell function in children with type 1 diabetes","volume":"18","author":"M Paw\u0142owicz","year":"2017","journal-title":"Pediatr Diabetes"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0286743","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T17:36:38Z","timestamp":1686764198000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0286743"}},"subtitle":[],"editor":[{"given":"Cinzia","family":"Ciccacci","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,6,14]]},"references-count":43,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,6,14]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0286743","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,14]]}}}