{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T13:54:24Z","timestamp":1764251664017,"version":"build-2065373602"},"reference-count":35,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,12,9]],"date-time":"2020-12-09T00:00:00Z","timestamp":1607472000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>The clinical phenotype of celiac disease varies considerably among patients and the dosage of HLA-DQ2.5 alleles has been suggested to be a contributing factor. We investigated whether HLA-DQ2.5 allele dosage is associated with distinct clinical parameters at the time of diagnosis and with patients\u2019 response to a gluten-free diet. The final cohort included 605 carefully phenotyped non-related Finnish celiac disease patients grouped as having 0, 1 or 2 copies of HLA-DQ2.5. Clinical data at the time of diagnosis and during gluten-free diet were collected systematically from medical records and supplementary interviews. An increasing HLA-DQ2.5 dose effect was detected for celiac disease antibody positivity at diagnosis (p = 0.021) and for the presence of any first-degree relatives with celiac disease (p = 0.011 and p = 0.031, respectively). Instead, DQ2.5-negative patients were suffering most often from classical symptoms at diagnosis (p = 0.007 between HLA groups). In addition, during follow-up they were most often symptomatic despite a gluten-free diet (p = 0.002 between groups). Our results thus suggest that increasing HLA-DQ2.5 dose only has a minor effect on the clinical picture of celiac disease. However, HLA-DQ2.5-negative patients should not be overlooked in clinical practice and particular attention should be paid to this patient group during gluten-free diet.<\/jats:p>","DOI":"10.3390\/nu12123775","type":"journal-article","created":{"date-parts":[[2020,12,9]],"date-time":"2020-12-09T09:17:58Z","timestamp":1607505478000},"page":"3775","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Influence of HLA-DQ2.5 Dose on Clinical Picture of Unrelated Celiac Disease Patients"],"prefix":"10.3390","volume":"12","author":[{"given":"Laura","family":"Airaksinen","sequence":"first","affiliation":[{"name":"Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pilvi","family":"Laurikka","sequence":"additional","affiliation":[{"name":"Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1372-430X","authenticated-orcid":false,"given":"Heini","family":"Huhtala","sequence":"additional","affiliation":[{"name":"Faculty of Social Sciences, Tampere University, 33520 Tampere, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4757-2164","authenticated-orcid":false,"given":"Kalle","family":"Kurppa","sequence":"additional","affiliation":[{"name":"Tampere Centre for Child Health Research, Tampere University Hospital and Tampere University, 33521 Tampere, Finland"},{"name":"Department of Pediatrics, Sein\u00e4joki Central Hospital and University Consortium of Sein\u00e4joki, 60220 Sein\u00e4joki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teea","family":"Salmi","sequence":"additional","affiliation":[{"name":"Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland"},{"name":"Department of Dermatology, Tampere University Hospital, 33521 Tampere, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P\u00e4ivi","family":"Saavalainen","sequence":"additional","affiliation":[{"name":"Research Programs Unit, Immunobiology, and Haartman Institute, Department of Medical Genetics, University of Helsinki, 00014 Helsinki, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katri","family":"Kaukinen","sequence":"additional","affiliation":[{"name":"Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland"},{"name":"Department of Internal Medicine, Tampere University Hospital, 33521 Tampere, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7417-5151","authenticated-orcid":false,"given":"Katri","family":"Lindfors","sequence":"additional","affiliation":[{"name":"Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1472-6963-10-105","article-title":"Impact of symptoms on quality of life before and after diagnosis of coeliac disease: Results from a UK population survey","volume":"10","author":"Gray","year":"2010","journal-title":"BMC Health Serv. Res."},{"doi-asserted-by":"crossref","unstructured":"Norstr\u00f6m, F., Lindholm, L., Sandstr\u00f6m, O., Nordyke, K., and Ivarsson, A. (2011). Delay to celiac disease diagnosis and its implications for health-related quality of life. BMC Gastroenterol., 11.","key":"ref_2","DOI":"10.1186\/1471-230X-11-118"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1016\/S0140-6736(09)60254-3","article-title":"Coeliac disease","volume":"373","author":"Corazza","year":"2009","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12916-019-1380-z","article-title":"Celiac disease: A comprehensive current review","volume":"17","author":"Caio","year":"2019","journal-title":"BMC Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1111\/j.1572-0241.2003.07632.x","article-title":"High rate of gastrointestinal symptoms in celiac patients living on a gluten-free diet: Controlled study","volume":"98","author":"Midhagen","year":"2003","journal-title":"Am. J. Gastroenterol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1309\/EVXT-851X-WHLC-RLX9","article-title":"Histologic follow-up of people with celiac disease on a gluten-free diet: Slow and incomplete recovery","volume":"118","author":"Wahab","year":"2002","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1007\/s11894-020-0756-8","article-title":"Refractory Celiac Disease","volume":"22","author":"Hujoel","year":"2020","journal-title":"Curr. Gastroenterol. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1038\/ajg.2015.296","article-title":"Risk of celiac disease in the first- and second-degree relatives of patients with celiac disease: A systematic review and meta-analysis","volume":"110","author":"Singh","year":"2015","journal-title":"Am. J. Gastroenterol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1007\/BF02602553","article-title":"Peptide binding characteristics of the coeliac disease associated DQ(\u03b11(*)0501, \u03b21(*)0201) molecule","volume":"44","author":"Kooy","year":"1996","journal-title":"Immunogenetics"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2764","DOI":"10.1002\/eji.1830261132","article-title":"The peptide binding motif of the disease associated HLA-DQ (\u03b1 1(*) 0501, \u03b2 1(*) 0201) molecule","volume":"26","author":"Vartdal","year":"1996","journal-title":"Eur. J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/0016-5085(93)90912-V","article-title":"HLA susceptibility genes in celiac disease: Genetic mapping and role in pathogenesis","volume":"105","author":"Sollid","year":"1993","journal-title":"Gastroenterology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1111\/j.1399-0039.1993.tb01998.x","article-title":"On the HLA-DQ(\u03b11*0501, \u03b21*0201)-associated susceptibility in celiac disease: A possible gene dosage effect of DQB1*0201","volume":"41","author":"Ploski","year":"1993","journal-title":"Tissue Antigens"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/sj.gene.6364061","article-title":"Defining the contribution of the HLA region to cis DQ2-positive coeliac disease patients","volume":"5","author":"Koeleman","year":"2004","journal-title":"Genes Immun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1111\/j.0001-2815.2004.00237.x","article-title":"HLA-DQ relative risks for coeliac disease in European populations: A study of the European Genetics Cluster on Coeliac Disease","volume":"63","author":"Babron","year":"2004","journal-title":"Tissue Antigens"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"12390","DOI":"10.1073\/pnas.2135229100","article-title":"The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T cell responses","volume":"100","author":"Vader","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"doi-asserted-by":"crossref","unstructured":"Bajor, J., Szak\u00e1cs, Z., Farkas, N., Hegyi, P., Ill\u00e9s, A., Solym\u00e1r, M., P\u00e9terv\u00e1ri, E., Balask\u00f3, M., P\u00e1r, G., and Sarl\u00f3s, P. (2019). Classical celiac disease is more frequent with a double dose of HLA-DQB102: A systematic review with meta-analysis. PLoS ONE, 14.","key":"ref_16","DOI":"10.1371\/journal.pone.0212329"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1136\/gutjnl-2011-301346","article-title":"The Oslo definitions for coeliac disease and related terms","volume":"62","author":"Ludvigsson","year":"2013","journal-title":"Gut"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1136\/jcp.2005.035345","article-title":"Coeliac disease: An update for pathologists","volume":"59","author":"Dickson","year":"2006","journal-title":"J. Clin. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1038\/nm0797-797","article-title":"Identification of tissue transglutaminase as the autoantigen of celiac disease","volume":"3","author":"Dieterich","year":"1997","journal-title":"Nat. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1111\/j.1749-6632.1983.tb22220.x","article-title":"IgA Class Endomysium Antibodies in Dermatitis Herpetiformis and Coeliac Disease","volume":"420","author":"Chorzelski","year":"1983","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1136\/gut.18.12.991","article-title":"IgA and IgG reticulin antibodies in coeliac and non-coeliac patients","volume":"18","author":"Eade","year":"1977","journal-title":"Gut"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1080\/00365529850170810","article-title":"IgA- and IgG-class antihuman umbilical cord antibody tests in adult coeliac disease","volume":"33","author":"Sulkanen","year":"1998","journal-title":"Scand. J. Gastroenterol."},{"doi-asserted-by":"crossref","unstructured":"Monsuur, A.J., de Bakker, P.I.W., Zhernakova, A., Pinto, D., Verduijn, W., Romanos, J., Auricchio, R., Lopez, A., van Heel, D.A., and Crusius, J.B.A. (2008). Effective detection of human leukocyte antigen risk alleles in celiac disease using tag single nucleotide polymorphisms. PLoS ONE, 3.","key":"ref_23","DOI":"10.1371\/journal.pone.0002270"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/s00251-009-0361-3","article-title":"Cost-effective HLA typing with tagging SNPs predicts celiac disease risk haplotypes in the Finnish, Hungarian, and Italian populations","volume":"61","author":"Koskinen","year":"2009","journal-title":"Immunogenetics"},{"doi-asserted-by":"crossref","unstructured":"Mart\u00ednez-Ojinaga, E., Fern\u00e1ndez-Prieto, M., Molina, M., Polanco, I., Urcelay, E., and N\u00fa\u00f1ez, C. (2019). Influence of HLA on clinical and analytical features of pediatric celiac disease. BMC Gastroenterol., 19.","key":"ref_25","DOI":"10.1186\/s12876-019-1014-0"},{"doi-asserted-by":"crossref","unstructured":"du Pr\u00e9, M.F., Blazevski, J., Dewan, A.E., Stamnaes, J., Kanduri, C., Sandve, G.K., Johannesen, M.K., Lindstad, C.B., Hnida, K., and Fugger, L. (2020). B cell tolerance and antibody production to the celiac disease autoantigen transglutaminase 2. J. Exp. Med., 217.","key":"ref_26","DOI":"10.1084\/jem.20190860"},{"doi-asserted-by":"crossref","unstructured":"Kauma, S., Kaukinen, K., Huhtala, H., Kivel\u00e4, L., Pekki, H., Salmi, T., Saavalainen, P., Lindfors, K., Kurppa, K., and Kauma, S. (2019). The Phenotype of Celiac Disease Has Low Concordance between Siblings, Despite a Similar Distribution of HLA Haplotypes. Nutrients, 11.","key":"ref_27","DOI":"10.3390\/nu11020479"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1097\/MIB.0b013e31828029a9","article-title":"The duodenal microbiota composition of adult celiac disease patients is associated with the clinical manifestation of the disease","volume":"19","author":"Wacklin","year":"2013","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.cgh.2005.12.011","article-title":"Human leukocyte antigen-DQ2 homozygosity and the development of refractory celiac disease and enteropathy-associated T-cell lymphoma","volume":"4","author":"Goerres","year":"2006","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1038\/ajg.2014.194","article-title":"Incidence of malignancies in diagnosed celiac patients: A population-based estimate","volume":"109","author":"Ilus","year":"2014","journal-title":"Am. J. Gastroenterol."},{"doi-asserted-by":"crossref","unstructured":"Paarlahti, P., Kurppa, K., Ukkola, A., Collin, P., Huhtala, H., M\u00e4ki, M., and Kaukinen, K. (2013). Predictors of persistent symptoms and reduced quality of life in treated coeliac disease patients: A large cross-sectional study. BMC Gastroenterol., 13.","key":"ref_31","DOI":"10.1186\/1471-230X-13-75"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1038\/ajg.2014.355","article-title":"Altered Duodenal microbiota composition in celiac disease patients suffering from persistent symptoms on a long-term gluten-free diet","volume":"109","author":"Wacklin","year":"2014","journal-title":"Am. J. Gastroenterol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1111\/j.1572-0241.2003.07379.x","article-title":"High prevalence of small intestinal bacterial overgrowth in celiac patients with persistence of gastrointestinal symptoms after gluten withdrawal","volume":"98","author":"Tursi","year":"2003","journal-title":"Am. J. Gastroenterol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1038\/ajg.2010.10","article-title":"Mucosal recovery and mortality in adults with celiac disease after treatment with a gluten-free diet","volume":"105","author":"Rahim","year":"2010","journal-title":"Am. J. Gastroenterol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1007\/s00251-017-0985-7","article-title":"The roles of MHC class II genes and post-translational modification in celiac disease","volume":"69","author":"Sollid","year":"2017","journal-title":"Immunogenetics"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/12\/3775\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:42:53Z","timestamp":1760179373000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/12\/3775"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,9]]},"references-count":35,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["nu12123775"],"URL":"https:\/\/doi.org\/10.3390\/nu12123775","relation":{},"ISSN":["2072-6643"],"issn-type":[{"type":"electronic","value":"2072-6643"}],"subject":[],"published":{"date-parts":[[2020,12,9]]}}}