{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T05:21:15Z","timestamp":1792300875713,"version":"4.4.0"},"reference-count":44,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2019,5,22]],"date-time":"2019-05-22T00:00:00Z","timestamp":1558483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007365","name":"Fondazione IRCCS Policlinico San Matteo","doi-asserted-by":"publisher","award":["870-rcr2016-50"],"award-info":[{"award-number":["870-rcr2016-50"]}],"id":[{"id":"10.13039\/100007365","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: Celiac disease (CD) is a multifactorial immune-mediated disorder, triggered by the ingestion of gluten in genetically-predisposed subjects carrying MHC-DQ2 and -DQ8 heterodimers, which are encoded by four HLA-DQ allelic variants, overall. This meta-analysis aims at providing further epidemiological support to the predominant relevance of one specific allele, namely HLA-DQB1*02, in the predisposition and genetic risk of CD. Materials and Methods: We performed a search of MEDLINE\/PubMed, Embase, Web of Science, and Scopus, retrieving all publications (case\u2013control study, cross-sectional, and retrospective cohort study) on the association between HLA class II polymorphisms and first-degree relatives (FDRs) of children with CD. After a critical reading of the articles, two investigators independently performed data extraction according to the following inclusion criteria: HLA class II genes, any DQ and DR molecules, and CD diagnosed following the current clinical guidelines. A third participant was consulted for discussion to reach an agreement concerning discrepancies. Results: Our search strategy selected 14 studies as being eligible for inclusion, and those were submitted for data extraction and analysis. These studies were published between 1999 and 2016 and, collectively, enrolled 3063 FDRs. Positive and negative likelihood ratios (LR+ and LR\u2212, respectively) for CD diagnosis, according to the presence of the HLA-DQ genotype coding a complete MHC-DQ2 and\/or MHC-DQ8 molecules, were 1.449 (CI 1.279\u20131.642) and 0.187 (CI 0.096\u20130.362), respectively. If only the isolated presence of HLA-DQB1*02 allele is considered, the pooled estimation of LR+ was 1.659 (CI 1.302\u20132.155) and, importantly, the LR\u2212 still showed a very good discriminatory power of 0.195 (CI 0.068\u20130.558). Conclusions: Through our differential meta-analysis, comparing the presence of the genotype coding the full MHC-DQ2 and\/or DQ8 molecules with the isolated presence of HLA-DQB1*02 allelic variant, we found that the LR\u2212 of the latter analysis maintained the same value. This observation, along with previous evidences, might be useful to consider potential cost-effective widened screening strategies for CD in children.<\/jats:p>","DOI":"10.3390\/medicina55050190","type":"journal-article","created":{"date-parts":[[2019,5,23]],"date-time":"2019-05-23T03:22:03Z","timestamp":1558581723000},"page":"190","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Relevance of HLA-DQB1*02 Allele in the Genetic Predisposition of Children with Celiac Disease: Additional Cues from a Meta-Analysis"],"prefix":"10.3390","volume":"55","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2204-8449","authenticated-orcid":false,"given":"Cristina","family":"Capittini","sequence":"first","affiliation":[{"name":"Scientific Direction, Clinical Epidemiology and Biometric Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3128-8441","authenticated-orcid":false,"given":"Annalisa","family":"De Silvestri","sequence":"additional","affiliation":[{"name":"Scientific Direction, Clinical Epidemiology and Biometric Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Rebuffi","sequence":"additional","affiliation":[{"name":"Grant Office and Scientific Documentation Center, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmine","family":"Tinelli","sequence":"additional","affiliation":[{"name":"Scientific Direction, Clinical Epidemiology and Biometric Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6431-9334","authenticated-orcid":false,"given":"Dimitri","family":"Poddighe","sequence":"additional","affiliation":[{"name":"Department of Medicine, Nazarbayev University School of Medicine, Nur-Sultan City 010000, Kazakhstan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41572-018-0054-z","article-title":"Coeliac disease","volume":"5","author":"Lindfors","year":"2019","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/S0140-6736(17)31796-8","article-title":"Coeliac disease","volume":"391","author":"Lebwohl","year":"2018","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/j.giec.2012.07.005","article-title":"Mortality and malignancy in celiac disease","volume":"22","author":"Ludvigsson","year":"2012","journal-title":"Gastrointest. Endosc. Clin. N. Am."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1136\/gutjnl-2014-308285","article-title":"Causes of death in people with coeliac disease in England compared with the general population: A competing risk analysis","volume":"64","author":"Crooks","year":"2015","journal-title":"Gut"},{"key":"ref_5","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.","DOI":"10.1186\/1471-230X-13-75"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1097\/MPG.0b013e3182a455dd","article-title":"Epidemiology of coeliac disease and comorbidity in Norwegian children","volume":"57","author":"Stordal","year":"2013","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1097\/MPG.0b013e3181b477a6","article-title":"Screening detects a high proportion of celiac disease in young HLA-genotyped children","volume":"50","author":"Bjorck","year":"2010","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1038\/pr.2017.307","article-title":"HLA-DQ genetics in children with celiac disease: A meta-analysis suggesting a two-step genetic screening procedure starting with HLA-DQ \u03b2 chains","volume":"83","author":"Capittini","year":"2018","journal-title":"Pediatr. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1097\/MPG.0b013e31821a23d0","article-title":"ESPGHAN Working Group on Coeliac Disease Diagnosis; ESPGHAN Gastroenterology Committee; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease","volume":"54","author":"Husby","year":"2012","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1007\/s00431-018-3251-6","article-title":"Individual screening strategy for pediatric celiac disease","volume":"177","author":"Poddighe","year":"2018","journal-title":"Eur. J. Pediatr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/jgh3.12090","article-title":"Validation of a novel single-drop rapid human leukocyte antigen-DQ2\/-DQ8 typing method to identify subjects susceptible to celiac disease","volume":"2","author":"Verma","year":"2018","journal-title":"JGH Open"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Poddighe, D. (2019). Relevance of HLA-DQB1*02 allele in predisposing to Coeliac Disease. Int. J. Immunogenet., in press.","DOI":"10.1111\/iji.12427"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1016\/j.jclinepi.2009.06.005","article-title":"Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement","volume":"62","author":"Moher","year":"2009","journal-title":"J. Clin. Epidemiol."},{"key":"ref_14","first-page":"461","article-title":"Round table discussion. Diagnostic criteria in coeliac disease","volume":"59","author":"Meeuwisse","year":"1970","journal-title":"Acta Paediatr. Scand."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1136\/adc.65.8.909","article-title":"Revised criteria for diagnosis of coeliac disease","volume":"65","author":"Guandalini","year":"1990","journal-title":"Arch. Dis. Child."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Zamora, J., Abraira, V., Muriel, A., Khan, K., and Coomarasamy, A. (2006). Meta-DiSc: A software for metaanalysis of test accuracy data. BMC Med. Res. Methodol., 6.","DOI":"10.1186\/1471-2288-6-31"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1002\/sim.1186","article-title":"Quantifying heterogeneity in a meta-analysis","volume":"21","author":"Higgins","year":"2002","journal-title":"Stat. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/0197-2456(86)90046-2","article-title":"Meta-analysis in clinical trials","volume":"7","author":"Laird","year":"1986","journal-title":"Control. Clin. Trials"},{"key":"ref_19","unstructured":"Higgins, J.P.T., and Green, S. (2015, March 01). Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0 (updated March 2011). The Cochrane Collaboration. Available online: http:\/\/ www.cochrane-handbook.org."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4955","DOI":"10.3390\/nu7064955","article-title":"DQ2, DQ7 and DQ8 Distribution and Clinical Manifestations in Celiac Cases and Their First-Degree Relatives","volume":"7","author":"Araya","year":"2015","journal-title":"Nutrients"},{"key":"ref_21","first-page":"381","article-title":"Celiac disease in a Chilean population carrying Amerindian traits","volume":"31","author":"Araya","year":"2000","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1097\/01.mpg.0000189337.08139.83","article-title":"Serologic and genetic markers of celiac disease: A sequential study in the screening of first degree relatives","volume":"42","author":"Bonamico","year":"2006","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.humimm.2006.04.009","article-title":"HLA DQA1*0501 and DQB1*02 in Cuban celiac patients","volume":"67","author":"Cintado","year":"2006","journal-title":"Hum. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1179\/146532810X12858955921195","article-title":"Frequency of HLA-DQA1*0501 and DQB1*0201 alleles in patients with coeliac disease, their first-degree relatives and controls in Jordan","volume":"30","author":"Migdady","year":"2010","journal-title":"Ann. Trop. Paediatr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2344","DOI":"10.1023\/A:1026685527228","article-title":"Serological markers and HLA-DQ2 haplotype among first-degree relatives of celiac patients","volume":"44","author":"Humbert","year":"1999","journal-title":"Dig. Dis. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1080\/00365520600684548","article-title":"HLA genotyping is useful in the evaluation of the risk for coeliac disease in the 1st-degree relatives of patients with coeliac disease","volume":"41","author":"Karinen","year":"2006","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1590\/S0004-28032010000300009","article-title":"Serologic screening and genetic testing among brazilian patients with celiac disease and their first degree relatives","volume":"47","author":"Martins","year":"2010","journal-title":"Arq. Gastroenterol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.humimm.2008.10.018","article-title":"HLA-DQ and risk gradient for celiac disease","volume":"70","author":"Megiorni","year":"2009","journal-title":"Hum. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.dld.2015.11.007","article-title":"Prevalence of celiac disease among first-degree relatives of Indian celiac disease patients","volume":"48","author":"Mishra","year":"2016","journal-title":"Dig. Liver Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1016\/j.cgh.2008.04.008","article-title":"Predictors of family risk for celiac disease: A population-based study","volume":"6","author":"Lahr","year":"2008","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1007\/s12098-016-2146-7","article-title":"HLA Profile of Celiac Disease among First-Degree Relatives from a Tertiary Care Center in North India","volume":"83","author":"Singla","year":"2016","journal-title":"Ind. J. Pediatr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1111\/j.1440-1746.2009.06044.x","article-title":"Prevalence, human leukocyte antigen typing and strategy for screening among Asian first-degree relatives of children with celiac disease","volume":"25","author":"Srivastava","year":"2010","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1097\/MEG.0000000000000020","article-title":"Coeliac disease screening in first-degree relatives on the basis of biopsy and genetic risk","volume":"26","author":"Vaquero","year":"2014","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1007\/s10620-007-9939-5","article-title":"Cost-effectiveness analysis of strategies for diagnosing celiac disease","volume":"53","author":"Dorn","year":"2008","journal-title":"Dig. Dis. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1186\/1423-0127-19-88","article-title":"HLA-DQA1 and HLA-DQB1 in Celiac disease predisposition: Practical implications of the HLA molecular typing","volume":"19","author":"Megiorni","year":"2012","journal-title":"J. Biomed. Sci."},{"key":"ref_36","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"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1038\/nri885","article-title":"Coeliac disease: Dissecting a complex inflammatory disorder","volume":"2","author":"Sollid","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Poddighe, D., Capittini, C., Gaviglio, I., Brambilla, I., and Marseglia, G.L. (2019). HLA-DQB1*02 allele in children with Celiac Disease: Potential usefulness for screening strategies. Int. J. Immunogenet., in press.","DOI":"10.1111\/iji.12441"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1097\/MPG.0000000000002195","article-title":"Prevalence of Celiac Disease in a Long-Term Study of a Spanish At-Genetic-Risk Cohort from the General Population","volume":"68","author":"Borrell","year":"2019","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1097\/MPG.0000000000001007","article-title":"Prevalence and Natural History of Celiac Disease in a Cohort of At-risk Children","volume":"62","author":"Cilleruelo","year":"2016","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1007\/s00431-018-3199-6","article-title":"Towards an individual screening strategy for first-degree relatives of celiac patients","volume":"177","author":"Wessels","year":"2018","journal-title":"Eur. J. Pediatr."},{"key":"ref_42","first-page":"101","article-title":"Celiac Disease in Asia. Gastroenterol","volume":"48","author":"Makharia","year":"2019","journal-title":"Clin. N. Am."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Poddighe, D., Rakhimzhanova, M., Marchenko, Y., and Catassi, C. (2019). Pediatric Celiac Disease in Central and East Asia: Current Knowledge and Prevalence. Medicina, 55.","DOI":"10.3390\/medicina55010011"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.cgh.2017.06.037","article-title":"Global Prevalence of Celiac Disease: Systematic Review and Meta-analysis","volume":"16","author":"Singh","year":"2018","journal-title":"Clin. Gastroenterol. Hepatol."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/55\/5\/190\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:54:19Z","timestamp":1760187259000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/55\/5\/190"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,22]]},"references-count":44,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2019,5]]}},"alternative-id":["medicina55050190"],"URL":"https:\/\/doi.org\/10.3390\/medicina55050190","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,22]]}}}