Observational Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 7, 2018; 24(1): 96-103
Published online Jan 7, 2018. doi: 10.3748/wjg.v24.i1.96
HLA-DQ: Celiac disease vs inflammatory bowel disease
Marta Maia Bosca-Watts, Miguel Minguez, Dolores Planelles, Samuel Navarro, Alejandro Rodriguez, Jesus Santiago, Joan Tosca, Francisco Mora
Marta Maia Bosca-Watts, Miguel Minguez, Joan Tosca, IBD Unit, Digestive Disease Department of the University Clinic Hospital of Valencia, University of Valencia, Valencia 46017, Spain
Dolores Planelles, Histocompatibility Department of the Transfusion Center of the Valencian Community, Valencia 46014, Spain
Samuel Navarro, Pathology Department of the University Clinic Hospital of Valencia, University of Valencia, Valencia 46017, Spain
Alejandro Rodriguez, Digestive Disease Department of the Hospital Virgen del Castillo of Yecla, Yecla 30510, Spain
Jesus Santiago, Digestive Disease Department of the Hospital de Manises, Valencia 46940, Spain
Francisco Mora, Digestive Disease Department of the University Clinic Hospital of Valencia, University of Valencia, Valencia 46017, Spain
Author contributions: The first four authors designed the study, and corrected the results and article; Bosca-Watts MM was responsible of carrying out the study and coordinating the parts; Rodriguez A and Santiago J did part of the technical interventions; Tosca J helped doing it and reviewing the statistical analysis; and Mora F supervised and corrected the article.
Supported by the Carlos III Institute and the University Clinic Hospital Research Institute, with a Rio Hortega specialised healthcare post-training contract granted to Bosca-Watts MM (No. CM07/00240).
Informed consent statement: All involved persons (subjects or legally authorized representative) gave their informed consent (written or verbal, as appropriate) prior to study inclusion.
Conflict-of-interest statement: No potential conflicts of interest relevant to this article were reported.
Data sharing statement: Participants gave informed consent for data sharing, although the presented data are anonymized and risk of identification is low.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Marta Maia Bosca-Watts, PhD, MD, Attending Doctor, Research Scientist, Staff Physician, IBD Unit, Digestive Disease Department of the University Clinic Hospital of Valencia, University of Valencia, C/ Blasco Ibañez 17, Valencia 46010, Spain. inflamatoriahcuv@gmail.com
Telephone: +34-9-61973500- 436449
Received: October 28, 2017
Peer-review started: October 29, 2017
First decision: November 14, 2017
Revised: November 22, 2017
Accepted: November 27, 2017
Article in press: November 27, 2017
Published online: January 7, 2018
Research background

Celiac disease (CeD) and inflammatory bowel disease (IBD) are chronic intestinal disorders with progressively increasing incidences and prevalences. Both diseases are thought to be secondary to the interaction of certain environmental factors which either directly cause or enable others to trigger the disease (gluten -cause of CeD-, infections, dysbiosis, etc.), in genetically predisposed patients, by producing an altered immunological response. CeD has defined diagnostic criteria, which include blood antibodies, genetic testing, upper endoscopy findings and, especially, histological small-bowel changes. The involvement of human leucocyte antigen (HLA) genes codifying HLA-DQ2 and -DQ8 antigens in the susceptibility to the disease is clearly established and HLA typing has been accepted as a useful test to exclude CeD, because only 0.5 % of CeD patients lack both DQ2 and DQ8 antigens. IBD patients have historically been considered to be at higher risk for CeD, which could be supported by the fact that IBD and CeD are quite prevalent and due to a theoretically similar pathogenesis, with the interaction of genetic, immunological, and environmental factors (gut flora, gastroenteritis, etc.). Two more recent studies have analyzed CeD-related antibodies and biopsies and observed that CeD is just as frequent or even less in the IBD population, but CeD is still included as a more prevalent disease in IBD in some texts. None of them have analyzed the frequency of HLA-DQ2 and 8 (HLA-CeD) in IBD patients. Only one study has done so but it only included 36 patients.

Research motivation

We wanted to know if IBD patients are genetically predisposed to CeD. Since negative HLA-CeD has a very high predictive negative value, not having it discards having CeD in most cases. We wanted to determine the frequency of HLA-CeD in IBD, which has never been calculated, and whether having the haplotypes is related to having ulcerative colitis (UC) or Crohn’s disease (CD).

Research objectives

To determine whether or not IBD patients are genetically predisposed to CeD, we conducted a study to determine the frequency of CeD-related HLA (alleles encoding DQ2 and DQ8 dimers: HLA-CeD) in our IBD population (both in patients with UC as with CD). An analysis of HLA-CeD frequencies according to sex was also performed in our IBD population.

Research methods

We conducted a prospective study with IBD patients from our Unit. Clinical information was gathered and blood was tested for HLA-CeD. The control group was made up of unrelated Valencian organ donors.

Research results

A total of 1034 patients were analyzed: 457 IBD (207 UC, and 250 CD) patients and 577 healthy controls. 39% of the controls and 34% of the patients had HLA-CeD (P = 0.0852). HLA-DQ2 was less frequent in UC patients (P = 0.0287), and HLA-DQ8 in CD (P = 0.0217). In women with UC, the frequency of DQ2.5cis (DQB1*02:01-DQA1*05:01) was reduced ≥ 50% [P = 0.0344; preventive fraction (PF) = 13%]. PFs (7%-14%) were obtained with all HLA-CeD haplotypes. HLA DQB1*02:02-DQA1*02:01 (HLA-DQ2.2) was more frequent in CD patients with respect to controls (P = 0.001) and UC patients (etiological fraction = 15%).

Research conclusions

HLA-CeD is not more frequent in IBD patients, with an even lower frequency of HLA-DQ2 and -DQ8 in UC and CD respectively. HLA-DQ2.5 confers protection from the development of UC, especially in women, and HLA-DQ8 does so for the appearance of CD. HLA-DQ2.2 is present in 34% of the CeD patients and may constitute a genetic risk factor for CeD development. This helps answer the ongoing question of whether or not IBD patients have a higher risk of CeD. According to our study, IBD patients have the same genetic predisposition of CeD than the general population, showing an even lower frequency when subanalyzing by haplotypes and type of IBD. To our knowledge, it is the first time a frequency of the HLA-CeD haplotypes is given in a large enough IBD population. We also found a high frequency of HLA-DQ2.2 in Crohn’s disease, pointing to it as a risk factor.

Research perspectives

This study supports the change in trend of the relationship between CeD and IBD, confirming it is not more frequent. We found HLA-DQ2 was less frequent in UC and HLA-DQ8 in CD, but we did not find any relationship with the presence or absence of CeD haplotypes and certain IBD phenotypes. We might need larger studies to find if these alleles can be related to phenotypes. Future studies will help confirm HLA-DQ 2.2 as a risk factor for Crohn’s. This could help decision taking in unclear cases (example with indeterminate colitis). Studies are also needed to see if to correlates with disease severity.