Retrospective Cohort Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Mar 15, 2019; 10(3): 189-199
Published online Mar 15, 2019. doi: 10.4239/wjd.v10.i3.189
Targeted genotyping for the prediction of celiac disease autoimmunity development in patients with type 1 diabetes and their family members
Maureen M Leonard, Stephanie Camhi, Victoria Kenyon, Rebecca A Betensky, Craig Sturgeon, Shu Yan, Alessio Fasano
Maureen M Leonard, Stephanie Camhi, Victoria Kenyon, Craig Sturgeon, Shu Yan, Alessio Fasano, Mucosal Immunology and Biology Research Center, Mass General Hospital for Children, Boston, MA 02115, United States
Maureen M Leonard, Stephanie Camhi, Victoria Kenyon, Craig Sturgeon, Shu Yan, Alessio Fasano, Center for Celiac Research and Treatment, Mass General Hospital for Children, Boston, MA 02115, United States
Maureen M Leonard, Stephanie Camhi, Victoria Kenyon, Craig Sturgeon, Shu Yan, Alessio Fasano, Department of Pediatric Gastroenterology and Nutrition, Mass General Hospital for Children, Boston, MA 02114, United States
Rebecca A Betensky, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States
Author contributions: All authors contributed to writing the manuscript and reviewing the manuscript.
Supported by The Center for Celiac Research and Treatment, The Nutrition Obesity Research Center at Harvard, No. P30-DK04561; to MML and RAB and The Harvard Clinical and Translational Science Center, the Harvard Catalyst, NCRR and NCATS, NIH Award, No. UL1 TR001102.
Institutional review board statement: All study procedures were reviewed and approved by the Partners Human Research Committee Institutional Review Board (IRB).
Informed consent statement: All patients signed informed consent for the investigations carried out.
Conflict-of-interest statement: The authors declare no conflict of interest.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items
Data sharing statement: Data can be provided on request by the corresponding author.
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/
Corresponding author: Maureen M Leonard, MD, MSc, Instructor, Clinical Director, Department of Pediatric Gastroenterology, Mass General Hospital for Children, 55 Fruit Street (Jackson 14), Boston, MA 02114, United States. mleonard7@mgh.harvard.edu
Telephone: +1-617-7244155
Received: February 6, 2019
Peer-review started: February 9, 2019
First decision: February 19, 2019
Revised: March 4, 2019
Accepted: March 8, 2019
Article in press: March 9, 2019
Published online: March 15, 2019
Processing time: 38 Days and 9.2 Hours
ARTICLE HIGHLIGHTS
Research background

Patients with type 1 diabetes (T1D) and their first-degree relatives (FDRs) are at increased risk of developing celiac disease (CD). The majority of patients with T1D and CD are asymptomatic at diagnosis and there are no universally accepted screening guidelines to evaluate for CD in patients with T1D or their FDRs. We employed a prospective program to serologically screen patients with T1D and their FDRs for CD. We then retrospectively aimed to identify clinical and genetic predictors that may increase the risk of developing CD in this cohort of individuals at high-risk of developing CD.

Research motivation

Patients with T1D are up to eight times more likely to develop CD, and their FDR’s are up to six times more likely to develop CD. Given that many may be asymptomatic, there is a need to identify predictors of CDA development in this high-risk cohort. The main topics, the key problems to be solved, and the significance of solving these problems for future research in this field should be described in detail.

Research objectives

Our objective was to identify clinical and genetic predictors that may increase the risk of developing CD in patients with T1D. In addition, we aimed to understand which FDRs of the patients with T1D, who are already at an increased risk of developing autoimmune disease, were more likely to develop CD. Our ultimate goal was to identify which subjects may benefit most from screening to help guide future screening recommendations.

Research methods

Participants included patients diagnosed with T1D or FDR of a patient with T1D attending the annual Children with Diabetes (CWD) conference over a 5 year time period. Participants answered clinical questionnaires and had blood drawn for CD serological testing and genotyping. Prevalence of celiac disease autoimmunity (CDA) was described. We then retrospectively fit univariate and multiple logistic regression models for CDA, separately for subjects with T1D and for FDRs of subjects with T1D accounting for the correlation within families when indicated in order to identify predictors of developing CDA.

Research results

Implementation of a prospective screening program in patients with T1D and their FDRs increased identification of CDA by 2 and 2.8-fold respectively. Participants with T1D carrying DR7-DQ2/DR4-DQ8 were more likely to screen positive for CDA. In FDRs of patients with T1D, screening positive for CDA was significantly increased in those who reported having a family member diagnosed with CD. Haptoglobin genotype did not predict the development of CDA in this high-risk population.

Research conclusions

CDA is under recognized in patients with T1D and their FDR’s and that prospective screening in this high-risk cohort increased the identification of CDA by at least 2 fold. Clinical symptoms were not helpful in distinguishing patients with CDA, as the majority of patients reported no symptoms. Haptoglobin genotype was not found to be a predictor of CDA in this cohort. In our cohort, FDRs of patients with T1D were more likely to screen positive for CDA if they had a family history of CD, while patients with T1D who carried the HLA genotype DR7-DQ2/DR4-DQ8 were more likely to screen positive for CDA.

Research perspectives

Given the high frequency of CDA in patients with T1D and their FDRs, physicians should have a low threshold to screen for CDA even in the absence of symptoms.