A locus at 7p14.3 predisposes to refractory celiac disease progression from celiac disease.

Eur J Gastroenterol Hepatol
Authors
Keywords
Abstract

BACKGROUND: Approximately 5% of patients with celiac disease (CeD) do not respond to a gluten-free diet and progress to refractory celiac disease (RCD), a severe progression that is characterized by infiltration of intraepithelial T lymphocytes. Patients with RCD type II (RCDII) show clonal expansions of intraepithelial T lymphocytes that result in a poor prognosis and a high mortality rate through development of aggressive enteropathy-associated T-cell lymphoma. It is not known whether genetic variations play a role in severe progression of CeD to RCDII.

PATIENTS AND METHODS: We performed the first genome-wide association study to identify the causal genes for RCDII and the molecular pathways perturbed in RCDII. The genome-wide association study was performed in 38 Dutch patients with RCDII, and the 15 independent top-associated single nucleotide polymorphism (SNP) variants (P

RESULTS: After replication, SNP rs2041570 on chromosome 7 was significantly associated with progression to RCDII (P=2.37×10, odds ratio=2.36) but not with CeD susceptibility. SNP rs2041570 risk allele A was associated with lower levels of FAM188B expression in blood and small intestinal biopsies. Stratification of RCDII biopsies based on rs2041570 genotype showed differential expression of innate immune and antibacterial genes that are expressed in Paneth cells.

CONCLUSION: We have identified a novel SNP associated with the severe progression of CeD to RCDII. Our data suggest that genetic susceptibility to CeD might be distinct from the progression to RCDII and suggest a role for Paneth cells in RCDII progression.

Year of Publication
2018
Journal
Eur J Gastroenterol Hepatol
Volume
30
Issue
8
Pages
828-837
Date Published
2018 08
ISSN
1473-5687
DOI
10.1097/MEG.0000000000001168
PubMed ID
29787419
PubMed Central ID
PMC6373482
Links
Grant list
R01 DK067180 / DK / NIDDK NIH HHS / United States