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

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 studyto identify the causal genes for RCDII and the molecular pathways perturbed in RCDII. The genome-wide association studywas 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=2.37x10(-8), 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 cellsin RCDII progression. Copyright (C) 2018 Wolters Kluwer Health, Inc. All rights reserved.