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

Barbara Hrdlickova, Chris J. Mulder, Georgia Malamut, Bertrand Meresse, Mathieu Platteel, Yoichiro Kamatani, Isis Ricaño-Ponce, Roy L. J. van Wanrooij, Maria M. Zorro, Marc Jan Bonder, Javier Gutierrez-Achury, Christophe Cellier, Alexandra Zhernakova, Petula Nijeboer, Pilar Galan, Sebo Withoff, Mark Lathrop, Gerd Bouma, Ramnik J. Xavier, Bana Jabri & 3 others Nadine C. Bensussan, Cisca Wijmenga, Vinod Kumar

Research output: Contribution to journalArticleAcademicpeer-review

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<5×10-5) were replicated in 56 independent French and Dutch patients with RCDII. Results After replication, SNP rs2041570 on chromosome 7 was significantly associated with progression to RCDII (P=2.37×10-8, 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 cells in RCDII progression.
Original languageEnglish
Pages (from-to)828-837
JournalEuropean Journal of Gastroenterology and Hepatology
Volume30
Issue number8
DOIs
Publication statusPublished - 2018

Cite this

Hrdlickova, Barbara ; Mulder, Chris J. ; Malamut, Georgia ; Meresse, Bertrand ; Platteel, Mathieu ; Kamatani, Yoichiro ; Ricaño-Ponce, Isis ; van Wanrooij, Roy L. J. ; Zorro, Maria M. ; Jan Bonder, Marc ; Gutierrez-Achury, Javier ; Cellier, Christophe ; Zhernakova, Alexandra ; Nijeboer, Petula ; Galan, Pilar ; Withoff, Sebo ; Lathrop, Mark ; Bouma, Gerd ; Xavier, Ramnik J. ; Jabri, Bana ; Bensussan, Nadine C. ; Wijmenga, Cisca ; Kumar, Vinod. / A locus at 7p14.3 predisposes to refractory celiac disease progression from celiac disease. In: European Journal of Gastroenterology and Hepatology. 2018 ; Vol. 30, No. 8. pp. 828-837.
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title = "A locus at 7p14.3 predisposes to refractory celiac disease progression from celiac disease",
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<5×10-5) were replicated in 56 independent French and Dutch patients with RCDII. Results After replication, SNP rs2041570 on chromosome 7 was significantly associated with progression to RCDII (P=2.37×10-8, 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 cells in RCDII progression.",
author = "Barbara Hrdlickova and Mulder, {Chris J.} and Georgia Malamut and Bertrand Meresse and Mathieu Platteel and Yoichiro Kamatani and Isis Rica{\~n}o-Ponce and {van Wanrooij}, {Roy L. J.} and Zorro, {Maria M.} and {Jan Bonder}, Marc and Javier Gutierrez-Achury and Christophe Cellier and Alexandra Zhernakova and Petula Nijeboer and Pilar Galan and Sebo Withoff and Mark Lathrop and Gerd Bouma and Xavier, {Ramnik J.} and Bana Jabri and Bensussan, {Nadine C.} and Cisca Wijmenga and Vinod Kumar",
year = "2018",
doi = "10.1097/MEG.0000000000001168",
language = "English",
volume = "30",
pages = "828--837",
journal = "European Journal of Gastroenterology and Hepatology",
issn = "0954-691X",
publisher = "Lippincott Williams and Wilkins",
number = "8",

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Hrdlickova, B, Mulder, CJ, Malamut, G, Meresse, B, Platteel, M, Kamatani, Y, Ricaño-Ponce, I, van Wanrooij, RLJ, Zorro, MM, Jan Bonder, M, Gutierrez-Achury, J, Cellier, C, Zhernakova, A, Nijeboer, P, Galan, P, Withoff, S, Lathrop, M, Bouma, G, Xavier, RJ, Jabri, B, Bensussan, NC, Wijmenga, C & Kumar, V 2018, 'A locus at 7p14.3 predisposes to refractory celiac disease progression from celiac disease' European Journal of Gastroenterology and Hepatology, vol. 30, no. 8, pp. 828-837. https://doi.org/10.1097/MEG.0000000000001168

A locus at 7p14.3 predisposes to refractory celiac disease progression from celiac disease. / Hrdlickova, Barbara; Mulder, Chris J.; Malamut, Georgia; Meresse, Bertrand; Platteel, Mathieu; Kamatani, Yoichiro; Ricaño-Ponce, Isis; van Wanrooij, Roy L. J.; Zorro, Maria M.; Jan Bonder, Marc; Gutierrez-Achury, Javier; Cellier, Christophe; Zhernakova, Alexandra; Nijeboer, Petula; Galan, Pilar; Withoff, Sebo; Lathrop, Mark; Bouma, Gerd; Xavier, Ramnik J.; Jabri, Bana; Bensussan, Nadine C.; Wijmenga, Cisca; Kumar, Vinod.

In: European Journal of Gastroenterology and Hepatology, Vol. 30, No. 8, 2018, p. 828-837.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - A locus at 7p14.3 predisposes to refractory celiac disease progression from celiac disease

AU - Hrdlickova, Barbara

AU - Mulder, Chris J.

AU - Malamut, Georgia

AU - Meresse, Bertrand

AU - Platteel, Mathieu

AU - Kamatani, Yoichiro

AU - Ricaño-Ponce, Isis

AU - van Wanrooij, Roy L. J.

AU - Zorro, Maria M.

AU - Jan Bonder, Marc

AU - Gutierrez-Achury, Javier

AU - Cellier, Christophe

AU - Zhernakova, Alexandra

AU - Nijeboer, Petula

AU - Galan, Pilar

AU - Withoff, Sebo

AU - Lathrop, Mark

AU - Bouma, Gerd

AU - Xavier, Ramnik J.

AU - Jabri, Bana

AU - Bensussan, Nadine C.

AU - Wijmenga, Cisca

AU - Kumar, Vinod

PY - 2018

Y1 - 2018

N2 - 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<5×10-5) were replicated in 56 independent French and Dutch patients with RCDII. Results After replication, SNP rs2041570 on chromosome 7 was significantly associated with progression to RCDII (P=2.37×10-8, 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 cells in RCDII progression.

AB - 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<5×10-5) were replicated in 56 independent French and Dutch patients with RCDII. Results After replication, SNP rs2041570 on chromosome 7 was significantly associated with progression to RCDII (P=2.37×10-8, 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 cells in RCDII progression.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85050008778&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/29787419

U2 - 10.1097/MEG.0000000000001168

DO - 10.1097/MEG.0000000000001168

M3 - Article

VL - 30

SP - 828

EP - 837

JO - European Journal of Gastroenterology and Hepatology

JF - European Journal of Gastroenterology and Hepatology

SN - 0954-691X

IS - 8

ER -