https://www.ncbi.nlm.nih.gov/pubmed/29787419
Eur J Gastroenterol Hepatol. 2018 Aug;30(8):828-837. doi: 10.1097/MEG.0000000000001168.
A locus at 7p14.3 predisposes to refractory celiac disease progression from celiac disease.
Hrdlickova B1, Mulder CJ2, Malamut G3,4, Meresse B3, Platteel M1, Kamatani Y5, Ricaño-Ponce I1, van Wanrooij RLJ2, Zorro MM1, Jan Bonder M1, Gutierrez-Achury J1, Cellier C3,4, Zhernakova A1, Nijeboer P2, Galan P5, Withoff S1, Lathrop M6, Bouma G2, Xavier RJ7,8, Jabri B9, Bensussan NC3, Wijmenga C1,10, Kumar V1. 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 (IEL). 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 56="" and="" dutch="" french="" in="" independent="" p="" patients="" rcdii.="" replicated="" were="" with="">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.
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 56="" and="" dutch="" french="" in="" independent="" p="" patients="" rcdii.="" replicated="" were="" with="">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.
- PMID:
- 29787419
- PMCID:
- PMC6373482
- DOI:
- 10.1097/MEG.0000000000001168
- [Indexed for MEDLINE]
https://www.ncbi.nlm.nih.gov/pubmed/11986981
https://www.ncbi.nlm.nih.gov/pubmed/2151084
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