Association between genetic variants in the HNF4A gene and childhood-onset Crohn’s disease
Hepatocyte nuclear 4 alpha (HNF4α), involved in glucose and lipid metabolism, has been linked to intestinal inflammation and abnormal mucosal permeability. Moreover, in a genome-wide association study, the HNF4A locus has been associated with ulcerative colitis. The objective of our study was to eva...
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Published in | Genes and immunity Vol. 13; no. 7; pp. 556 - 565 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
01.10.2012
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | Hepatocyte nuclear 4 alpha (HNF4α), involved in glucose and lipid metabolism, has been linked to intestinal inflammation and abnormal mucosal permeability. Moreover, in a genome-wide association study, the
HNF4A
locus has been associated with ulcerative colitis. The objective of our study was to evaluate the association between HNF4α genetic variants and Crohn’s disease (CD) in two distinct Canadian pediatric cohorts. The sequencing of the
HNF4A
gene in 40 French Canadian patients led to the identification of 27 single nucleotide polymorphism (SNP)s with a minor allele frequency >5%. To assess the impact of these SNPs on disease susceptibility, we first conducted a case–control discovery study on 358 subjects with CD and 542 controls. We then carried out a replication study in a separate cohort of 416 cases and 1208 controls. In the discovery cohort, the genotyping of the identified SNPs revealed that six were significantly associated with CD. Among them, rs1884613 was replicated in the second CD cohort (odds ratio (OR): 1.33;
P
<0.012) and this association remained significant when both cohorts were combined and after correction for multiple testing (OR: 1.39;
P
<0.004). An 8-marker P2 promoter haplotype containing rs1884613 was also found associated with CD (
P
<2.09 × 10
−4
for combined cohorts). This is the first report showing that the
HNF4A
locus may be a common genetic determinant of childhood-onset CD. These findings highlight the importance of the intestinal epithelium and oxidative protection in the pathogenesis of CD. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 |
ISSN: | 1466-4879 1476-5470 |
DOI: | 10.1038/gene.2012.37 |