Association between genetic variants in the HNF4A gene and childhood-onset Crohns disease

V. Marcil, D. Sinnett, E. Seidman, F. Boudreau, F. P. Gendron, J. F. Beaulieu, D. Menard, M. Lambert, A. Bitton, R. Sanchez, D. Amre, E. Levy

Research output: Contribution to journalArticle

Abstract

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 Crohns 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; P0.012) and this association remained significant when both cohorts were combined and after correction for multiple testing (OR: 1.39; P0.004). An 8-marker P2 promoter haplotype containing rs1884613 was also found associated with CD (P2.09 × 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.

Original languageEnglish (US)
Pages (from-to)556-565
Number of pages10
JournalGenes and immunity
Volume13
Issue number7
DOIs
StatePublished - Oct 1 2012

Keywords

  • Crohn's disease
  • HNF4a
  • genetic variants
  • oxidative stress

ASJC Scopus subject areas

  • Immunology
  • Genetics
  • Genetics(clinical)

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    Marcil, V., Sinnett, D., Seidman, E., Boudreau, F., Gendron, F. P., Beaulieu, J. F., Menard, D., Lambert, M., Bitton, A., Sanchez, R., Amre, D., & Levy, E. (2012). Association between genetic variants in the HNF4A gene and childhood-onset Crohns disease. Genes and immunity, 13(7), 556-565. https://doi.org/10.1038/gene.2012.37