HNF4 alpha: A New Susceptibility Gene for Crohnʼs Disease?: 2010 Presidential Poster

Abstract

Purpose: Hepatocyte nuclear factor 4 alpha (HNF4α) is a transcription factor mainly expressed in liver, intestine, kidney and pancreas involved in regulating many metabolic functions. Our recent studies in an experimental knock out model supports its potential implication in the physiopathology underlying IBD. However, little is known regarding its potential involvement in humans with Crohn's disease (CD). The aim of this study was to evaluate the association between HNF4α genetic variants and CD. Methods: The sequencing of the promoter, coding and strategic regions of the HNF4α gene was first carried out in a sample population of 40 French Canadian patients, in order to identify the genetic variants prevalent in our population. Thereafter, the identified polymorphisms were genotyped in an extensive French Canadian cohort including 350 CD patients and 650 controls. Results: Sequencing the HNF4α gene led to the identification of 28 polymorphisms. Genotyping these variants in our cohort revealed that 8 polymorphisms demonstrated significant allelic association with CD. Among these variants, one polymorphism leading to a change in the amino acid sequence of the protein, appears to be highly protective against the risk of developing CD (OR: 0.2546, P<0.00001). Moreover, haplotype analyses revealed that one specific haplotype composed of 8 polymorphisms in high linkage disequilibrium and located in the promoter region is also protective against CD (OR: 0.5097, P<0.0027). Conclusion: In a French Canadian population, several HNF4α genetic variants are associated with CD. Our genetic results further support the hypothesis of a relation between HNF4α and physiopathology underlying CD. This study is the first to demonstrate a relationship between HNF4α genetic variants and CD susceptibility.