Higher prevalence of Hirschsprung disease in China explained by a common RET mutation

Abstract

RET is the major gene implicated in Hirschsprung disease (HSCR), congenital megacolon. TDT analysis of 13 RET SNPs on 876 HSCR families from three continents showed that all SNPs tested were associated with HSCR. The largest contribution to risk was made by an enhancer mutation in intron 1. This mutation is predominantly associated with male patients with the least severe form of HSCR. The overall frequencies of the HSCR-associated SNPs and haplotypes were significantly higher in Chinese, in both patients and general population. The haplotype composition also differed between populations: two main HSCR-haplotypes (long and short), sharing the 5’ RET region were identified in Caucasians while only one (long) in Chinese. SNPs and haplotypes were tested in an expanded Chinese case-control sample. By estimating the association of each single SNP conditional on the haplotype background, five markers (including the enhancer mutation) wrere highly correlated with HSCR. These 5 markers were distributed across the shared 5’ region coinciding with a single origin for a HSCR susceptibility locus. The most frequent haplotype in the Chinese patients (long) was also the most prevalent in the general population. Over 55% of the patients were homozygous for the long HSCR-associated RET haplotype and 72% homozygous for all those haplotypes comprising the most HSCR correlated markers. This detailed profile of the RET gene in the Chinese population provides an insight for the higher incidence of the disease in this population.