Genetic variants of IL ‐11 associated with risk of Hirschsprung disease

Background Hirschsprung disease ( HSCR ) is a congenital and heterogeneous disorder characterized by the absence of enteric ganglia during enteric nervous system ( ENS ) development. Our recent genome‐wide association study has identified a variant (rs6509940) of interleukin‐11 ( IL ‐11 ) as a potential susceptible locus for HSCR . As interleukins play important roles in the ENS , we further studied associations with HSCR of nine common single nucleotide polymorphisms ( SNP s) on IL ‐11 . Methods Biopsy specimens or surgical materials from all patients that were tested for histological examination based on the absence of the enteric ganglia were collected. A total of nine SNP s on IL ‐11 were genotyped in 187 HSCR patients and 283 unaffected controls using TaqMan genotyping assay. Key Results Combined analysis revealed that several SNP s (minimum p  = 1.57 × 10 −7 ) showed statistically significant associations with HSCR , even after Bonferroni correction ( p corr  = 1.73 × 10 −6 for the SNP ). Moreover, the most common haplotype was strongly associated with HSCR ( p corr  = 2.20 × 10 −6 ). In further analysis among three HSCR subtypes (short segment, S‐ HSCR ; long segment, L‐ HSCR ; total colonic aganglionosis, TCA ) based on the extent of aganglionic segment, the result showed a different association pattern depending on the subtypes (minimum p corr  = 6.12 × 10 −5 for rs6509940 in S‐ HSCR ; but no significant SNP in L‐ HSCR and TCA ). Conclusions & Inferences Although further replication in a larger cohort and functional evaluations are needed, our findings suggest that genetic variations of IL ‐11 may be associated with the risk of HSCR and/or the mechanisms related to ENS development.