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

Abstract

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 (SNPs) 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 SNPs on IL-11 were genotyped in 187 HSCR patients and 283 unaffected controls using TaqMan genotyping assay. Key Results Combined analysis revealed that several SNPs (minimum p = 1.57 x 10(-7)) showed statistically significant associations with HSCR, even after Bonferroni correction (p(corr) = 1.73 x 10(-6) for the SNP). Moreover, the most common haplotype was strongly associated with HSCR (p(corr) = 2.20 x 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 x 10(-5) for rs6509940 in S-HSCR; but no significant SNP in L-HSCR and TCA). Conclusions (sic) 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.