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 (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 × 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. Physical map, LD, and haplotypes of IL-11.