Xq28 Variants as Novel Male-Specific Susceptibility Factors for Hirschsprung Disease

Hirschsprung's disease (HSCR) is a complex congenital digestive tract disease affected by multiple genes. Despite the identification of >20 risk loci, no susceptibility variants map to sex chromosomes-a striking gap given the 4- to 6-fold male predominance in short-segment HSCR. This study investigates the contribution of X-chromosomal variation to HSCR pathogenesis.

We conducted a large case-control study involving a South Chinese population. Four single nucleotide polymorphisms (SNPs) in a disease hotspot region spanning on Xq28 were genotyped through MassARRAY genotyping platform. Association analysis of the selected SNPs with HSCR were performed using PLINK1.9. RNA quantitative analysis, immunohistochemistry staining, and Western blot analysis were performed to observe the expression of the newly identified gene IRAK1 of colon tissues of HSCR patients.

This study included 1470 HSCR patients and 1473 ethnically matched controls. Four SNPs (rs2071128, rs17422, rs1059702, and rs2734647) were identified as associated with HSCR in a male-specific manner, with odds ratios ranging from 1.20 to 1.52. These variants conferred an even higher risk for long-segment HSCR in males, with odds ratios between 1.75 and 2.53. We demonstrated higher expression of the newly identified gene IRAK1 in aganglionic colon samples compared with ganglionic colon tissues, especially in the males (P = 0.00046).

We identified a novel male-specific region Xq28 as associated with HSCR. The differential expression of the newly identified gene IRAK1 in HSCR patients suggests an important role for the HSCR-associated common variants in shaping the male-specific disease.