Cumulative Risk Impact of RET, SEMA3, and NRG1 Polymorphisms Associated With Hirschsprung Disease in Han Chinese

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Hirschsprung disease (HSCR) is a congenital aganglionosis of myenteric and submucosal plexuses affecting a variable length of the intestine. The incidence of HSCR is approximately 1 of 5000 live births; however, the risk shows remarkable individual variation caused by single nucleotide polymorphisms (SNPs) at the RET, SEMA3, and NRG1 loci. The present study investigated the effects of these variants on the disease development and phenotype in a Chinese population.


In total, 6 SNPs were genotyped in a cohort consisting of 115 patients with HSCR and 117 unaffected controls using a TaqMan genotyping assay. Histological identification of the affected-segment length (short, long, or total colonic aganglionosis) was performed for all of the samples before DNA extraction.


Significant genetic risk was imparted by rs2435357 and rs2506030 at RET and by rs12707682 at SEMA3. In addition, the average cumulative risk score in the patients with HSCR was significantly higher than that in the controls. Through the assessment of risk alleles by effect size, individuals were classified into 3 weighted risk score groups: low (≤3), medium (4), and high (≥5). Individuals in the high group were significantly more susceptible to HSCR than those in the low group with an odds ratio of 7.7 (95% confidence interval 3.7–16.3).


Cumulative genetic risk varied >35-fold between newborns with zero and >5 accumulated susceptibility alleles. The SNPs rs2435357, rs2506030, and rs12707682 may be useful for stratifying the Chinese population into distinct risk groups.

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