Abstract
The RET proto-oncogene was identified as a major locus involved in Hirschsprung disease (HSCR). A genome-wide association study (GWAS) and whole exome sequencing identified NRG1 and NRG3 as additional HSCR susceptibility loci. We investigated the effects of RET (rs2506030 and rs2435357), NRG1 (rs2439302, rs16879552 and rs7835688) and NRG3 (rs10748842, rs10883866 and rs6584400) polymorphisms in a Chinese population with HSCR. We assessed single nucleotide polymorphisms (SNPs) in the RET, NRG1 and NRG3 genes in a cohort of 362 sporadic HSCR patients and 1,448 normal controls using a TaqMan genotyping assay. Significant associations were found between HSCR risk and rs2506030, rs2435357, rs2439302 and rs7835688 (odds ratio [OR] 1.64, P = 1.72E-06; 2.97, P = 5.15E-33; 1.84, P = 9.36E-11; and 1.93, P = 1.88E-12, respectively). Two locus analyses of SNPs indicated increased disease risks of HSCR between NRG1 rs2439302 and RET rs2435357 or rs2506030. RET rs2506030 (GG genotype) and rs2435357 (TT genotype), in combination with NRG1 rs2439302 (GG genotype), were strongly associated with the highest risk of HSCR (OR = 56.53, P = 4.50E-07) compared with the two loci or a single SNP of either RET or NRG1. Our results support the association between genetic variation of RET and NRG1 and susceptibility to HSCR in the Chinese population.
Highlights
The genetic reasons for the variable phenotypes, including the segment length of aganglionosis, sex bias with a male preponderance, high recurrence among descendants and associated phenotypes, remain largely unknown[8]
It has been related to schizophrenia and Hirschsprung disease (HSCR) in some genome-wide association studies (GWAS) in individuals of Asian descent[26,27] as well as survival of enteric neural crest cells (ENCCs)[28]
Some studies have demonstrated that the ErbB family plays an important role in the development of ENCCs40
Summary
The genetic reasons for the variable phenotypes, including the segment length of aganglionosis, sex bias with a male preponderance, high recurrence among descendants and associated phenotypes, remain largely unknown[8]. Our previous study confirmed exome genetic variation in NRG3 as a risk factor for HSCR9. Our previous exome sequencing identified coding region polymorphisms at NRG3 and indicated that this novel gene is associated with susceptibility to HSCR in a Chinese population. A fine-mapping study identified the genetic variants rs10883866, rs10748842 and rs6584400 in intron 1 of NRG3 as risk factors that are associated with the development of the nervous system and that influence NRG3 gene expression[30,34]. In a study conducted by Li, rs2435357 and rs2506030 in RET were confirmed to be risk factors for HSCR in a Chinese population Among these variants, rs2435357 was investigated in different ethnicities[35,36,37]. We detected differential gene expression levels by qRT-PCR and western blotting in colon tissues from patients
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