Abstract
Hischsprung disease (HSCR) is an intestinal disorder with strong genetic components. RET was considered as the strongest contributor. Multiple single nucleotide polymorphisms (SNP) were demonstrated as associated with HSCR in different populations. However, whether the associations of reported SNPs derived from one causal variants or congregations of multiple variants were still not clear. In this study, we successfully genotyped 16 SNPs in RET with a largest case-control study to date, totaling 1470 HSCR and 1473 control subjects in South Chinese population. Multiple independent contributors were identified through pairwise and stepwise logistic regression. The intragenic synergistic effect among these SNPs were further explored and cross validated by logistic regression and multifactor dimensionality reduction (MDR). Noteworthy, in further subclinical manifestation analysis, the six potential independent contributors in RET were more essential for the patients with short-segment aganglionosis (S-HSCR). Although functional evaluations are required, our comprehensive analysis for RET gene integrating detailed disease subphenotypes might facilitate improved understanding for the genetic understanding of HSCR etiology.
Highlights
Hirschsprung disease (HSCR) is an intestinal disorder characterized by the absence of nerves in parts of the intestine
Sixteen single nucleotide polymorphisms (SNP) centered by SNP rs2435357 aggregating in a 400kb span were selected for replication in South Chinese population using 1470 cases and 1473 controls, to identify multiple independent variants associated with the disease (The selection criteria were listed in Method)
We focused on 16 SNPs centered by SNP rs2435357 in RET through a total number of 1470 cases and 1473 controls matched geographically and ethnically
Summary
Hirschsprung disease (HSCR) is an intestinal disorder characterized by the absence of nerves in parts of the intestine. Hirschsprung disease affects all races; it is roughly 3 times more common among Asians. This disease occurs more often in males than in females, with a male-to-female ratio of approximately 4:1 [2]. There is growing evidence showing that some potentially functional single nucleotide polymorphisms (SNPs) of RET gene could act as susceptibility factors and modify the phenotype of HSCR, especially in certain combinations of alleles, haplotypes [6]. Several SNPs were subsequently replicated in multiple www.aging‐us.com studies [8,9,10] Whether those SNPs derived from multiple independent signals or come out from one single casual mutation was unclear and seldom investigated. Further exploration of those independent effects will enrich the list of HSCR susceptibility genes, and has a potential to advance our understanding on the etiology of this complicated disease
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