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Large-scale replication study identified multiple independent SNPs in RET synergistically associated with Hirschsprung disease in Southern Chinese population.

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.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC5636671 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Large-scale replication study identified multiple independent SNPs in RET synergistically associated with Hirschsprung disease in Southern Chinese population.

Zhang Yan Y He Qiuming Q Zhang Ruizhong R Zhang Hong H Zhong Wei W Xia Huimin H

Aging 20170901 9

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 ...[more]

PMID: 28930629

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Project description:Hirschsprung disease (HSCR) is a rare congenital anomaly characterized by the absence of enteric ganglia in the distal intestinal tract. While classified as a multigenic disorder, the altered function of the RET tyrosine kinase receptor is responsible for the majority of the pathogenesis of HSCR. Recent evidence demonstrate a strong association between RET and the homeostasis of immune system. Here, we utilize a unique cohort of fifty HSCR patients to fully characterize the expression of RET receptor on both innate (monocytes and Natural Killer lymphocytes) and adaptive (B and T lymphocytes) human peripheral blood mononuclear cells (PBMCs) and to explore the role of RET signaling in the immune system. We show that the increased expression of RET receptor on immune cell subsets from HSCR individuals correlates with the presence of loss-of-function RET mutations. Moreover, we demonstrate that the engagement of RET on PBMCs induces the modulation of several inflammatory genes. In particular, RET stimulation with glial-cell line derived neurotrophic factor family (GDNF) and glycosyl-phosphatidylinositol membrane anchored co-receptor ?1 (GFR?1) trigger the up-modulation of genes encoding either for chemokines (CCL20, CCL2, CCL3, CCL4, CCL7, CXCL1) and cytokines (IL-1?, IL-6 and IL-8) and the down-regulation of chemokine/cytokine receptors (CCR2 and IL8-R?). Although at different levels, the modulation of these "RET-dependent genes" occurs in both healthy donors and HSCR patients. We also describe another set of genes that, independently from RET stimulation, are differently regulated in healthy donors versus HSCR patients. Among these "RET-independent genes", there are CSF-1R, IL1-R1, IL1-R2 and TGF?-1, whose levels of transcripts were lower in HSCR patients compared to healthy donors, thus suggesting aberrancies of inflammatory responses at mucosal level. Overall our results demonstrate that immune system actively participates in the physiopathology of HSCR disease by modulating inflammatory programs that are either dependent or independent from RET signaling.

Dataset Information

Large-scale replication study identified multiple independent SNPs in RET synergistically associated with Hirschsprung disease in Southern Chinese population.

Publications

Large-scale replication study identified multiple independent SNPs in <i>RET</i> synergistically associated with Hirschsprung disease in Southern Chinese population.

Similar Datasets

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