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Research Paper|Volume 12, Issue 5|pp 4379—4393

Genetic variants in RET, ARHGEF3 and CTNNAL1, and relevant interaction networks, contribute to the risk of Hirschsprung disease

Yang Wang1,3,4, Qian Jiang2, Hao Cai1,3,4, Ze Xu1,3,4, Wenjie Wu1,3,4, Beilin Gu1,3,4, Long Li5, Wei Cai1,3,4
  • 1Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  • 2Department of Medical Genetics, Capital Institute of Pediatrics, Beijing, China
  • 3Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
  • 4Shanghai Institute for Pediatric Research, Shanghai, China
  • 5Department of General Surgery, Capital Institute of Pediatrics Affiliated Children's Hospital, Beijing, China
* Equal contribution
Received: October 19, 2019Accepted: February 25, 2020Published: March 6, 2020
https://doi.org/10.18632/aging.102891

Copyright © 2020 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Hirschsprung disease (HSCR), the most common enteric neuropathy, stands as a model for complex genetic disorders. It has recently been demonstrated that both ARHGEF3 and CTNNAL1 map to the RET-dependent HSCR susceptibility loci. We therefore sought to explore whether genetic variants within RET, ARHGEF3 and CTNNAL1, and their genetic interaction networks are associated with HSCR. Taking advantage of a strategy that combined the MassArray system and gene-gene interaction analysis with case-control study, we interrogated 38 polymorphisms within RET, ARHGEF3 and CTNNAL1 in 1015 subjects (502 HSCR cases and 513 controls) of Han Chinese origin. There were statistically significant associations between 20 genetic variants in these three genes and HSCR. Haplotype analysis also revealed some significant global P values, i.e. RET_ rs2435357-rs752978-rs74400468-rs2435353-rs2075913-rs17028-rs2435355 (P = 3.79×10-58). Using the MDR and GeneMANIA platforms, we found strong genetic interactions among RET, ARHGEF3, and CTNNAL1 and our previously studied GAL, GAP43, NRSN1, PTCH1, GABRG2 and RELN genes. These results offer the first indication that genetic markers of RET, ARHGEF3 and CTNNAL1 and relevant genetic interaction networks confer the altered risk to HSCR in the Han Chinese population.