Abstract
Background
Hirschsprung’s disease (HSCR) is the most common congenital cause of intestinal obstruction in children. Sotos syndrome (SoS) is an overgrowth disorder with constipation and sometimes accompanied by HSCR. NSD1 gene mutation is the main cause of SoS. We aimed to investigate association of NSD1 common single nucleotide polymorphisms (SNPs) with HSCR susceptibility in Chinese Han population.
Method
We genotyped 15 SNPs encompassing NSD1 gene region in 420 HSCR patients and 1665 controls on Fludigm EP1 platform. Association analysis was performed between cases and controls.
Result
Rs244709 was the most associated SNP with HSCR susceptibility of the sample set (PAllelic = 9.69 × 10−5, OR = 1.37, 95% CI: 1.17–1.61). Gender stratification analysis revealed that NSD1 SNPs were associated with HSCR in males, but not in females. The nonsynonymous coding SNP rs28932178 in NSD1 exon 5 represented the most significant signal in males (PAllelic = 6.43 × 10−5, OR = 1.42, 95% CI: 1.20–1.69). The associated SNPs were expression quantitative trait loci (eQTLs) of nearby genes in multiple tissues. NSD1 expression levels were higher in aganglionic colon tissues than ganglionic tissues (P = 3.00 × 10−6).
Conclusion
NSD1 variation conferred risk to HSCR in males, indicating SoS and HSCR may share common genetic factors.
Impact
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This is the first study to reveal that NSD1 variation conferred risk to Hirschsprung’s disease susceptibility in males of Chinese Han population, indicating Sotos syndrome and Hirschsprung’s disease may share some common genetic background.
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This study indicates more attention should be paid to the symptom of constipation in patients with Sotos syndrome.
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Our results raise questions about the role of NSD1 in the development of enteric nervous system and the pathogenesis of Hirschsprung’s disease.
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Acknowledgements
We thank all the participants of this research. This work was supported by National Natural Science Foundation of China (31671317, 31471190 and Key Program 81630039), Foundation of Shanghai Municipal Health Commission (201840014) and Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition (17DZ2272000).
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All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work; W.C. and X.C. designed the research and revised the article; X.-X.Y. drafted the article; X.C. and X.-X.Y. analyzed the data; X.-X.Y., W.-J.W., H.-L.S., Z.-L.W., M.-R.B., Y.J.L., and Y.-M.G. performed the experiment and collected the data.
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Yu, XX., Chu, X., Wu, WJ. et al. Common variation of the NSD1 gene is associated with susceptibility to Hirschsprung’s disease in Chinese Han population. Pediatr Res 89, 694–700 (2021). https://doi.org/10.1038/s41390-020-0933-3
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DOI: https://doi.org/10.1038/s41390-020-0933-3
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