Abstract
Hirschsprung disease (HSCR) is a congenital developmental defect of the enteric nervous system known to be associated with the RET-protooncogene and other candidates. Recently, a genome-wide association study has added NRG1, a regulator of the development of the enteric ganglia precursors, as a new candidate gene. The aim of this study is to validate the association of the RET-protooncogene and the NRG1 in HSCR in Thai patients. The study used TaqMan single-nucleotide polymorphism (SNP) genotyping and PCR–restriction fragment length polymorphism for genotyping of 10 SNPs within the RET-protooncogene and four SNPs within the NRG1, in 68 Thai sporadic HSCR cases and 120 ethnic-matched controls. On univariate disease association analysis, 9 of 10 RET-protooncogene SNPs and all four NRG1 SNPs showed an association with HSCR. The rs2435357 (RET-protooncogene) and rs2439305 (NRG1) showed the strongest associations with the disease at P-values of 8.17E-09 (odds ratio (OR)=6.43, 95% confidence intervals (CI)=3.33–12.40) and 6.94E-03 (OR=3.28, 95% CI=1.28–8.38), respectively. The RET-protooncogene rs2435357 (TT genotype) in combination with the NRG1 rs2439305 (GG genotype) was strongly associated with an increased risk of HSCR with a P-value of 1.99E-04 (OR=20.34, 95% CI; 2.54–162.78) when compared with a single SNP of the RET-protooncogene or NRG1. Genetic variation of the RET-protooncogene and NRG1 is involved in the risk of HSCR development in the Thai population. Moreover, the study also detected a combined effect of SNPs by SNP–SNP interaction, which may help in predicting HSCR risk.
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Acknowledgements
The study was supported by grant from under the program Strategic Scholarships for Frontier Research Network for the Ph.D. Program Thai Doctoral degree from the Office of the Higher Education Commission, Thailand, and the Graduate Fund of Prince of Songkla University. We thank the Blood Bank Unit of Songklanagarind and Pattani Hospitals for the control samples. Dave Patterson helped with English language editing.
Author contributions: All authors contributed to this study as declared below; T Phusantisampan: experiments, data analysis, manuscript writing; S Sangkhathat: manuscript writing, data analysis; A Phongdara: methodology review; P Chiengkriwate, S Patrapinyokul: samples collection and clinical data provision; S Mahasirimongkol: instrument provision and technical consultant.
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Phusantisampan, T., Sangkhathat, S., Phongdara, A. et al. Association of genetic polymorphisms in the RET-protooncogene and NRG1 with Hirschsprung disease in Thai patients. J Hum Genet 57, 286–293 (2012). https://doi.org/10.1038/jhg.2012.18
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DOI: https://doi.org/10.1038/jhg.2012.18
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