Center for Genomics and Bioinformatics Research, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla, Thailand.
J Hum Genet. 2012 May;57(5):286-93. doi: 10.1038/jhg.2012.18. Epub 2012 Mar 1.
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.
先天性巨结肠（HSCR）是一种肠神经系统先天性发育缺陷，已知与 RET 原癌基因和其他候选基因有关。最近，全基因组关联研究将 NRG1（肠神经节前体细胞发育的调节剂）添加为新的候选基因。本研究旨在验证 RET 原癌基因和 NRG1 与泰国患者 HSCR 的关联。该研究使用 TaqMan 单核苷酸多态性（SNP）基因分型和聚合酶链反应-限制性片段长度多态性对 10 个 RET 原癌基因内的 SNP 和 4 个 NRG1 内的 SNP 进行基因分型，在 68 例泰国散发性 HSCR 病例和 120 例种族匹配的对照中。在单变量疾病关联分析中，10 个 RET 原癌基因 SNP 中有 9 个和所有 4 个 NRG1 SNP 与 HSCR 相关。rs2435357（RET 原癌基因）和 rs2439305（NRG1）与疾病的关联最强，P 值分别为 8.17E-09（优势比（OR）=6.43，95%置信区间（CI）=3.33-12.40）和 6.94E-03（OR=3.28，95% CI=1.28-8.38）。RET 原癌基因 rs2435357（TT 基因型）与 NRG1 rs2439305（GG 基因型）相结合，与 HSCR 风险增加强烈相关，P 值为 1.99E-04（OR=20.34，95% CI；2.54-162.78），与单个 RET 原癌基因或 NRG1 SNP 相比。RET 原癌基因和 NRG1 的遗传变异参与了泰国人群 HSCR 发病的风险。此外，该研究还通过 SNP-SNP 相互作用检测了 SNP 的联合效应，这可能有助于预测 HSCR 风险。
