Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Hum Mol Genet. 2010 Apr 15;19(8):1461-7. doi: 10.1093/hmg/ddq020. Epub 2010 Jan 20.
Receptor tyrosine kinase (RET) single nucleotide polymorphisms (SNPs) are associated with the Hirschsprung's disease (HSCR). We investigated whether the amount of RET expressed in the ganglionic gut of human was dependent on the genotype of three regulatory SNPs (-5G>A rs10900296 and -1A>C rs10900297 in the promoter, and C>T rs2435357 in intron 1). We examined the effects of three regulatory SNPs on the RET gene expression in 67 human ganglionic gut tissues using quantitative real-time PCR. Also, 315 Chinese HSCR patients and 325 ethnically matched controls were genotyped for the three SNPs by polymerase chain reaction (PCR) and direct sequencing. The expression of RET mRNA in human gut tissue did indeed correlate with the genotypes of the individuals. The lowest RET expression was found for those individuals homozygous for the three risk alleles (A-C-T/A-C-T), and the highest for those homozygous for the 'wild-type' counterpart (G-A-C/G-A-C), with expression values ranging from 218.32 +/- 125.69 (mean +/- SE) in tissues from individuals carrying G-A-C/G-A-C to 31.42 +/- 8.42 for individuals carrying A-C-T/A-C-T (P = 0.018). As expected, alleles -5A, -1C and intron 1 T were associated with HSCR (P = 5.94 x 10(-31), 3.12 x 10(-24) and 5.94 x 10(-37), respectively) as was the haplotype encompassing the three associated alleles (A-C-T) when compared with the wild-type counterpart G-A-C (chi2 = 155.29, P << 0.0001). To our knowledge, this is the first RET expression genotype-phenotype correlation study conducted on human subjects to indicate common genetic variants in the regulatory region of RET may play a role in mediating susceptibility to HSCR, by conferring a significant reduction of the RET expression.
受体酪氨酸激酶 (RET) 单核苷酸多态性 (SNP) 与先天性巨结肠 (HSCR) 有关。我们研究了人神经节肠道中 RET 的表达量是否依赖于三个调节 SNP 的基因型 (-5G>A rs10900296 和 -1A>C rs10900297 在启动子，以及 C>T rs2435357 在内含子 1)。我们使用定量实时 PCR 检查了三个调节 SNP 对 67 个人类神经节肠道组织中 RET 基因表达的影响。此外，通过聚合酶链反应 (PCR) 和直接测序，对 315 名中国 HSCR 患者和 325 名种族匹配的对照者进行了三个 SNP 的基因分型。人肠道组织中 RET mRNA 的表达确实与个体的基因型相关。携带三个风险等位基因 (A-C-T/A-C-T) 的个体的 RET 表达最低，而携带 '野生型' 对应物 (G-A-C/G-A-C) 的个体的 RET 表达最高，表达值从携带 G-A-C/G-A-C 的个体的组织中 218.32 +/- 125.69(平均值 +/- SE) 到携带 A-C-T/A-C-T 的个体的 31.42 +/- 8.42(P = 0.018)。正如预期的那样，等位基因 -5A、-1C 和内含子 1 T 与 HSCR 相关 (P = 5.94 x 10(-31)、3.12 x 10(-24) 和 5.94 x 10(-37)，分别)，以及与野生型对应物 G-A-C 相比，包含三个相关等位基因 (A-C-T) 的单倍型 (chi2 = 155.29，P << 0.0001)。据我们所知，这是首次在人类受试者中进行的 RET 表达基因型-表型相关性研究，表明 RET 调节区的常见遗传变异可能通过显著降低 RET 的表达，在介导 HSCR 易感性方面发挥作用。
