Reduced RET expression in gut tissue of individuals carrying risk alleles of Hirschsprung's disease

作者：Xiaoping Miao, Thomas Yuk-Yu Leon, Esw Ngan, Man‐Ting So, Zhengwei Yuan, Vincent Chi‐Hang Lui, Yan Chen, Kenneth Kak‐Yuen Wong, Paul Kwong‐Hang Tam, Mercè Garcia-Barceló · 发表于：Human Molecular Genetics · 年份：2010 · DOI：10.1093/hmg/ddq020 · 被引用次数：48 · 研究领域：Congenital gastrointestinal and neural anomalies、Digestive system and related health、Gastrointestinal disorders and treatments

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-phen...