RET基因调控区遗传变异与先天性巨结肠患病风险研究

目的先天性巨结肠（HSCR）是一种复杂的先天性疾病,RET是其主要的易感性基因。本研究对RET非编码区单核甘酸多态性（SNP）-5G〉A（rs10900296）,-1A〉C（rs10900297）和intron1 C〉T（rs2435357）进行分型分析,评估RET基因调控区SNPs及单倍型与先天性巨结肠之间的相关性。方法选取115名病例组病人和139名对照组正常人群,应用聚合酶链反应（PCR）技术和直接测序的方法进行基因分型。回归模型中使用OR值和95%置信区间（CI）作为基因型危险性的评价指标。结果 -5G〉A,-1A〉C,intron1C〉T各基因型频率在病例和对照人群的分布具有显著差异。-5 AA（OR=6.26,95%CI=3.62-10.83）,-1 CC（OR=7.54,95%CI=2.06-27.66）和intron1 TT（OR=19.22,95% CI=7.54-48.99）基因型均能显著增加HSCR发病的风险。单倍型A-C-T（OR=6.28,95% CI=3.77-10.46）和双体型A-C-T/A-C-T（OR=13.62,95% CI=3.48-53.30）分析同样表明与HSCR发病风险存在较强的相关性,并呈现出一定的累积效应。结论 RET基因调控区的基因多态性可能与HSCR的发病易感性有关,支持RET通路的常见变异在HSCR的发展过程中起着重要的作用的假设。

The association of RET gene regulatory region polymorphisms with the susceptibility in Hirschsprung disease

Objective:Hirschsprung disease(HSCR) is a complex congenital disorder and RET is the major susceptibility gene.Single nucleotide polymorphisms(-5G>A(rs10900296),-1A>C(rs10900297 and intron1 C>T,rs2435357) in non-coding region of RET gene,were genotyped to assess the association between these SNPs and haplotypes and the risk of Hirschsprung disease.Methods:Genotypes of-5G>A(rs10900296),-1A>C(rs10900297),intron1 C>T,(rs2435357) were analyzed in 140 HSCR patients and 148 controls by polymerase chain reaction amplification and direct sequencing.Associations with risk of HSCR were estimated by odds ratio(OR) and their 95% confidence intervals(95% CI) using logistic regression.Results:There were significant differences in the frequency distribution of-5G>A,-1A>C,intron1C>T among cases and controls.We observed significantly increased risk of HSCR associated with the-5 AA(OR=6.26,95% CI=3.62-10.83),-1 CC(OR=7.54,95%CI=2.06-27.66),intron1 TT(OR=19.22,95%CI=7.54-48.99),respectively.The haplotype A-C-T(OR=6.28,95%CI=3.77-10.46)and diplotype A-C-T/A-C-T(OR=13.62,95%CI=3.48-53.30) were also contributing to the susceptibility of HSCR,indicating a cumulative effect of these SNPs.Conclusion:There may be a potential relation between variations located at the regulating region of RET gene and the risk of HSCR,which supports the hypothesis that common variations in RET pathway play an important role in the development of HSCR.