单纯性先天性心脏病易感区域12q13内HOXC簇基因单核苷酸多态单倍型分析

目的 在人类单纯性先天性心脏病（congenital heart disease，CHD）易感区12q13内，选取HOXC4、HOXC5、HOXC6基因内4个已知单核苷酸多态（single nucleotide polymorphism，SNP）G7471T、C16476T、A17860G、A36130G，检测其在单纯性CHD患者和正常人群中的分布情况，分析各个SNP位点及所构成单倍型与单纯性CDH的相关性。方法 应用限制性片段长度多态性和变性高效液相色谱法结合测序，分析108例单纯性先天性心脏病患者及200名正常人4个SNP位点基因型；应用列联表法统计分析患者组和对照组各SNP位点基因型及等位基因频率；应用PHASE软件构建单倍型并统计分析患者组及对照组单倍型频率是否存在差异。结果 C16476T未检测到多态；位于HOXC5基因3’侧翼序列的SNP位点A17860G等位基因频率及基因型频率在患者组和对照组中的分布差异有统计学意义，患者组G等位基因频率明显高于对照组（P〈0．05）；单倍型分析可见4种单倍型在患者组和对照中的分布频率有统计学意义（P〈0．01）；G7471／G17860／G36130和G7471／G17860／A36130为人群中常见单倍型，与对照组相比，患者组中G7471／G17860／G36130、G7471／G17860／A36130两种单倍型频率较高。结论 HOXC5基因3’侧翼序列的SNP位点A17860G与单纯性CHD有明显的相关性，具有G等位基因的人发生CHD的危险性相对增高；3个SNP位点所构成的单倍型有一定意义，可能与单纯性CHD易感基因相连锁。

Analysis of single nucleotide polymorphisms and haplotypes in HOXC gene cluster within susceptible region 12q13 of simple congenital heart disease

OBJECTIVE: In the candidate region 12q13 of simple congenital heart disease(CHD), four single nucleotide polymorphisms(SNPs) in HOXC4 gene were chosen in order to investigate the distribution of SNP and haplotypes in simple CHD patients and normal people. METHODS: The genotype of 4 SNPs in 108 simple CHD patients and 200 normal people were analyzed by restriction fragment length polymorphism(RFLP) and denaturing high-performance liquid chromatography(DHPLC). The statistical contingency table method was used to analyze SNP genotype frequency and gene frequency in patients and control group; then, the haplotypes were established and their frequencies in the two groups were assessed by PHASE software. RESULTS: C16476T polymorphism was not detected; A17860G located in 3' flanking sequence of HOXC5 gene displayed significant difference between the two groups. The G allele frequency in simple CHD patients was higher than that in healthy controls(P < 0.05); the distribution of frequencies of 4 haplotypes showed significant difference(P < 0.01). CONCLUSION: The A17860G located in 3'flanking sequence of HOXC5 gene is associated with simple CHD; the risk of CHD in the persons with G17860 is higher than that in those with A17860. the haplotype of 3 SNPs may be linked with the susceptible gene of simple CHD.