青年科学工作者论坛2008年第4期

《卫生研究》--2008年第四期 CBS基因变异与血清同型半胱氨酸水平及先天性心脏病的关系研究

CBS基因变异与血清同型半胱氨酸水平及先天性心脏病的关系研究

朱文丽宋晓明李孟忆刀京晶李书琴[1] 李勇²

北京大学医学部公共卫生学院营养与食品卫生学系，北京 100083

摘要：目的 探讨核心家庭胱硫脒b-合酶（CBS）基因变异与子代发生先天性心脏病（CHDs）的关系。方法选择辽宁省234名CHDs患者（男116人，女118人）及其生物学父母作为病例组；选取同地区无出生缺陷病史及家族史的136名正常人（男78人，女58人）及其生物学父母作为对照组。所有研究对象均采集血样，提取血凝块DNA，分别以PCR和PCR-ARMS方法检测CBS基因844ins68和G919A位点基因型；对部分家庭的母亲和子代以荧光免疫偏振法检测血清tHcy水平。结果本研究对象各组人群CBS基因844ins68和G919A位点基因型分布已达到Hardy-Weinberg遗传平衡。CBS 844ins68位点分析表明，与纯合野生型（DD）相比，母亲、父亲、子代杂合子（DI）的比值比［ORs（95％CI）］值分别为14.19(2.21, 591.52) 、4.37(1.24, 23.47)和4.77(1.38, 25.37)。CBS基因G919A位点分析表明，与GG基因型相比，杂合子GA和纯合子AA的ORs（95％CI）值分别为0.45(0.23, 0.87) 和0.34(0.11, 1.01)；母亲GA、父亲GA和AA基因型携带者其子代罹患先心病的危险性均明显降低，ORs（95％CI）值分别为0.44(0.23, 0.84) 、0.54(0.29, 1.00) 和0.24(0.08, 0.71)。基因型联合分析表明，与无危险等位基因的基因型组合（0组）相比，母亲、父亲、子代携带2个危险等位基因者（组2）的ORs（95％CI）值分别为4.32(1.07, 20.66)、3.43(0.88, 13.71)和8.62(1.69, 82.72)，且均有统计学意义。不同组别血清tHcy水平比较表明，病理组与对照组tHcy水平无明显差异，CBS不同基因型间tHcy水平差异亦无显著性（P>0.05）。结论 CBS基因844ins68位点杂合子（DI）以及G919A位点突变等位基因（A）与先心病高危险性有关，但对血清tHcy水平无明显影响。

关键词：先天性心脏病胱硫醚β-合酶同型半胱氨酸基因变异

中图分类号：R541.1 Q754

Associations of CBS gene variations with serum homocysteine level and congenital heart defects

ZHU Wenli, SONG Xiaoming, LI Mengyi, DAO Jingjing, et al.

Department of Nutrition and Food Hygiene, Peking University Health Science Center, Beijing 100083, China

Abstract: Objective We investigated the relationship between two common CBS gene variations and CHDs in a nuclear family-based study. Methods 234 Chinese CHDs patients and their biological parents were collected as case groups. And another 136 normal individuals and their parents were collected as controls. By PCR and PCR-ARMS methods the CBS gene 844ins68 and G919A variations were analyzed. The serum total homocysteine (tHcy) concentration were detected by Fluorescence Polarization Immunoassay. Results CBS 844ins68 variation was associated with high risk of CHDs, the odds ratios (ORs) between heterozygotes (DI) versus wild homozygotes (DD) were 14.19(95％CI: 2.21-591.52), 4.37(95%CI: 1.24-23.47) and 4.77(95％CI: 1.38-25.37) in mothers, fathers and offspring respectively (P<0.05). CBS G919A was associated significantly with low risk of CHDs. The ORs between heterozygotes (GA) and mutant homozygotes (AA) versus wild homozygotes (GG) were 0.45(95％CI: 0.23-0.87) and 0.34(95％CI: 0.11-1.01) in offspring (P<0.05). And the parents carrying GA and AA genotypes also had lower risk of CHDs. For both of above two loci, the significant relations occurred especially in ventricular septal defect subgroup. Genotype combination analysis showed the more risk alleles (I and G) the family members carried, the higher risk the offspring had for the happening of CHDs. And the serum fasting tHcy concentration were not significantly different among various groups and genotypes.

Conclusion CBS gene 844ins68 and G919A variations in nuclear families were associated with risk of CHDs in offspring.

Key words: congenital heart defects, cystathionine beta-synthase, homocysteine, gene variation

基金项目：国家自然科学基金面上项目（No.30600676）和教育部“新世纪优秀人才支持计划”（No.NCET-07-0034）

作者简介：朱文丽，女，博士，副教授，研究方向：营养与疾病，E-mail：zhuwenli@hsc.pku.edu.cn

1中国医科大学附属第二医院

2通讯作者