Risks of human conotruncal heart defects associated with 32 single nucleotide polymorphisms of selected cardiovascular disease-related genes
Risks of human conotruncal heart defects associated with 32 single nucleotide polymorphisms of selected cardiovascular disease-related genes
复制标题
DOI：
10.1002/ajmg.a.30924
复制
发表时间：
2005-09-15
影响因子：
2
通讯作者：
Lammer, EJ
中科院分区：
文献类型：
--
作者：
Shaw, GM;Iovannisci, DM;Lammer, EJ
研究人类圆锥干畸形病因学中可能的遗传多态和基因-环境交互作用是一种谨慎的研究方法。在这项研究中，我们探索了32个单核苷酸多态(SNPs)对圆锥干缺陷风险的遗传和基因环境影响。携带这些SNPs的基因参与了同型半胱氨酸代谢、凝血、细胞-细胞相互作用、炎症反应和血压调节五个致病过程之一。我们使用了一项基于加州人群的病例对照访谈研究(1987-1988出生队列)的DNA样本和数据。我们采用了多位点等位基因特异性杂交试验。通过对155例圆锥干缺陷儿(病例组)和437例无畸形婴儿(对照组)进行基因分型，确定等位基因变异。在32个SNP中，4个的优势比为2或更高，2个的优势比为0.5或更低。这4个SNP分别是F2G20210A(凝血酶原)，其优势比为2.5(95%可信区间；0.9-7.0)；F7启动子(-323)10bpdel/ins，其优势比为2.3(0.8-6.8)；ITGB3 leu33Pro(血小板膜糖蛋白IIIa)，其优势比为2.2(0.9-5.7)；NPPA T2238C(心钠素前体)，其优势比为2.9(0.8-10.1)。有两个SNP与风险降低相关：肿瘤坏死因子(肿瘤坏死因子，G(-376A))和Add1 Gly460trp(α内收蛋白)，其优势比分别为0.5(0.1-2.3)和0.5(0.2-1.9)。研究母亲孕周维生素使用和MTHFR基因类型之间潜在的基因-营养交互作用的分析没有表明，即使母亲没有使用含有叶酸的多种维生素补充剂，CT或TT基因也不会导致婴儿圆锥体干缺陷的风险。研究了NOS3基因与母亲吸烟之间潜在交互作用的分析显示，与母亲不吸烟且基因类型为野生型的婴儿相比，母亲吸烟且NOS3A(-922G)或NOS3Glu298asp变异等位基因之一的婴儿患圆锥干缺陷的风险更高。我们的结果为某些出生缺陷的生物相关候选基因的遗传变异提供了一定的支持，这些出生缺陷的发病机制可能与血管张力或完整性改变有关。特别是，NPPA似乎是圆锥干缺陷的一个很好的候选基因，值得进一步研究。(C)2005年Wiley-Liss，Inc.
Investigating possible genetic polymorphisms and gene-environment interactions in the etiology of human conotruncal defects is a prudent research approach. In this study we explore geneonly and gene-environment effects of 32 single nucleotide polymorphisms (SNPs) on conotruncal defect risks. The genes bearing these SNPs participate in one of five pathogenetic processes, homocysteine metabolism, coagulation, cell-cell interaction, inflammatory response, and blood pressure regulation. We used DNA samples and data from a California population-based case-control interview study (1987-1988 birth cohort). We employed a multilocus allele-specific hybridization assay. Allelic variants were determined by genotyping 155 infants with conotruncal defects (cases) and 437 infants without malformations (controls). Among the 32 SNPs, four were associated with odds ratios of 2 or more, and two with odds ratios of 0.5 or less. The four SNPs were F2 G20210A (prothrombin) with an odds ratio of 2.5 (95% confidence interval; 0.9-7.0), F7 promoter (-323) 10-bp del/ins with an odds ratio of 2.3 (0.8-6.8), ITGB3 leu33pro (platelet glycoprotein IIIa) with an odds ratio of 2.2 (0.9-5.7), and NPPA T2238C (atrial natriuretic precursor peptide) with an odds ratio of 2.9 (0.8-10.1). Two SNPs were associated with decreased risks: TNF (tumor necrosis factor, G (-376A)) and ADD1 gly460trp (alpha adducin) with odds ratios of 0.5 (0.1-2.3) and 0.5 (0.2-1.9), respectively. Analyses that investigated a potential gene-nutrient interaction between maternal periconceptional vitamin use and MTHFR genotypes did not indicate that the CT or TT genotype contributed to conotruncal defect risk in infants even in the absence of maternal use of multivitamin supplements with folic acid. Analyses that investigated a potential interaction on risk between NOS3 genes and maternal cigarette smoking, revealed some evidence for higher risk of conotruncal defects in infants whose mothers smoked cigarettes periconceptionally and who had one of the variant alleles for NOS3 A(-922G) or NOS3 glu298asp compared to those infants whose mothers did not smoke and whose genotypes were wild-type. Our results provide some support for involvement of genetic variation of biologically relevant candidate genes for some birth defects whose pathogenesis may be related to altered vascular tone or integrity. In particular, NPPA appears to be a good candidate gene for conotruncal defects and warrants further investigation. (c) 2005 Wiley-Liss, Inc.