Shaw Gary M, Iovannisci David M, Yang Wei, Finnell Richard H, Carmichael Suzan L, Cheng Suzanne, Lammer Edward J
March of Dimes Birth Defects Foundation, California Birth Defects Monitoring Program, Berkeley 94710, USA.
Am J Med Genet A. 2005 Sep 15;138(1):21-6. doi: 10.1002/ajmg.a.30924.
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 gene-only 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.
研究人类圆锥动脉干缺陷病因中可能存在的基因多态性以及基因 - 环境相互作用是一种审慎的研究方法。在本研究中，我们探讨了32个单核苷酸多态性（SNP）对圆锥动脉干缺陷风险的基因单独效应和基因 - 环境效应。携带这些SNP的基因参与五个致病过程之一，即同型半胱氨酸代谢、凝血、细胞 - 细胞相互作用、炎症反应和血压调节。我们使用了来自加利福尼亚州一项基于人群的病例对照访谈研究（1987 - 1988年出生队列）的DNA样本和数据。我们采用了多位点等位基因特异性杂交测定法。通过对155例患有圆锥动脉干缺陷的婴儿（病例）和437例无畸形的婴儿（对照）进行基因分型来确定等位基因变体。在这32个SNP中，4个与2或更高的比值比相关，2个与0.5或更低的比值比相关。这4个SNP分别是：F2 G20210A（凝血酶原），比值比为2.5（95%置信区间：0.9 - 7.0）；F7启动子（-323）10-bp缺失/插入，比值比为2.3（0.8 - 6.8）；ITGB3 leu33pro（血小板糖蛋白IIIa），比值比为2.2（0.9 - 5.7）；NPPA T2238C（心钠素前体肽）,比值比为2.9（0.8 - 10.1）。两个SNP与风险降低相关：TNF（肿瘤坏死因子，G（-376A））和ADD1 gly460trp（α - 内收蛋白），比值比分别为0.5（0.1 - 2.3）和0.5（0.2 - 1.9）。对母亲受孕前维生素使用与MTHFR基因型之间潜在基因 - 营养素相互作用的分析表明，即使母亲未使用含叶酸的多种维生素补充剂，CT或TT基因型也不会增加婴儿圆锥动脉干缺陷的风险。对NOS3基因与母亲吸烟之间潜在风险相互作用的分析显示，有一些证据表明，与母亲未吸烟且基因型为野生型的婴儿相比，母亲在受孕前吸烟且具有NOS3 A（-922G）或NOS3 glu298asp变异等位基因之一的婴儿患圆锥动脉干缺陷的风险更高。我们的结果为某些出生缺陷的生物学相关候选基因的遗传变异参与其中提供了一些支持，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似乎是圆锥动脉干缺陷的一个良好候选基因，值得进一步研究。
