Carmichael Suzan L, Shaw Gary M, Yang Wei, Iovannisci David M, Lammer Edward
March of Dimes Birth Defect Foundation/California Department of Health Services, California Birth Defects Monitoring Program, Berkeley, California 94710, USA.
Am J Med Genet A. 2006 Sep 15;140(18):1915-22. doi: 10.1002/ajmg.a.31402.
Increasing epidemiologic evidence suggests that genetic susceptibilities contribute to birth defects risks, especially in combination with other environmental exposures. This analysis examines the association of risk of limb deficiency defects with infant genotypes for N-acetyltranferases (NAT1, NAT2), glutathione-S-tranferases (GSTT1, GSTM1), and endothelial nitric oxide synthase (NOS3). The combined effects of infant genotype with maternal smoking and supplement intake were also examined. The authors genotyped 92 cases and 201 non-malformed controls from a California population-based case-control study (1987-1988 birth cohort). Several of the infant genotypes were associated with an at least 1.5-fold increased risk for limb deficiency defects: homozygosity for the NAT1 1088 and 1095 polymorphisms, heterozygosity and homozygosity for the NOS3 A(-922)G polymorphism, and heterozygosity (but not homozygosity) for the NOS3 G894T polymorphism. The authors hypothesized that the effects of selected variant genotypes in the presence of maternal smoking, or in the absence of supplement intake, may exceed effects of any of these factors alone. A few observations suggested that risks were greatest among infants with variant genotypes, whose mothers also smoked or did not take supplements, but most did not, and risk estimates were imprecise. Further studies exploring genetic susceptibility and combined gene-environment effects with respect to limb development will be important to continued improvement of our understanding of the etiology of limb anomalies.
越来越多的流行病学证据表明，遗传易感性会增加出生缺陷风险，尤其是与其他环境暴露因素共同作用时。本分析研究了肢体缺陷性出生缺陷风险与婴儿N-乙酰转移酶（NAT1、NAT2）、谷胱甘肽-S-转移酶（GSTT1、GSTM1）和内皮型一氧化氮合酶（NOS3）基因型之间的关联。还研究了婴儿基因型与母亲吸烟及补充剂摄入的联合作用。作者对一项基于加利福尼亚人群的病例对照研究（1987 - 1988年出生队列）中的92例病例和201例无畸形对照进行了基因分型。几种婴儿基因型与肢体缺陷性出生缺陷风险至少增加1.5倍相关：NAT1 1088和1095多态性的纯合子、NOS3 A(-922)G多态性的杂合子和纯合子，以及NOS3 G894T多态性的杂合子（而非纯合子）。作者推测，在母亲吸烟或不摄入补充剂的情况下，所选变异基因型的影响可能超过这些因素单独作用时产生的影响。一些观察结果表明，基因型变异且母亲也吸烟或不摄入补充剂的婴儿风险最高，但大多数情况并非如此，风险估计并不精确。进一步研究肢体发育方面的遗传易感性以及基因 - 环境联合效应，对于持续增进我们对肢体异常病因的理解非常重要。
