Chevrier Cécile, Bahuau Michel, Perret Claire, Iovannisci David M, Nelva Agnès, Herman Christine, Vazquez Marie-Paule, Francannet Christine, Robert-Gnansia Elisabeth, Lammer Edward J, Cordier Sylvaine
INSERM U625, Université de Rennes I, GERHM, Rennes, France.
Am J Med Genet A. 2008 Sep 15;146A(18):2396-406. doi: 10.1002/ajmg.a.32505.
Maternal tobacco consumption is considered as a risk factor for nonsyndromic oral clefts. However, this risk is moderate and may be modulated by genetic susceptibilities, including variants of the TGFA, TGFB3 and MSX1 developmental genes and polymorphisms of genes of the CYP (1A1, 2E1) and GST (M1, T1) families involved in metabolic pathways of tobacco smoke compounds. This French case-control study (1998-2001; 240 nonsyndromic cases, 236 controls) included a case-parent design (175 triad-families) that made it possible to distinguish the direct effect of the child's genotype and maternally mediated effects. Maternal smoking during the first trimester of pregnancy was not associated with the oral cleft risk in this population, but we observed statistically significant increased risks associated with maternal exposure to environmental tobacco smoke (ETS). No variant of any of the three developmental genes was significantly associated with oral cleft. The fetal CYP1A12C variant allele was associated with a statistically significant decreased risk, compared with the homozygous wild-type: relative risk = 0.48, 95% confidence interval: 0.2, 1.0. Suggestive reduced risks were also observed for the maternal CYP1A12C allele and the fetal CYP2E1*5 allele. The GSTM1 and GSTT1 deletions appeared to play no role. Our findings suggest some interactions, with the strongest between ETS and CYP1A1 or MSX1 and between maternal smoking and CYP2E1. We did not confirm the maternal smoking-infant GSTT1 null interaction previously reported by other investigators.
母亲吸烟被认为是非综合征性口腔裂隙的一个风险因素。然而，这种风险是中等程度的，并且可能受到遗传易感性的调节，包括TGFA、TGFB3和MSX1发育基因的变异以及参与烟草烟雾化合物代谢途径的CYP（1A1、2E1）和GST（M1、T1）家族基因的多态性。这项法国病例对照研究（1998 - 2001年；240例非综合征性病例，236例对照）采用了病例 - 父母设计（175个三联体家庭），使得区分儿童基因型的直接效应和母亲介导的效应成为可能。在该人群中，孕期头三个月母亲吸烟与口腔裂隙风险无关，但我们观察到母亲暴露于环境烟草烟雾（ETS）与统计学上显著增加的风险相关。三个发育基因中的任何一个变体均与口腔裂隙无显著关联。与纯合野生型相比，胎儿CYP1A12C变异等位基因与统计学上显著降低的风险相关：相对风险 = 0.48，95%置信区间：0.2，1.0。对于母亲的CYP1A12C等位基因和胎儿的CYP2E1*5等位基因，也观察到了提示性的风险降低。GSTM1和GSTT1基因缺失似乎没有作用。我们的研究结果表明存在一些相互作用，其中ETS与CYP1A1或MSX1之间以及母亲吸烟与CYP2E1之间的相互作用最强。我们没有证实其他研究者先前报道的母亲吸烟 - 婴儿GSTT1基因缺失的相互作用。
