Genetic susceptibilities in the association between maternal exposure to tobacco smoke and the risk of nonsyndromic oral cleft

Abstract

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 CYP1A1*2C 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 CYP1A1*2C 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.

Nicotine Exposure During Pregnancy Results in Persistent Midline Epithelial Seam With Improper Palatal Fusion

“…6,21,[39][40][41][42][43] Our results demonstrated that not only the Tgfβ-pathway genes but also other pathway-related genes might interact each other to regulate medial edge epithelium disintegration and complete palatogenesis (Supplementary Figure 2) In several studies, it has been suggested that there is a gene-environment interaction exists between smoking and TGFα expression for the induction of cleft palate. 8,25,[44][45][46][47][48][49] By using our microarray analysis and filtering cleft palate-related genes, we determined that nicotine is the highly susceptible element of smoking to induce down-regulation of TGFα, which may explain the palatal size abnormality observed in nicotine-treated pups. The presence of partial palatal seam in the newborn pups, which otherwise would have disintegrated at 14.5 to 16.5 dpc indicates: (1) the growth of the palate towards each other to form a seam, although in smaller size and shape, is not altered; (2) the genes that causes immaculate seam disintegration might have been effected by nicotine exposure.…”

Pharmacological safety during pregnancy: the principles of teratogenesis and teratogenicity of drugs

“…Кроме того, в ряде исследований изучалось влия-ние полиморфизма генов, вовлеченных в регулирование продукции связанных с табакокурением АФК. Аллельные варианты фетального гена CYP1A1, участвующего в акти-вации химических веществ табачного дыма, уменьша-ли риск возникновения оральных расщелин [50,51]. Вместе с тем для детоксицирующего фермента глутатион-S-трансферазы показано, что делеции в гене GSTT1 свя-заны с высоким риском развития оральных расщелин у детей, чьи матери курили [51,52].…”

“…Вместе с тем для детоксицирующего фермента глутатион-S-трансферазы показано, что делеции в гене GSTT1 свя-заны с высоким риском развития оральных расщелин у детей, чьи матери курили [51,52]. Однако, этот риск не наблюдался в случае делеций в гене GSTM1 [50,53]. Вари антные аллели в генах N-ацетилтрансферазы 2…”

8 Epidemiology of Cleft Lip and Palate

“…The most common risk factors reported were maternal exposure to tobacco products [81,82], alcohols [83], some viral infections [70], pesticides [84], and teratogens in the workplace or at home in early pregnancy [85][86][87]. Recognized teratogens included rare exposures such as phenytoin, valproic acid, thalidomide, and herbicides such as dioxin.…”