Orofacial Cleft Risk Is Increased with Maternal Smoking and Specific Detoxification-Gene Variants

Abstract

Maternal smoking is a recognized risk factor for orofacial clefts. Maternal or fetal pharmacogenetic variants are plausible modulators of this risk. In this work, we studied 5,427 DNA samples, including 1,244 from subjects in Denmark and Iowa with facial clefting and 4,183 from parents, siblings, or unrelated population controls. We examined 25 single-nucleotide polymorphisms in 16 genes in pathways for detoxification of components of cigarette smoke, to look for evidence of gene-environment interactions. For genes identified as related to oral clefting, we studied gene-expression profiles in fetal development in the relevant tissues and time intervals. Maternal smoking was a significant risk factor for clefting and showed dosage effects, in both the Danish and Iowan data. Suggestive effects of variants in the fetal NAT2 and CYP1A1 genes were observed in both the Iowan and the Danish participants. In an expanded case set, NAT2 continued to show significant overtransmission of an allele to the fetus, with a final P value of .00003. There was an interaction between maternal smoking and fetal inheritance of a GSTT1-null deletion, seen in both the Danish (P=.03) and Iowan (P=.002) studies, with a Fisher's combined P value of <.001, which remained significant after correction for multiple comparisons. Gene-expression analysis demonstrated expression of GSTT1 in human embryonic craniofacial tissues during the relevant developmental interval. This study benefited from two large samples, involving independent populations, that provided substantial power and a framework for future studies that could identify a susceptible population for preventive health care.

The I105V polymorphism in glutathione S-transferase P1, parental smoking and the risk for nonsyndromic cleft lip with or without cleft palate

“…Also, our results on the interaction between smoking and the I105V polymorphism are in line with data of Shi et al 25 The I105V polymorphism has also been associated with other health effects, such as lung cancer, bladder cancer and head and neck cancers. 30 -32 A common mechanism for polymorphisms in GSTP1 and smoking, in the aetiology of both cancer and orofacial clefts could be an increase in DNA damage due to the decreased detoxification of toxins and carcinogens.…”

“…25,29 Moreover, the case-parents design allows for the inclusion of both the parental and child data and for transmission equilibrium testing.…”

“…22 GSTP1 is important in the detoxification of toxic compounds present in tobacco smoke. 23 Just recently, Ramirez et al 24 and Shi et al 25 could not find an association between the GSTP1 I105V polymorphism and CL/P. However, in their unadjusted Danish data, they showed a two-fold increased CL/P risk in homozygous I105V foetuses with a smoking mother.…”

“…However, in their unadjusted Danish data, they showed a two-fold increased CL/P risk in homozygous I105V foetuses with a smoking mother. 25 Data on paternal smoking were not available in their study. Studies in knockout mice lacking gstp1 in a clean environment did not result in abnormal phenotypes.…”

The MSX1 allele 4 homozygous child exposed to smoking at periconception is most sensitive in developing nonsyndromic orofacial clefts

“…The eVect of the interaction between smoking and MSX1 might also be a result of gene-gene interaction with genes involved in detoxiWcation pathways. Results of a preliminary analysis suggested gene-gene interaction between MSX1 with CYP1B1, GSTM1, HIF1A, and SULT1A1 (Shi et al 2007).…”