Copyright © 2007 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 80, Issue 1, 76-90, 1 January 2007
doi:10.1086/510518
Article
Orofacial Cleft Risk Is Increased with Maternal Smoking and Specific Detoxification-Gene Variants
Min Shia, e, Kaare Christensend, Clarice R. Weinberge, Paul Romittib, Lise Bathumd, Anthony Lozadac, Richard W. Morrisf, Michael Lovettg and Jeffrey C. Murraya, b, c, 
, 
a Department of Biology (M.S.; J.C.M.) University of Iowa, Iowa City;
b Department of Biology Epidemiology (P.R.; J.C.M.) University of Iowa, Iowa City;
c Department of Biology Pediatrics (A.L.; J.C.M.) University of Iowa, Iowa City;
d Center for the Prevention of Congenital Malformations, Institute of Public Health, University of Southern Denmark, Odense, (K.C.; L.B.) Durham, NC;
e Biostatistics Branch, National Institute of Environmental Health Sciences (M.S.; C.R.W.) Durham, NC;
f Department of Anesthesiology, Duke University (R.W.M.) Durham, NC;
g Department of Genetics, Washington University School of Medicine, St. Louis (M.L.)
Address for correspondence and reprints: Dr. Jeffrey C. Murray, University of Iowa, Department of Pediatrics, South Grand Avenue, 2182 ML, Iowa City, IA 52242. E-mail: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.
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