Facial clefts are one of the most common birth defects, affecting 2 out of every thousand babies. While the main causes of facial clefts are unknown, it is obvious that genetics plays a strong role. We've shown that families with one member affected by clefts are 40 times as likely to have a baby with a cleft. Environmental factors are also presumed to play a role in clefts. For example, clefts are easily produced in experimental animals exposed to teratogens. It is likely that humans vary in their genetic susceptibility to teratogens that cause clefts.? ? More than a decade ago, we anticipated that genetic susceptibility would become an important area of epidemiologic research at NIEHS. Accordingly, we selected facial clefts as a condition with both genetic and environmental causes, and we began in 1992 to develop a study to address the causes of clefts. In 1996 we launched a population-based case-control study of facial clefts in Norway. (Norway has one of the highest rates of cleft lip and palate in the world.) The field phase was completed in 2002. We enrolled 88% of all babies with facial clefts born in Norway between 1996 and 2002 (574 cases), and 76% of eligible control infants (763) selected randomly from the population. ? ? Mothers of these infants provided detailed information on occupational and other exposures during pregnancy, as well as on nutrition, personal habits and medical history. Biological samples for DNA analysis were collected from cases and controls as well as their mothers, fathers and siblings. These total nearly 4000 people. DNA has been extracted from these samples and is now ready for genetic analysis. In the course of carrying out this study, we developed and published a new statistical strategy for the analysis of genetic data in case-parent triads that has been widely adapted. We have demonstrated the application of this new method in a preliminary analysis of 262 case-parent triads. We are working intensively on analyses of folic acid, cigarette smoking and hazardous occupations, and their effects on the risk of facial clefts.? ? In our most recent analyses we have demonstrated a strong dose-response association between maternal cigarette smoking and facial clefts. In order to pursue a more biologically based understanding of this association, we completed DNA analysis of eleven genes associated with various aspects of cigarette metabolism, and searched for evidence of genetic susceptibility. We found no evidence that these metabolism genes play a role in the smoking effect on clefts. ? ? In a similar effort, we explored the effect of genes involved with the metabolism of folic acid. We recently showed that folic acid supplementation reduces the risk of cleft lip with or without cleft palate, although not the risk of cleft palate alone (which is a distinct birth defect in its embryologic development). We assessed nine genes that are involved in the metabolism of folic acid, in order to see whether the effect of folic acid supplementation may be stronger among certain groups of metabolically susceptible women. We found no evidence of such susceptibility.? ? The lack of evidence for gene-environment interaction in these two analyses points to the difficulties of identifying such interactions, and the need to extend genetic analyses to a much wider range of genes. We are currently participating in collaborative efforts to look at more than 1000 SNPs from candidate genes, and thereafter to explore whole genome scans of these biological samples.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES049027-12
Application #
7734450
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2008
Total Cost
$370,207
Indirect Cost
City
State
Country
United States
Zip Code
Skuladottir, Hildur; Wilcox, Allen; McConnaughey, Robert et al. (2014) First-trimester nonsystemic corticosteroid use and the risk of oral clefts in Norway. Ann Epidemiol 24:635-40
Johansen, Anne Marte W; Wilcox, Allen J; Lie, Rolv T et al. (2009) Maternal consumption of coffee and caffeine-containing beverages and oral clefts: a population-based case-control study in Norway. Am J Epidemiol 169:1216-22
Nguyen, Ruby H N; Wilcox, Allen J; Moen, Bente E et al. (2007) Parent's occupation and isolated orofacial clefts in Norway: a population-based case-control study. Ann Epidemiol 17:763-71
Harville, Emily W; Wilcox, Allen J; Lie, Rolv Terje et al. (2007) Epidemiology of cleft palate alone and cleft palate with accompanying defects. Eur J Epidemiol 22:389-95
Sivertsen, Ase; Lie, Rolv Terje; Wilcox, Allen J et al. (2007) Prevalence of duplications and deletions of the 22q11 DiGeorge syndrome region in a population-based sample of infants with cleft palate. Am J Med Genet A 143:129-34
Wilcox, Allen J; Lie, Rolv Terje; Solvoll, Kari et al. (2007) Folic acid supplements and risk of facial clefts: national population based case-control study. BMJ 334:464
Harville, Emily W; Wilcox, Allen J; Lie, Rolv Terje et al. (2005) Cleft lip and palate versus cleft lip only: are they distinct defects? Am J Epidemiol 162:448-53
Jugessur, Astanand; Lie, Rolv T; Wilcox, Allen J et al. (2003) Variants of developmental genes (TGFA, TGFB3, and MSX1) and their associations with orofacial clefts: a case-parent triad analysis. Genet Epidemiol 24:230-9
Jugessur, Astanand; Wilcox, Allen J; Lie, Rolv T et al. (2003) Exploring the effects of methylenetetrahydrofolate reductase gene variants C677T and A1298C on the risk of orofacial clefts in 261 Norwegian case-parent triads. Am J Epidemiol 157:1083-91
Jugessur, Astanand; Lie, Rolv T; Wilcox, Allen J et al. (2003) Cleft palate, transforming growth factor alpha gene variants, and maternal exposures: assessing gene-environment interactions in case-parent triads. Genet Epidemiol 25:367-74

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