The Solution is Research: Genes + Environment

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chromosome
cleft lip
cleft palate
DNA
Down syndrome
environment
exposure
gene
genetic
oral cleft

Past studies of birth defects have been hampered by limited perspective. Epidemiologic research—looking at occurrence patterns in a population—assumes that all individuals are equally susceptible to environmental exposures. Genetic studies—looking at biologic variation between individuals— tend to ignore environmental influences. In either case, misclassification of conditions (for example, lumping together defects with different origins) can mask links between birth defects and their causes.

The California Birth Defects Monitoring Program is at the forefront of a new era of birth defects research, combining both genetic and environmental information. Recent studies take advantage of genetic discoveries accompanying the Human Genome Project as well as technologic advances in measuring exposures. When combined with in-depth interview data, biologic testing often clarifies associations. Some of the techniques we use include:

	DNA testing. Study subjects are often asked to swab the inside of their mouths to painlessly collect cells for genetic analysis. These results help supplement exposure information gained from interviews.

	Biomarkers. Saved blood samples from prenatal or newborn screening tests can be analyzed for substances that indicate the presence of infection or other environmental exposures at the time of fetal development

	Refined classification. Genetic tests can help distinguish different types of birth defects, guiding the search for clues. For example, determining whether the extra chromosome seen in Down syndrome came from the egg or sperm can focus attention to exposures in either the mother or father.

One example of gene-environment interactions was uncovered in a study of smoking and oral clefts. Past research had been confusing— some investigators found an association between clefts and tobacco use, but others did not. Our study combined interview data detailing mothers' smoking habits with DNA testing to determine the infants' status for a particular gene, transforming growth factor alpha (TGFA). We found:

	Mothers who smoked in early pregnancy were more likely to have babies with oral clefts. Risk increased with the amount smoked—heavy smokers had double the risk of nonsmokers.

	Babies with a rare form of the TGFA gene were slightly more likely to have isolated cleft palate but not cleft lip.

	The combination of both factors—gene status and smoking—created a huge jump in risk. Babies with the uncommon gene form whose mothers smoked had a 6-10 times higher risk of oral clefts