Note: This release is based on a news release issued by the National Institute of Dental and Craniofacial Research
Photo: Jeff Murray, M.D., the study's senior author and professor of pediatrics in the UI Roy J. and Lucille A. Carver College of Medicine. Click here for a high-resolution version of the image.
Audio: Listen to Jeff Murray answer questions about his research here.
Jan. 3, 2007
Genetic Inability To Detoxify Cigarette Smoke Increases Cleft Lip Risk
A fetus that lacks both copies of a gene involved in detoxifying cigarette smoke and whose mother smokes during the pregnancy has a substantially increased risk of developing a cleft lip and/or palate, according a University of Iowa-led international study.
About 25 percent of babies of European ancestry and up to 60 percent of those of Asian ancestry lack both copies of the gene, which is called GSTT1. The finding is believed to mark the first time a gene-environment interaction in clefting has been documented at the molecular level. The study, which appears in the January issue of the American Journal of Human Genetics, was funded by the National Institute of Dental and Craniofacial Research (NIDCR), part of the National Institutes of Health.
"If a pregnant woman smokes 15 cigarettes or more per day, and her fetus doesn't have any working copies of the GSTT1 gene, then the chances of the fetus developing a cleft increase nearly 20 fold," said Jeff Murray, M.D., the study's senior author and professor of pediatrics in the UI Roy J. and Lucille A. Carver College of Medicine with joint appointments in pediatric dentistry in the College of Dentistry, biology in the College of Liberal Arts and Sciences, and epidemiology in the College of Public Health.
"We've known for years that complex traits such as cleft lip and palate are caused by the interactions between genes and the environment," said Murray, who also is the Roy J. Carver Chair in Perinatal Health. "The pregnant mother who smokes provides a toxic environmental exposure, which can then be greatly amplified by the genetics of the fetus to produce the cleft.
"We hope this finding will give families further motivation to stop smoking during pregnancy," he added.
Without the functioning gene, a fetus cannot remove the toxins that may be transferred across the placenta when the mother smokes.
In the United States, about one in every 600 babies is born with isolated, also called nonsyndromic, cleft lip and/or palate. Although the condition is largely correctable with several surgeries, the condition can take an emotional and financial toll on families.
Murray said the bulk of the research was carried out by Min Shi, Ph.D., a former UI graduate student in biology who is now a researcher at the National Institute of Environmental Health Sciences.
"Min was particularly capable in carrying out both the laboratory benchwork and conducting the statistical analysis to bring together data on more than 5,000 individuals," Murray said.
The UI teamed with colleagues in Denmark to assemble a list of 16 genes of interest, each of which encode proteins that plug into various pathways involved in detoxifying dangerous chemicals.
"We picked genes that previous evidence showed either are directly involved in cigarette smoke toxicity or are major players in general toxicity management in people," said Kaare Christensen, a scientist at the University of Southern Denmark in Odense and a lead author on the paper.
Because these genes can vary considerably from person to person, the team wanted to see which variations might adversely affect a person's ability to break down the toxic products of cigarette smoke.
Using an existing database of 1,244 children with clefts, as well as their parents and siblings, the scientists analyzed 5,000 DNA samples. Data from participating families in Denmark and Iowa helped the team independently confirm the findings. The Iowa data was gathered through the Iowa Registry for Congenital and Inherited Disorders, directed by Paul Romitti, Ph.D.
The researchers also used the free-access NIDCR-funded COGENE project, a comprehensive online database of genes expressed throughout the various stages of development. Working closely with Mike Lovett at Washington University in St Louis, one of COGENE's founders, the team used the database to focus on genes that are both expressed and switched on in craniofacial structures during the first five to 12 weeks of fetal development, when cleft lip and/or palate occurs.
The data from Iowa and Denmark helped reveal that pregnant women who smoked and also carried fetuses that lacked the GSTT1 enzyme were much more likely to give birth to a baby with a cleft.
"It may be that be that the lip and palate can form normally without GSTT1," said Murray. "But when the chemicals in cigarette smoke challenge the normal development of these structures, fetuses that lack the gene are at a distinct disadvantage."
Murray said he and his collaborators will continue their genetic analyses.
"We now have data from about 350 genes on this cohort of families," he said. "It's certainly a more complicated analysis to perform, but we're working our way through it and hope to have some very interesting data in the months ahead."
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