Gastroschisis: maternal smoking and genetic variation

Institution:	Children's Hospital Oakland Research Institute
Investigator(s):	Edward Lammer, M.D.
Award Cycle:	2007 (Cycle 16)	Grant #: 16RT-0086	Award: $668,429
Subject Area:	General Biomedical Science
Award Type:	Research Project Awards

Abstracts

Initial Award Abstract

Several recent investigations have linked tobacco smoking during pregnancy with higher risk to deliver a baby with gastroschisis, a severe birth defect in which there is a hole in the abdominal wall near the umbilical cord, allowing intestines and other organs to spill outside of the body cavity. Gastroschisis is also one of the few birth defects whose frequency has been increasing-- essentially doubling in frequency over a generation --which has raised alarms about its underlying causes. Gastroschisis is also notable for being more frequent among young mothers. We recently completed a small pilot investigation of California infants and found that smoking mothers doubled their chances of delivering an infant with gastroschisis, compared to non-smokers. The results also suggested a dose-response effect, that is, higher risk among the greater smokers. Further, we found some evidence for genetic susceptibility for some babies -- that the risk to be born with gastroschisis when a mother smoked was even higher when the baby inherited a less common type (a genetic variant) of a gene involved either in blood pressure regulation in the developing fetus or a gene involved in cell adhesion; a property that is essential for cells to link tightly to others as the babies tissues are forming. These processes, blood pressure regulation and adhesion of cells within tissues, are both thought to be involved in the aberrant process that results in a baby being born with gastroschisis. Our investigation was the first to provide clues as to the types of genes that might contribute to gastroschisis. The purposes of the proposed research are to continue and to enlarge upon our investigations of risks for gastroschisis caused by tobacco exposures during pregnancy, both maternal smoking and secondhand smoke. Further, we plan to measure the contributions of genetic susceptibility to smoking-induced gastroschisis by investigating differences in mothers and babies inherited ability to detoxify toxins in tobacco smoke, specifically a group of toxic chemicals called aromatic and heterocyclic amines. Our proposed research program will use interview data from mothers whose infants participate in the National Birth Defects Prevention Study (NBDPS), a nine-state research study of infants delivered with 30 major birth defects, including gastroschisis. This project is unique because of its unusually large and ethnically diverse study population. The California population who participate in NBDPS are mothers residing in 11 Central Valley counties centered on Fresno. For the proposed research, we will include infants delivered from 1997-2006 and enrolled in NBDPS, a study population of 758 infants with gastroschisis and 6664 non-malformed comparison babies (controls), to measure mothers' risks for delivering a baby with gastroschisis if they smoke during pregnancy or are exposed to secondhand tobacco smoke. Then, we will measure differences in DNA sequences of 12 genes among California NBDPS enrollees (178 babies with gastroschisis, 882 controls, and their mothers). The twelve genes are involved in detoxification of tobacco toxins or involved in processes that are important for closing the abdominal wall properly. We want to see if certain differences in DNA sequence translate into differences in risk for having a baby with gastroschisis when mothers smoke during pregnancy. This research reflects our long-term goal of identifying environmental and genetic causes of gastroschisis, a severe and life-threatening birth defect, so that strategies can be better developed for its prevention.

Publications

Gasttroschisis: a gene-environment model involing the VEGF-NOS3 pathway.
Periodical: American Journal of Medical Genetics			Index Medicus:
Authors: Lammer EJ, Iovannisci DM, Tom L, Schultz K, Shaw GM				ART
Yr: 2008	Vol:	Nbr: 148C	Abs:	Pg: 213-218

Gasttroschisis: a gene-environment model involing the VEGF-NOS3 pathway.
Periodical: American Journal of Medical Genetics			Index Medicus:
Authors: Lammer EJ, Iovannisci DM, Tom L, Schultz K, Shaw GM				ART
Yr: 2008	Vol:	Nbr: 148C	Abs:	Pg: 213-218