Clin Genet 2009: 75: 409–423 Printed in Singapore. All rights reserved # 2009 The Authors Journal compilation # 2009 Blackwell Munksgaard CLINICAL GENETICS doi: 10.1111/j.1399-0004.2009.01174.x Review Importance of gene–environment interactions in the etiology of selected birth defects Zhu H, Kartiko S, Finnell RH. Importance of gene–environment interactions in the etiology of selected birth defects. Clin Genet 2009: 75: 409–423. # Blackwell Munksgaard, 2009 It is generally understood that both genetic and environmental factors contribute to the highly complex etiology of structural birth defects, including neural tube defects, oral clefts and congenital heart defects, by disrupting highly regulated embryonic developmental processes. The intrauterine environment of the developing embryo/fetus is determined by maternal factors such as health/disease status, lifestyle, medication, exposure to environmental teratogens, as well as the maternal genotype. Certain genetic characteristics of the embryo/fetus also predispose it to developmental abnormalities. Epidemiologic and animal studies conducted over the last few decades have suggested that the interplay between genes and environmental factors underlies the etiological heterogeneity of these defects. It is now widely believed that the study of gene–environment interactions will lead to better understanding of the biological mechanisms and pathological processes that contribute to the development of complex birth defects. It is only through such an understanding that more efficient measures will be developed to prevent these severe, costly and often deadly defects. In this review, we attempt to summarize the complex clinical and experimental literature on current hypotheses of interactions between several select environmental factors and those genetic pathways in which they are most likely to have significant modifying effects. These include maternal folate nutritional status, maternal diabetes/obesity-related conditions, and maternal exposure to selected medications and environmental contaminants. Our goal is to highlight the potential gene–environment interactions affecting early embryogenesis that deserve comprehensive study. H Zhu, S Kartiko and RH Finnell Center for Environmental and Genetic Medicine, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA Key words: birth defects – folic acid – gene-environment interaction – neural tube defects – oral clefts – risk factors Corresponding author: H. Zhu, 2121 West Holcombe Rm. 418, Houston, Tx 77030, USA. Tel.: 713 677 7410; fax: 713 677 7784; e-mail: hzhu@ibt.tamhsc.edu Received 17 October 2008, revised and accepted for publication 9 January 2009 Birth defects are structural malformations present in a baby at or before birth affecting multiple dif- ferent organs. These defects can occur for many different reasons, including, but not limited to, genetic factors, exposure to environmental terato- gens, birth injury and, unfortunately, for most cases, unknown reasons. All women are at risk of having a baby with a congenital defect, regard- less of age, race, income or place of residence. In the USA, one of every 33 babies is born with a birth defect. The most common birth defects are congenital heart defects (CHD). About one in every 100–200 babies is born with a heart defect. The second most common type of birth defect is neural tube defect (NTD), which is the abnormal- ity of the spine (spina bifida) and brain (anenceph- aly). This defect can be extremely serious and is often life threatening. Craniofacial malformations, which include cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO), are also unfor- tunately common. There are many other common birth defects, such as hypospadias, which are rarely life threatening, although they often require com- prehensive medical and surgical attention. After years of study, we have come to appreciate the fact that the more common birth defects rep- resent complex traits with complex etiologies, which explains why very few genes that contribute to these defects are well known, despite the com- pletion of the Human Genome Project in 2003 (1–3). Substantial experimental and epidemiolog- ical data have demonstrated the importance of the 409