Grantee Research Project Results
Final Report: Gene-Environment Interaction and Human Malformations
EPA Grant Number: R828292Title: Gene-Environment Interaction and Human Malformations
Investigators: Shaw, Gary M. , Loffredo, Christopher A. , Finnell, Richard H. , Lammer, Edward J. , Carmichael, Suzan L. , Torfs, Claudine P.
Institution: California Birth Defects Monitoring Program , Public Health Institute , Children’s Hospital Oakland Research Institute , Texas A & M University , Georgetown University
Current Institution: California Birth Defects Monitoring Program , Children’s Hospital Oakland Research Institute , Georgetown University , Public Health Institute , Texas A & M University
EPA Project Officer: Aja, Hayley
Project Period: July 1, 2000 through June 30, 2005 (Extended to September 30, 2006)
Project Amount: $3,373,557
RFA: Genetic Susceptibility and Variability of Human Malformations (1999) RFA Text | Recipients Lists
Research Category: Human Health
Objective:
The goal of our research program was to determine whether an association exists between gene variants and specific exposures in their contribution to selected congenital anomalies. The specific aims were to: (1) analyze if genetic variations in infant and maternal genes involved in biotransformation and detoxification modify risks of malformations, in the presence or absence of selected maternal exposures to toxicants; (2) analyze if genetic variations in infant or maternal folate-pathway genes modify risks of malformations, in the presence of variations in maternal folate intakes; and (3) analyze if genetic variations in infant genes associated with vascular development and function modify risks of malformations, in the presence or absence of maternal exposures to vasoactive chemicals. The case-control research design includes 5,000 cases and controls and focuses on these malformations: neural tube defects, selected heart malformations, orofacial clefts, limb defects, gastroschisis, and intestinal atresias. The analytic plan will combine maternal interview data with multiplex polymerase chain reaction-based genotyping for more than 40 candidate genes on more than 7,200 samples.
Summary/Accomplishments (Outputs/Outcomes):
During the course of this 5-year research program, no revisions were made to our originally proposed three aims. Each specific aim has been completed, and in several circumstances, the scientific research has far exceeded that which was originally proposed. These aims and a summary of the scientific highlights follow.
Aim 1–To Analyze if Genetic Variations in Infant and Maternal Genes Involved in Biotransformation and Detoxification Modify Risks of Malformations, in the Presence or Absence of Selected Maternal Exposures to Toxicants
Highlights of Findings Associated With Aim 1. Among birth defects of unknown etiology, we suspect that maternal and embryonic susceptibility factors (genetically determined) may interact with environmental exposures to increase risks. Such interactions are difficult to identify and measure in human studies. Utilizing modern molecular genetic methods, we developed a research model that looked at environmental exposures and how they may interact with genetic variation of host susceptibility factors. We chose one of the most frequent environmental exposures during pregnancy, tobacco smoking, to develop this model. Toxins in tobacco smoke enter maternal blood, cross the placenta to reach the embryo, and have the potential to adversely affect developmental processes. Cigarettes contain N-nitroso compounds and polycyclic aromatic hydrocarbons (PAHs), many of which are known or suspected teratogens in laboratory animals. Teratogenesis, like cancer, may be initiated by chemical adducts, such as those in tobacco smoke, covalently bonding to developmentally expressed proteins and/or DNA. Tobacco-related teratogens may disrupt proteins expressed during human embryogenesis or cause somatic DNA mutations, thus leading to developmental toxicity. Because the mother and embryo must detoxify such chemicals, genetic variation of metabolic biotransformation of xenobiotics by placental or embryonic tissues may be an important determinant of embryotoxicity in humans. This interindividual variation in genetic susceptibility is a recognized principle of developmental toxicology. A fetus may be more susceptible to tobacco-related toxins if it has a variant form of a biotransforming (xenobiotic metabolizing) enzyme that has unusually low activity or unusually high activity. Slower biotransformation may result in longer exposure to the proximate toxin, or exposure to a higher dose, whereas unusually rapid biotransformation may produce greater amounts of highly reactive intermediate chemicals that are more toxic than the parent compound. This has been suggested for infants of smoking mothers, for whom placental oxidation activities for metabolizing PAHs were observed to be lower in infants with major malformations than in nonmalformed infants whose mothers smoked during pregnancy.
We explored a number of birth defect phenotypes and xenobiotic enzyme genotypes. Here we highlight findings associated with orofacial clefts. Details of these findings and details about other work associated with this aim can be found in the publications listed below.
Some important results from our investigations of genetic variation of biotransformation enzymes involved interactions between maternal smoking, N-acetyltransferase 1 (NAT1), and two glutathione-S-transferases (GSTT1 and GSTM1). Although smoking was independently associated with increased risks for both isolated cleft lip with or without cleft palate (CLP) and isolated cleft palate (CP), no independent associations were found for NAT1 1088 or 1095 genotypes. Infant NAT1 1088 and 1095 polymorphisms, however, were strongly associated with the risk of clefts among smoking mothers; infants with NAT1 1088 genotype AA versus TT (odds ratio [OR] = 3.9; 95% confidence interval (CI) 1.1–17) and with NAT1 1095 genotype AA versus CC (OR = 4.2; 95% CI 1.2–18). These results suggest that maternal smoking during pregnancy increases risk for orofacial clefts particularly among smokers whose fetuses have polymorphic variants of NAT1. For analyses of the glutathione-S-transferase genes, we investigated polymorphisms in which both copies of the GST gene were completely deleted (homozygous null). Lack of GSTT1 or GSTM1 function was not associated with increased risk for a cleft. However, if a mother smoked during pregnancy and her fetus was homozygous null for GSTT1, we found a three-fold increased risk of isolated cleft lip plus or minus cleft palate [OR = 2.9 (95% CI 1.2-7.2)]. For fetuses who were homozygous null for GSTM1 and whose mothers smoked any amount during pregnancy, we found a smaller increased risk for isolated cleft lip plus or minus cleft palate [OR = 1.8 (95% CI 1.1-2.9)], but a nearly seven-fold increased risk among women who smoked ≥ 20 cigarettes/day [OR = 6.8 (95% CI 2.0-23.7)]. Combined absence of GSTM1 and GSTT1 genes was associated with a nearly six-fold increased risk for cleft lip among infants delivered of smoking mothers. Similar analyses of polymorphisms of NAT2 and CYP2D6 genes showed no interactions with maternal smoking on risk of orofacial clefts. Our results suggest that maternal smoking during pregnancy increases risks for isolated orofacial clefts among smokers, and these risks are significantly higher among susceptible infants who inherited poorly functioning biotransformation enzymes for detoxifying tobacco-derived chemicals. This research represents one of the first demonstrations of gene-environment interaction as a cause of birth defects.
We also have explored other polymorphisms; for example, we completed CYP2D6 genotyping (3 alleles) and analyses. The “slow” phenotype was surprisingly uncommon in our population, about 3 percent. Slow CYP2D6 phenotype was not independently associated with cleft risk, nor did we find any evidence of interaction with parental smoking during pregnancy.
Our hypotheses and analyses also have led us toward other important explorations. For example, in a case-control study that used a classification approach that relies on assessment of occupational tasks by an industrial hygienist, we investigated whether women’s periconceptional occupational exposures increased risks of delivering infants with CP, CLP, conotruncal heart defects, or limb deficiencies. For CP and CLP, exposures were further considered in the presence/absence of infant genetic variants associated with polymorphisms of GSTM1, GSTT1, NAT1, and NAT2. The study population included stillbirths and livebirths among 1987-1989 California births. Reported occupational tasks were assigned to a priori defined exposure categories: 74 chemical groups and 9 “end-use” chemical groups. ORs of ≥1.5 were observed for a relatively small number of all possible exposure-defect comparisons. Risks associated with end-use groups revealed ORs of ≥ 1.5 for exposures to dyes and pigments (conotruncal heart defects and CP), propellants (CP), and insecticides (conotruncal heart defects and CP). Numerous ORs ≥ 2.5 were observed in comparisons that investigated the combined effects of exposures and homozygous mutant genotypes, particularly for CP defects. Although some potential associations were observed between anomaly risks and chemical exposures, including some associations involving susceptible genotype-chemical combinations, most results suggested that maternal occupational chemical exposures do not contribute substantially to the occurrence of these anomalies in our California population.
Aim 2–To Analyze if Genetic Variations in Infant or Maternal Folate-Pathway Genes Modify Risks of Malformations, in the Presence of Variations in Maternal Folate Intakes
Highlights of Findings Associated With Aim 2. Several lines of evidence support an association between maternal use of a vitamin with folic acid in early pregnancy and a reduced risk for offspring with several congenital malformations. The underlying process by which folic acid facilitates this reduced risk, however, remains unknown. Our investigations in this research program sought to determine whether variations in genetic polymorphisms explained some of the underlying mechanism associated with folic acid. Our team has considerable experience conducting human epidemiologic research involving assessments of folic acid supplementation, nutritional intake, and combined gene-environment interactions. In this research program, we investigated numerous folate-related genotypes, including methylene tetrahydrofolate reductase (MTHFR), methionine synthase, methionine synthase reductase, reduced folate carrier 1 (RFC1), NAT1, protein carboxyl methyltransferase (PCMT),phosphatidylethanolamine N-methyltransferase(PEMT),nitric oxide synthase (NOS3),platelet-derived growth factor receptor alpha (PDGFRA), betaine-homocysteine methyltransferase 1 (BHMT1), betaine-homocysteine methyltransferase 2 (BHMT2), and thymidylate synthase. All of these findings now have been published in the peer-reviewed literature. A listing of the related publications and others is contained in this report. Here we summarize three of these investigations focusing on RFC1, NAT1, and MTHFR polymorphisms.
Reduced folate carrier 1 (RFC1). In an effort to describe the underlying processes between folic acid intake and spina bifida risk, we were the first to investigate gene variants in infants for a coding region single nucleotide polymorphism (SNP) of RFC1. Higher plasma folate levels have been observed in A80/A80 individuals compared to G80/G80. We investigated whether spina bifida risk was influenced by an interaction between RFC1 and maternal periconceptional use of vitamins containing folic acid. The percentages of case infants with the A80/A80, G80/G80, and G80/A80 genotypes were 27.2 percent, 28.0 percent, and 44.7 percent, respectively. The percentages of control infants were similar (26.1%, 29.3%, and 44.7%). ORs of 1.0 (95% CI 0.5-2.0) for the G80/G80 genotype and 1.1 (0.6-2.0) for the G80/A80 genotype were observed relative to the A80/A80 genotype. Among mothers who did not use vitamins, spina bifida risk was 2.4 (0.8-6.9) for infants with genotype G80/G80 compared to those with A80/A80 genotype. Among mothers who did use vitamins, the risk was 0.5 (0.1-3.1) for infants with the G80/G80 genotype. Thus, this study revealed modest evidence for a gene-nutrient interaction between infant RFC1 G80/G80 genotype and maternal periconceptional intake of vitamins containing folic acid on the risk of spina bifida. More recently, we have identified similar evidence for a gene-nutrient interaction between infant homozygosity for RFC1 G80, maternal vitamin use, and risk for neural crest cell-derived heart defects (conotruncal defects).
N-acetyltransferase 1 (NAT1). NAT1 is involved in the human folate catabolic pathway. We investigated several NAT1 variants to determine whether they influenced an association between maternal folic acid intake and risk for another neural-crest cell-derived structure, orofacial clefts. Our working hypothesis was that infants whose mothers did not use vitamins in the periconceptional period and who were genetically susceptible would be at elevated risk for isolated cleft lip with/without cleft palate relative to those infants whose mothers who used vitamins periconceptionally and who were less genetically susceptible. Infants homozygous for the variant alleles were classified as genetically susceptible (genotypes AA for NAT1 1088 and 1095). We genotyped isolated cleft cases and controls for NAT1 1088 and 1095 polymorphisms. The NAT1 1088 variant was not associated with substantial increased clefting risk alone or in combination with low maternal intake (no vitamin use) of folic acid. The 1095 AA genotype, however, was associated with a modestly elevated risk, OR = 1.6 (0.9-2.6). Our hypothesis predicted that this risk would be more elevated in the infants whose mothers did not use vitamins in the periconceptional period. The results indicated modest evidence for this hypothesis, revealing an OR of 2.6 (0.9-7.5) in infants whose mothers did not use vitamins and 1.4 (0.7-2.7) among those whose mothers did use vitamins.
Methylene tetrahydrofolate reductase (MTHFR). This particular polymorphism has been well-studied for many human diseases. We previously rigorously investigated whether the TT genotype was associated with spina bifida or orofacial clefting risk. We did not observe evidence for an association. Because some studies observed associations between MTHFR TT genotypes and risk of congenital heart defects, we explored the effects of that genotype for the suspected group of folate-responsive heart defects known as conotruncal defects. This genetic investigation was made possible by a unique genotyping panel of 32 SNPs made available to us by colleagues at Roche Molecular Systems. We describe other important genotypes from this SNPlex panel under findings for Aim 3. Our analyses did not find increased risks of conotruncal defects for MTHFR 677T. Our analyses also did not find increased risks of conotruncal defects associated with NOS3 298asp. Both MTHFR 677T and NOS3 298asp can lead to elevated serum homocysteine in the presence of lowered levels of folate intake.
In addition to the substantial contributions we have made in this research program involving “gene-environment” interactions, we have extended those contributions further by investigating “gene-environment-environment” interactions. For example, we explored whether a potential association between clefting risks and NOS3 gene variants could be modified by maternal cigarette smoking and vitamin supplement intake in the periconceptional period. Risk of orofacial clefting has been associated with maternal cigarette smoking and lack of folic acid supplementation (which results in higher plasma homocysteine concentrations). Because endothelial NOS3 activity influences homocysteine concentration and because cigarette smoking compromises NOS3 activity, we reasoned that genetic variation in NOS3 might interact with the two exposures, cigarette smoking and supplemental folic acid use on risk of orofacial clefts. We genotyped 244 infants with isolated cleft lip with or without cleft palate, 99 infants with isolated cleft palate, and 588 controls from a large population-based California case-control interview study (1987-1989 birth cohort)for two NOS3 polymorphisms: A(-922)G and G894T. Analyses of gene-only effects for each NOS3 SNP revealed a 60 percent increased risk for CLP among NOS3 A(-922)G homozygotes, OR = 1.6 (95% CI 1.0-2.6). We found some evidence for higher risk of CLP in infants whose mothers smoked cigarettes periconceptionally and who had a NOS3 -922G allele (e.g., OR = 2.5 [1.2-5.6] for homozygotes), but not for the 894T allele. For risk of CLP, we observed OR > 4 among mothers who smoked cigarettes, who did not use vitamins periconceptionally, and whose infants had at least one variant allele for each of these two NOS3 SNPs (i.e., OR = 4.6 [2.1-10.2] for A[-922]G and OR = 4.4 [1.8-10.7] for 894T). No similar patterns were observed for risk of cleft palate. Risks were not substantially different after adjusting for potentially confounding effects of maternal race/ethnic background.
Aim 3–To Analyze if Genetic Variations in Infant Genes Associated With Vascular Development and Function Modify Risks of Malformations, in the Presence or Absence of Maternal Exposures to Vasoactive Chemicals
Highlights of Findings Associated With Aim 3. As the above highlights of Aims 1 and 2 indicate, investigating possible genetic polymorphisms and gene-environment interactions in the etiology of human birth defects is a prudent research approach. For Aim 3, we explored gene-only and gene-environment effects of 32 SNPs on the risks of three birth defects, conotruncal defects, limb anomalies, and gastroschisis. The genes bearing these SNPs participate in one of five pathogenetic processes: homocysteine metabolism, coagulation, cell-cell interaction, inflammatory response, and blood pressure regulation. For conotruncal heart defects, we used DNA samples and data from a California population-based case-control interview study (1987-1988 birth cohort). We employed a multilocus allele-specific hybridization assay. Allelic variants were determined by genotyping 155 infants with conotruncal defects (cases) and 437 infants without malformations (controls). Among the 32 SNPs, four were associated with ORs of 2 or more, and two with ORs of 0.5 or less. The four SNPs were F2 G20210A (prothrombin) with an OR of 2.5 (95% CI; 0.9-7.0), F7 promoter with an OR of 2.3 (0.8-6.8), integrin beta 3 (ITGB3) (platelet glycoprotein IIIa) with an OR of 2.2 (0.9-5.7), and NPPA (T2238C, atrial natriuretic precursor peptide) with an OR of 2.9 (0.8-10.1). Two SNPs were associated with decreased risks: TNF (tumor necrosis factor, G [-376A]) and ADD1 gly460trp (alpha adducin) with ORs of 0.5 (0.1-2.3) and 0.5 (0.2-1.9), respectively. Analyses that investigated a potential gene-nutrient interaction between maternal periconceptional vitamin use and MTHFR genotypes did not indicate that the CT or TT genotype contributed to conotruncal defect risk in infants even in the absence of maternal use of multivitamin supplements with folic acid. Analyses that investigated a potential interaction on risk between NOS3 genes and maternal cigarette smoking revealed some evidence for higher risk of conotruncal defects in infants whose mothers smoked cigarettes periconceptionally and who had one of the variant alleles for NOS3 A(-922G) or NOS3 glu298asp compared to those infants whose mothers did not smoke and whose genotypes were wildtype. Our results provide some support for involvement of genetic variation of biologically relevant candidate genes for some birth defects whose pathogenesis may be related to altered vascular tone or integrity. In particular, NPPA appears to be a good candidate gene for conotruncal defects and warrants further investigation.
In a related study of limb anomalies, we investigated 29 SNPs of genes involved in homocysteine metabolism, coagulation, cell-cell interaction, inflammatory response, and blood pressure regulation. We genotyped 96 cases and 437 nonmalformed controls from a California population-based case-control study (1987-1988 birth cohort). Increased risk of limb anomaly was observed for three SNPs: heterozygosity for F5 Arg506Gln, with an OR of 2.5 (95% CI 1.0, 6.5); heterozygosity for TNF (-376)G>A , OR of 2.1 (0.7, 6.2); and homozygosity for NPPA 2238T>C, OR of 4.0 (1.1, 15.4). We hypothesized that effects of variant genotypes in the presence of maternal smoking, and/or in the absence of supplement intake, may exceed effects of any of these factors alone. In particular, findings for polymorphisms in SERPINE1, ITGA2, SELE, TNF, lymphotoxin alpha (LTA), NPPA, GNB3, and ADRB2 supported the hypotheses, both for smoking and for supplement intake. These results suggest involvement of genetic variation of biologically relevant candidate genes and gene-environment interaction, for some limb anomalies whose pathogenesis may be related to altered vascular tone or integrity.
We also investigated the birth defect, gastroschisis, whose underlying etiology is suspected to be through a mechanism of vascular disruption. Gastroschisis is a severe birth defect in which the infant is born with a portion of the intestines extruding through a small tear in the abdominal wall, usually to the right of the umbilical cord. In a case-control study of 57 cases of gastroschisis and 506 controls, we investigated the risks associated with the 32 SNPs noted above. Our logistic regression analyses, adjusted for maternal race/ethnic background, and using the homozygote wildtype as referent, showed that the following gene polymorphisms were associated with an increased risk for gastroschisis for heterozygotes: intercellular adhesion molecule-1 (ICAM1) gly241arg, (OR = 1.9; 95% CI 1.0-3.4); NOS3 glu298asp (OR = 1.9, 1.1-3.4); NPPA 2238>C (OR = 1.9, 1.1-3.4); and ADD1 gly460trp (OR = 1.5, 0.8-2.8). Additionally, for the NPPA and ADD1 SNPs, the homozygote variants had a significantly higher risk than the heterozygotes (OR = 7.5, 1.7-33.5 and OR = 4.9, 1.9-12.9, respectively). Three SNPs showed a strong interaction with maternal smoking. The risk for smokers with one or two variant alleles compared to nonsmokers with the wildtype allele were NOS3 (OR = 5.2, 2.4-11.4); ICAM1 (OR = 5.2, 2.1-12.7); and NPPA (OR = 6.4, 2.8-14.6). Our results provide important support to the hypothesis of a vascular compromise being part of a multifactorial etiology of gastroschisis involving both genes and environmental factors.
This funded program has resulted in both high quality and a large quantity of contributions to the worldwide literature on congenital malformation etiologies. Thus far, work associated either directly or indirectly with our research program has produced approximately 50 scientific manuscripts or presentations.
Journal Articles on this Report : 36 Displayed | Download in RIS Format
Other project views: | All 55 publications | 42 publications in selected types | All 41 journal articles |
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Blom HJ, Shaw GM, den Heijer M, Finnell RH. Neural tube defects and folate: case far from closed. Nature Reviews Neuroscience 2006;7(9):724-731. |
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Carmichael SL, Shaw GM, Yang W, Lammer EJ, Zhu H, Finnell RH. Limb deficiency defects, MSX1, and exposure to tobacco smoke. American Journal of Medical Genetics Part A 2004;125A(3):285-289. |
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Carmichael SL, Shaw GM, Iovannisci DM, Yang W, Finnell RH, Cheng S, Lammer EJ. Risks of human limb deficiency anomalies associated with 29 SNPs of genes involved in homocysteine metabolism, coagulation, cell-cell interactions, inflammatory response, and blood pressure regulation. American Journal of Medical Genetics Part A 2006;140A(22):2433-2440. |
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Carmichael SL, Shaw GM, Yang W, Iovannisci DM, Lammer E. Risk of limb deficiency defects associated with NAT1, NAT2, GSTT1, GSTM1, and NOS3 genetic variants, maternal smoking, and vitamin supplement intake. American Journal of Medical Genetics Part A 2006;140A(18):1915-1922. |
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Finnell RH, Shaw GM, Lammer EJ, Brandl KL, Carmichael SL, Rosenquist TH. Gene-nutrient interactions: importance of folates and retinoids during early embryogenesis. Toxicology and Applied Pharmacology 2004;198(2):75-85. |
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Graham Jr. JM, Shaw GM. Gene-environment interactions in rare diseases that include common birth defects. Birth Defects Research Part A: Clinical and Molecular Teratology 2005;73(11):865-867. |
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Gupta T, Yang W, Lovannisci D, Carmichal S, Stevenson D, Shaw G, Lammer E. Considering the vascular hypothesis for the pathogenesis of small intestinal atresia:A case control study of genetic factors. AMERICAN JOURNAL OF MEDICAL GENETICS PART A 2013;161A(4):702-710. |
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Iovannisci DM, Kupperman SO, Lloyd EW, Lammer EJ. The READIT™ assay as a method for genotyping NAT1*10 polymorphisms. Genetic Testing 2002;6(4):245-253. |
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Iovannisci DM, Ha TT, Shaw GM. Recovery of genomic DNA from residual frozen archival blood clots suitable for amplification and use in genotyping assays. Genetic Testing 2006;10(1):44-49. |
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Kuehl K, Loffredo C, Lammer E, Lovannisci D, Snaw G. Association of Congenital Cardiovascular Malformations with 33 Single Nucleotide Polymorphisms of Selected Cardiovascular Disease-Related Genes. BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY 2010;88(2):101-110. |
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Lammer EJ, Shaw GM, Iovannisci DM, Van Waes J, Finnell RH. Maternal smoking and the risk of orofacial clefts: susceptibility with NAT1 and NAT2 polymorphisms. Epidemiology 2004;15(2):150-156. |
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Lammer EJ, Shaw GM, Iovannisci DM, Finnell RH. Periconceptional multivitamin intake during early pregnancy, genetic variation of acetyl-N-transferase 1 (NAT1), and risk for orofacial clefts. Birth Defects Research Part A: Clinical and Molecular Teratology 2004;70(11):846-852. |
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Lammer EJ, Shaw GM, Iovannisci DM, Finnell RH. Maternal smoking, genetic variation of glutathione S-transferases, and risk for orofacial clefts. Epidemiology 2005;16(5):698-701. |
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Lu W, Volcik K, Zhu H, Wen S, Shaw GM, Lammer EJ, Finnell RH. Genetic variation in the proto-oncogene SKI and risk for orofacial clefting. Molecular Genetics and Metabolism 2005;86(3):412-416. |
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Lu W, Zhu H, Wen S, Laurent C, Shaw GM, Lammer EJ, Finnell RH. Screening for novel PAX3 polymorphisms and risks of spina bifida. Birth Defects Research Part A: Clinical and Molecular Teratology 2007;79(1):45-49. |
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Miller SP, Wu YW, Lee J, Lammer EJ, Iovannisci DM, Glidden DV, Bonifacio SL, Collins A, Shaw GM, Barkovich AJ, Ferriero DM. Candidate gene polymorphisms do not differ between newborns with stroke and normal controls. Stroke 2006;37(11):2678-2683. |
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Olshan AF, Shaw GM, Millikan RC, Laurent C, Finnell RH. Polymorphisms in DNA repair genes as risk factors for spina bifida and orofacial clefts. American Journal of Medical Genetics Part A 2005;135A(3):268-273. |
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Rull RP, Ritz B, Shaw GM. Validation of self-reported proximity to agricultural crops in a case-control study of neural tube defects. Journal of Exposure Science & Environmental Epidemiology 2006;16(2):147-155. |
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Shaw GM, Lammer EJ, Zhu H, Baker MW, Neri E, Finnell RH. Maternal periconceptional vitamin use, genetic variation of infant reduced folate carrier (A80G), and risk of spina bifida. American Journal of Medical Genetics 2002;108(1):1-6. |
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Shaw GM, Nelson V, Iovannisci DM, Finnell RH, Lammer EJ. Maternal occupational chemical exposures and biotransformation genotypes as risk factors for selected congenital anomalies. American Journal of Epidemiology 2003;157(6):475-484. |
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Shaw GM, Zhu H, Lammer EJ, Yang W, Finnell RH. Genetic variation of infant reduced folate carrier (A80G) and risk of orofacial and conotruncal heart defects. American Journal of Epidemiology 2003;158(8):747-752. |
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Shaw GM, Carmichael SL, Yang W, Selvin S, Schaffer DM. Periconceptional dietary intake of choline and betaine and neural tube defects in offspring. American Journal of Epidemiology 2004;160(2):102-109. |
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Shaw GM, Iovannisci DM, Yang W, Finnell RH, Carmichael SL, Cheng S, Lammer EJ. Endothelial nitric oxide synthase (NOS3) genetic variants, maternal smoking, vitamin use, and risk of human orofacial clefts. American Journal of Epidemiology 2005;162(12):1207-1214. |
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Shaw GM, Carmichael SL, Yang W, Schaffer DM. Periconceptional dietary intake of myo-inositol and neural tube defects in offspring. Birth Defects Research Part A: Clinical and Molecular Teratology 2005;73(3):184-187. |
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Shaw GM, Iovannisci DM, Yang W, Finnell RH, Carmichael SL, Cheng S, Lammer EJ. Risks of human conotruncal heart defects associated with 32 single nucleotide polymorphisms of selected cardiovascular disease-related genes. American Journal of Medical Genetics Part A 2005;138A(1):21-26. |
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Shaw GM, Carmichael SL, Laurent C, Rasmussen SA. Maternal nutrient intakes and risk of orofacial clefts. Epidemiology 2006;17(3):285-291. |
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Torfs CP, Christianson RE, Iovannisci DM, Shaw GM, Lammer EJ. Selected gene polymorphisms and their interaction with maternal smoking, as risk factors for gastroschisis. Birth Defects Research Part A: Clinical and Molecular Teratology 2006;76(10):723-730. |
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Volcik KA, Shaw GM, Lammer EJ, Zhu H, Finnell RH. Evaluation of infant methylenetetrahydrofolate reductase genotype, maternal vitamin use, and risk of high versus low level spina bifida defects. Birth Defects Research Part A:Clinical and Molecular Teratology 2003;67(3):154-157. |
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Volcik KA, Shaw GM, Zhu H, Lammer EJ, Finnell RH. Risk factors for neural tube defects: associations between uncoupling protein 2 polymorphisms and spina bifida. Birth Defects Research Part A: Clinical and Molecular Teratology 2003;67:158-161. |
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Volcik KA, Shaw GM, Zhu H, Lammer EJ, Laurent C, Finnell RH. Associations between polymorphisms within the thymidylate synthase gene and spina bifida. Birth Defects Research Part A: Clinical and Molecular Teratology 2003;67(11):924-928. |
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Zhang J, Zhu H, Yang W, Shaw GM, Lammer EJ, Finnell RH. Phosphatidylethanolamine N-methyltransferase (PEMT) gene polymorphisms and risk of spina bifida. American Journal of Medical Genetics Part A 2006;140A(7):785-789. |
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Zhu HP, Barber R, Shaw GM, Lammer EJ, et al. Is sonic hedgehog (SHH) a candidate gene for spina bifida? A pilot study. American Journal of Medical Genetics 2003;117A(1):87-88. |
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Zhu HP, Wicker NJ, Shaw GM, Lammer EJ, Hendricks K, Suarez L, Canfield M, Finnell RH. Homocysteine remethylation enzyme polymorphisms and increased risks for neural tube defects. Molecular Genetics and Metabolism 2003;78(3):216-221. |
R828292 (2003) R828292 (2004) R828292 (2005) R828292 (Final) |
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Zhu HP, Wicker NJ, Volcik K, Zhang J, Shaw GM, Lammer EJ, Suarez L, Canfield M, Finnell RH. Promoter haplotype combinations for the human PDGFRA gene are associated with risk of neural tube defects. Molecular Genetics and Metabolism 2004;81(2):127-132. |
R828292 (2004) R828292 (2005) R828292 (Final) |
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Zhu HP, Curry S, Wen S, Wicker NJ, Shaw GM, Lammer EJ, Yang W, Jafarov T, Finnell RH. Are the betaine-homocysteine methyltransferase (BHMT and BHMT2) genes risk factors for spina bifida and orofacial clefts? American Journal of Medical Genetics Part A 2005;135A(3):274-277. |
R828292 (2004) R828292 (2005) R828292 (Final) |
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Zhu HP, Yang W, Lu W, Zhang J, Shaw GM, Lammer EJ, Finnell RH. A known functional polymorphism (Ile120Val) of the human PCMT1 gene and risk of spina bifida. Molecular Genetics and Metabolism 2006;87(1):66-70. |
R828292 (2005) R828292 (Final) |
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Supplemental Keywords:
health effects, exposure, teratogen, metabolism, genetic predisposition, genetic polymorphisms, susceptibility, chemicals, diet, epidemiology, genetics, measurement methods, western, region 9, California, CA,, RFA, Health, Scientific Discipline, Genetics, Health Risk Assessment, Epidemiology, Susceptibility/Sensitive Population/Genetic Susceptibility, Children's Health, genetic susceptability, Biology, health effects, risk assessment, sensitive populations, vulnerability, health risks, gene-environment interaction, exposure, human malformation, polymerase chain reaction, children, etiology, children's vulnerablity, toxicity, genotyping, biotransformation, dietary exposure, growth & development, pregnancy, developmental disorders, genetic susceptibility, maternal exposure, vascular development, environmental hazard exposuresRelevant Websites:
Progress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.
Project Research Results
- 2006
- 2005 Progress Report
- 2004 Progress Report
- 2003 Progress Report
- 2002 Progress Report
- 2001 Progress Report
- Original Abstract
41 journal articles for this project