Grantee Research Project Results
2005 Progress 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: University of California - Berkeley , California Birth Defects Monitoring Program
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 Period Covered by this Report: July 1, 2004 through June 30, 2005
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 project is to determine whether an association exists between gene variants and specific exposures in their contribution to selected congenital anomalies. The specific objectives of this research project are to analyze whether: (1) 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) genetic variations in infant or maternal folate-pathway genes modify risks of malformations in the presence of variations in maternal folate intakes; and (3) 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.
Progress Summary:
Progress on major project milestones is consistent with our projections that will ensure a successful completion of the project. In the initial 3 years of the project, our focus included the following activities and accomplishments:
- We have received Institutional Review Board approval.
- We have established contracts, including scopes of work, with all collaborating institutions.
- We further developed and re-tooled an electronic tracking system that monitors the status of all (thousands) DNA source samples being used in this research project. Bar code labels identify each specimen. This system has several rigorous features that ensure quality control. We also started to develop a sophisticated tracking system to accommodate the nearly exponential rise in the number of DNA samples that need to be tracked as a result of copies made from whole genome amplification.
- We have developed a detailed plan for the prioritization and procurement of DNA samples for genotyping as well as when analyses will be performed.
- We have procured all existing samples that will be used in our genotyping experiments. Additional DNA samples from ongoing epidemiologic studies that are part of this research program are being collected on schedule and are being stored frozen.
- From the perspective of laboratory activities, our focus has been on the development of multiplex polymerase chain reaction (PCR)-based genotyping methods, particularly PCR-based multiplex panels of variants of drug-metabolizing enzymes. We have developed new methods for multiplex genotyping for N-acetyltransferases1 and 2 (NAT1 and NAT2), glutathione-S-transferases M1 and T1, and CYP2D6. We have been working closely with scientists from Roche Molecular Systems on the multilocus genotyping assay cardiovascular panel B (detects 32 polymorphisms from 23 candidate genes). This assay has been performed successfully on more than 1,000 individuals. We also have genotyped more than 200 individuals for polymorphisms (VEGF) associated with angiogenesis, a major component of our analyses to address Objective 3, and completed more than 700 genotyping experiments for the reduced folate carrier polymorphism, which was a major focus of Objective 2 of this research project.
- We have been awarded a National Center for Research Resources Shared Instrumentation grant proposal from the National Institutes of Health providing funds that allowed us to purchase a Matrix Assisted Laser Desorption/Ionization Time of Flight (MALDI-TOF) mass spectrometer. We believe that this genotyping system would provide a superior approach to typing large numbers of single nucleotide polymorphisms for the large number of specimens in this research project. In the 4th and 5th years, the research project focused on the following activities:
- We had substantial success in preventing the extinction of our limited non-renewable resource of DNA by developing and using whole genome amplification methods.
- We continued to develop multiplex PCR-based genotyping methods for Objectives 1, 2, and 3. We completed the multilocus assay for 16 drug metabolizing enzymes on DNA samples from 2,200 infants. These results have been subjected to detailed epidemiologic analyses.
- Our laboratory efforts with the Roche Molecular Systems multilocus genotyping assay, cardiovascular panel B (detects 32 polymorphisms from 23 candidate genes), and the inflammation panel, genotyped more than 2,500 infant DNA samples. Epidemiologic analyses involving this large amount of data are being completed and several manuscripts are being written; one manuscript already has appeared in a scientific journal.
- Project scientists have presented new results from this research project at 10 national and international scientific meetings.
Future Activities:
We have requested and been approved for a 1-year, no-cost extension. In this no-cost extension period, we intend to follow up on a new set of data, which include some very important initial results identified during the funding period. We also intend to complete numerous manuscripts that will substantially extend the scientific literature in this important area of research.
Journal Articles on this Report : 30 Displayed | Download in RIS Format
Other project views: | All 55 publications | 42 publications in selected types | All 41 journal articles |
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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. |
R828292 (2005) R828292 (Final) |
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Carmichael SL, Shaw GM, Laurent C, Lammer EJ, et al. Hypospadias and maternal exposures to cigarette smoke. Pediatric and Perinatal Epidemiology 2005;19(6):406-412. |
R828292 (2005) |
not available |
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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. |
R828292 (2004) R828292 (2005) R828292 (Final) |
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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. |
R828292 (2002) R828292 (2003) R828292 (2004) R828292 (2005) R828292 (Final) |
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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. |
R828292 (2005) R828292 (Final) |
Exit Exit |
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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. |
R828292 (2005) R828292 (Final) |
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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. |
R828292 (2003) R828292 (2004) R828292 (2005) R828292 (Final) |
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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. |
R828292 (2005) R828292 (Final) |
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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. |
R828292 (2004) R828292 (2005) R828292 (Final) |
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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. |
R828292 (2004) R828292 (2005) R828292 (Final) |
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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. |
R828292 (2005) R828292 (Final) |
Exit Exit |
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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. |
R828292 (2002) R828292 (2003) R828292 (2004) R828292 (2005) R828292 (Final) |
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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. |
R828292 (2002) R828292 (2003) R828292 (2004) R828292 (2005) R828292 (Final) |
Exit Exit Exit |
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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. |
R828292 (2002) R828292 (2003) R828292 (2004) R828292 (2005) R828292 (Final) |
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Shaw GM, Quach T, Nelson V, Carmichael SL, et al. Neural tube defects in offspring associated with maternal periconceptional dietary intake of simple sugars and glycemic index. American Journal of Clinical Nutrition 2003;78(5):972-978. |
R828292 (2003) R828292 (2004) R828292 (2005) |
not available |
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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. |
R828292 (2004) R828292 (2005) R828292 (Final) |
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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. |
R828292 (2005) R828292 (Final) |
Exit Exit Exit |
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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. |
R828292 (2004) R828292 (2005) R828292 (Final) |
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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. |
R828292 (2004) R828292 (2005) R828292 (Final) |
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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. |
R828292 (2003) R828292 (2004) R828292 (2005) R828292 (Final) |
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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. |
R828292 (2003) R828292 (2004) R828292 (2005) R828292 (Final) |
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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. |
R828292 (2003) R828292 (2004) R828292 (2005) R828292 (Final) |
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Volcik KA, Zhu H, Shaw GM, Canfield M, et al. Evaluation of the Cited2 gene and risk for spina bifida and congenital heart defects. American Journal of Medical Genetics 2004;126A(3):324-325. |
R828292 (2003) R828292 (2004) R828292 (2005) |
not available |
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Volcik KA, Zhu H, Shaw GM, Lammer EJ, et al. Jumonji gene and risk for spina bifida and congenital heart defects. American Journal of Medical Genetics 2004;126A(2):215-217. |
R828292 (2003) R828292 (2004) R828292 (2005) |
not available |
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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. |
R828292 (2003) R828292 (2004) R828292 (2005) R828292 (Final) |
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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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Zhu H, Lu W, Laurent C, Shaw GM, et al. Genes encoding catalytic subunits of protein kinase A and risk of spina bifida. Birth Defects Research Part A: Clinical and Molecular Teratology 2005;73(9):591-596. |
R828292 (2004) R828292 (2005) |
not available |
Supplemental Keywords:
health effects, exposure, teratogen, metabolism, genetic predisposition, genetic polymorphisms, susceptibility, chemicals, diet, epidemiology, genetics, measurement methods, western, EPA 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
- Final Report
- 2006
- 2004 Progress Report
- 2003 Progress Report
- 2002 Progress Report
- 2001 Progress Report
- Original Abstract
41 journal articles for this project