Grantee Research Project Results
2003 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
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, 2002 through June 30, 2003
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 this 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 are 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 (PCR)-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. In the initial 2 years of the 5-year project, our focus has included the following activities and accomplishments:
1. We have received Institutional Review Board approval.
2. We have established contracts, including scopes of work, with all collaborating institutions.
3. We further developed and retooled an electronic tracking system that monitors the status of all (thousands) DNA source samples being used in this research program. 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.
4. We have developed a detailed plan for the prioritization and procurement of DNA samples for genotyping as well as when analyses will be performed.
5. 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.
6. From the perspective of laboratory activities, our focus has been on the development of multiplex 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-acetyltransferases 1 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 now been successfully performed 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 Aim 3, and have completed more than 700 genotyping experiments for the reduced folate carrier polymorphism, a major focus of Aim 2 of our research program.
7. We have been awarded a National Center for Research Resources Shared Instrumentation grant proposal from the National Institutes of Health, which provides funds that allowed us to purchase a matrix-assisted laser desorption/ionization time-of-flight mass spectrometer. We think that this genotyping system would provide a superior approach to typing large numbers of single nucleotide polymorphisms for the large number of specimens in our research program.
8. We have had substantial success in preventing the extinction of our limited nonrenewable resource of DNA by developing and using whole-genome amplification methods.
9. Our laboratory focus continued to be on the development of multiplex PCR-based genotyping methods for Objectives 1, 2, and 3. We have nearly completed the multilocus assay for 16 drug-metabolizing enzymes. DNA samples (totaling 2,200) are ready to be analyzed using this unique multilocus assay.
10. Extensive epidemiologic analyses have been initiated, and preliminary results look provocative.
Future Activities:
Our focus in Year 3 of the project will be to genotype the remaining hundreds of additional samples for biotransformation enzyme gene variants, angiogenesis gene variants, and genes available on the Roche Cardiovascular Panel B. Our major focus will be to incorporate this genotype information into epidemiologic analyses to identify potential risk factors for selected congenital anomalies.
Journal Articles on this Report : 13 Displayed | Download in RIS Format
Other project views: | All 55 publications | 42 publications in selected types | All 41 journal articles |
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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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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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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) |
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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) |
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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) |
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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) |
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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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Supplemental Keywords:
health effects, exposure, teratogen, metabolism, genetic predisposition, genetic polymorphisms, susceptibility, chemicals, diet, epidemiology, genetics, measurement methods, western, Region 9, California, CA, biotransformation, children, children's vulnerability, developmental disorders, dietary exposure, environmental hazard exposures, etiology, exposure, gene-environment interaction, genetic susceptibility, genotyping, growth and development, health risks, human malformation, maternal exposure, polymerase chain reaction, PCR, pregnancy, risk assessment, sensitive populations, toxicity, toxics, vascular development., 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
- 2005 Progress Report
- 2004 Progress Report
- 2002 Progress Report
- 2001 Progress Report
- Original Abstract
41 journal articles for this project