Grantee Research Project Results

2002 Progress Report: Gene-Environment Interaction and Human Malformations

EPA Grant Number: R828292
Title: 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
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, 2001 through June 30, 2002
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 analyze if: (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 2 years of this 5-year project, our focus has included the following activities and accomplishments:

· Received Institutional Review Board approval.

· Established contracts, including scopes of work, with all collaborating institutions.

· Developed an electronic tracking system that monitors the status of all DNA source samples being used in this research program.

· Developed a detailed plan for the prioritization and procurement of DNA samples for genotyping, as well as when analyses will be performed.

· 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, focused 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 now has been performed successfully on more than 600 individuals. We also have genotyped more than 100 individuals for polymorphisms (VEGF) associated with angiogenesis, a major component of our analyses to address the third objective, and have completed more than 700 genotyping experiments for the reduced folate carrier (RFC) polymorphism, a major focus of the second objective.

· Awarded a NCRR Shared Instrumentation grant proposal from NIH providing funds that allowed us to purchase a MALDI-TOF mass spectrometer. We feel that this genotyping system would provide a superior approach to typing large numbers of SNPs for the large number of specimens in our research program.

· Substantially succeeded in preventing the extinction of our limited nonrenewable resource of DNA by developing and using whole genome amplification methods.

Future Activities:

Future activities involve our major focus for the next reporting period, which is to genotype hundreds of additional samples for biotransformation enzyme gene variants, angiogenesis gene variants, as well as genes available on the Roche Cardiovascular Panel B. This genotype information will be incorporated into epidemiologic analyses to identify potential risk factors for selected congenital anomalies.

Journal Articles on this Report : 4 Displayed | Download in RIS Format

Publications Views
Other project views:	All 55 publications	42 publications in selected types	All 41 journal articles

Publications
Type	Citation	Project	Document Sources
Journal Article	Iovannisci DM, Kupperman SO, Lloyd EW, Lammer EJ. The READIT™ assay as a method for genotyping NAT110 polymorphisms. Genetic Testing* 2002;6(4):245-253.	R828292 (2002) R828292 (2003) R828292 (2004) R828292 (2005) R828292 (Final)	Abstract from PubMed Abstract: Liebert-Abstract Exit
Journal Article	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)	Abstract from PubMed Abstract: Wiley-Abstract Exit
Journal Article	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)	Abstract from PubMed Full-text: AJE-Full Text - HTML Exit Abstract: AJE-Abstract Exit Other: AJE- Full Text - PDF Exit
Journal Article	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)	Abstract from PubMed Full-text: AJE-Full Text - HTML Exit Abstract: AJE-Abstract Exit Other: AJE- Full Text - PDF Exit

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 exposures

Relevant Websites:

http://www.cbdmp.org Exit

Progress and Final Reports:

Original Abstract

The 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.