Grantee Research Project Results
2006 Progress Report: Molecular Epidemiology of Hypospadias
EPA Grant Number: R828599Title: Molecular Epidemiology of Hypospadias
Investigators: Manson, Jeanne M. , Carr, Michael
Institution: The Children's Hospital of Philadelphia
EPA Project Officer: Aja, Hayley
Project Period: July 1, 2002 through October 1, 2007
Project Period Covered by this Report: July 1, 2005 through October 1, 2006
Project Amount: $2,962,288
RFA: Genetic Susceptibility and Variability of Human Malformations (1999) RFA Text | Recipients Lists
Research Category: Human Health
Objective:
The objectives of this research are to characterize the genetic and environmental risk factors for hypospadias in the general population.
Progress Summary:
In the first 70 months of this project, a total of 807 families consented to join the study, and data are available on 579. The case and control groups are well balanced in terms of race/ethnicity and demographics. Environmental risk factors identified to date for hypospadias are paternal and maternal pesticide exposures at home and maternal paints/stain exposures at home. Major clinical risk factors are maternal family histories of male reproductive tract anomalies, maternal difficulty conceiving in the first pregnancy, and low birth weight. Buccal swab DNA collected from case and control infants is being assayed for any polymorphisms in the expressed portion of the SRD5A2 (steroid 5-alpha reductase type 2) gene, the 17βHSD3 (17β hydroxysteroid dehydrogenase type 3) gene, and trinucleotide repeats on the AR (androgen receptor) gene. Several common SNPs (single nucleotide polymorphisms) in exon 1 of the SRD5A2 gene have been identified: V89L and A49T. Both SNPs are known to be functionally significant in altering enzyme activity. Cases have a higher proportion of the wild type (V) allele, and transmission disequilibrium tests have confirmed that this allele is inherited at a significantly higher proportion from case parents to case infants but not from controls. The nucleotide sequence for the V allele is a potential methylation site, and DNA methylation could be involved in silencing the gene. A significantly higher proportion of the variant T allele in A49T has been associated with severity of hypospadias. There have been no significant associations found between trinucleotide repeat lengths on the AR and risks for hypospadias nor in allelic variants in the 17βHSD3 gene.
Future Activities:
The study is now closed to enrollment, and for the remaining study period we will attempt to collect as many outstanding questionnaires and DNA samples from subjects who consented to participate in the study. We will complete genotyping DNA samples for the V89L and A49T polymorphisms in SRD5A2 and CAG/GGC repeats on the AR gene in the remaining 7 months of the study. The primary effort will be to complete data analysis and prepare manuscripts for publication.
Journal Articles on this Report : 2 Displayed | Download in RIS Format
Other project views: | All 39 publications | 7 publications in selected types | All 7 journal articles |
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Barthold JS, Manson J, Regan V, Si X, Hassink SG, Coughlin MT, Lee PA. Reproductive hormone levels in infants with cryptorchidism during postnatal activation of the pituitary-testicular axis. The Journal of Urology 2004;172(4 Pt 2):1736-1741. |
R828599 (2005) R828599 (2006) R828599 (Final) |
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Manson JM, Carr MC. Molecular epidemiology of hypospadias: review of genetic and environmental risk factors. Birth Defects Research Part A:Clinical and Molecular Teratology 2003;67(10):825-836. |
R828599 (2002) R828599 (2003) R828599 (2004) R828599 (2005) R828599 (2006) R828599 (Final) |
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Supplemental Keywords:
infant, epidemiology, genetic, urogenital,, RFA, Scientific Discipline, Health, Environmental Chemistry, Health Risk Assessment, Susceptibility/Sensitive Population/Genetic Susceptibility, Biochemistry, Children's Health, genetic susceptability, Biology, male infants, prenatal exposure, infants, endocrine disruptors, Human Health Risk Assessment, hyposadias, children, assessment of exposure, children's vulnerablity, environmental toxicant, epidemeology, human susceptibility, pregnancy, developmental disorders, maternal exposure, toxicsProgress 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.