Grantee Research Project Results
Final 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 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.
Summary/Accomplishments (Outputs/Outcomes):
In the first 70 months of this project a total of 807 families consented to join study and data are available on 578. 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 1st pregnancy and low birth weight. Buccal swab DNA collected from case and control infants has been 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. A population-based association test was also conducted to determine if transmission of the V allele is influenced by any other covariates found to be important in analysis of maternal and paternal questionnaires. This test allows us to determine if there is a significant gene-environmental interaction, and results indicate there is not. Gene-environment interactions were also assessed using multivariable logistic regression analysis for clinical, environmental and genetic risk factors, and there was also no indication of an interaction from this analysis. Low birth weight was the strongest predictor of the risk for hypospadias, followed by maternal relatives with male reproductive tract anomalies, difficulty conceiving during the first pregnancy, paternal pesticide exposure at home and elevated levels of the V allele in the V89L SNP for SRD5A2. The nucleotide sequence for the V allele is a potential methylation site, and DNA methylation could be involved in silencing the gene. The A49T SNP is 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 17β HSD3 gene.
Journal Articles on this Report : 5 Displayed | Download in RIS Format
| Other project views: | All 39 publications | 7 publications in selected types | All 7 journal articles |
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Anand-Ivell R, Ivell R, Driscoll D, Manson J. Insulin-like factor 3 levels in amniotic fluid of human male fetuses. Human Reproduction 2008;23(5):1180-1186. |
R828599 (Final) |
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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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Wang Y, Barthold J, Kanetsky PA, Casalunovo T, Pearson E, Manson J. Allelic variants in HOX genes in cryptorchidism. Birth Defects Research Part A:Clinical and Molecular Teratology 2007;79(4):269-275. |
R828599 (Final) |
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Wang Y, Barthold J, Figueroa E, Gonzalez R, Noh PH, Wang M, Manson J. Analysis of five single nucleotide polymorphisms in the ESR1 gene in cryptorchidism. Birth Defects Research. Part A, Clinical and Molecular Teratology 2008;82(6):482-485. |
R828599 (Final) |
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Supplemental Keywords:
infant, epidemiology, genetic, urogenital,, Health, RFA, Scientific Discipline, Susceptibility/Sensitive Population/Genetic Susceptibility, Health Risk Assessment, Biology, genetic susceptability, Environmental Chemistry, Children's Health, Biochemistry, Human Health Risk Assessment, infants, epidemeology, male infants, pregnancy, maternal exposure, molecular epidemeology, prenatal exposure, children, endocrine disruptors, toxics, children's vulnerablity, environmental toxicant, assessment of exposure, human susceptibility, developmental disordersProgress 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
- 2007
- 2006 Progress Report
- 2005 Progress Report
- 2004 Progress Report
- 2003 Progress Report
- Original Abstract
7 journal articles for this project