Molecular Epidemiology of Hypospadias

EPA Grant Number: R828599
Title: Molecular Epidemiology of Hypospadias
Investigators: Manson, Jeanne M.
Current Investigators: Manson, Jeanne M. , Carr, Michael
Institution: Thomas Jefferson University
Current Institution: The Children's Hospital of Philadelphia
EPA Project Officer: Hahn, Intaek
Project Period: July 1, 2002 through October 1, 2007
Project Amount: $2,962,288
RFA: Genetic Susceptibility & Variability of Human Malformations (1999) RFA Text |  Recipients Lists
Research Category: Health Effects , Health


The hypothesis of this study is that allelic variants in genes controlling androgen action and metabolism (steroid 5-alpha reductase [SRD5A2], androgen receptor [AR] and 17-beta hydroxysteroid dehydrogenase type 3 [HSD17B3]) will be highly associated with the risk for hypospadias in male infants. Parental exposure to environmental agents with anti-androgenic activity during pregnancy may further increase the risk for hypospadias in male infants with a susceptible genotype, resulting in a gene by environment interaction. The association between allelic variants in these genes and hypospadias has only been evaluated to date in consanguineous families or small case series. Results from these studies indicate that SRD5A2 gene activity is critical to formation of the external male genital tract. Allelic variants in the AR and HSD1 7133 genes are expected to be rare but important in modifying effects due to allelic variants in the SRD5A2 gene and from environmental exposures. This will be the first study in a large, outbred population to investigate the association between allelic variants in these genes and environmental exposures on the risk for hypospadias.


A hospital-based case-control study will be conducted in which 400 male infants presenting for surgical repair of non-syndromic hypospadias (cases) are compared to 400 control infants presenting for surgical repair of urogenital anomalies not involving the penis, with frequency matching based on race/ethnicity. Buccal swabs will be collected from infants and parents at the time of diagnosis/surgery for gene analysis. Information of demographics, reproductive/obstetrical history and drug/environmental exposures of the parents prior to and during pregnancy of the index infant will be obtained via questionnaire administered to the parents within the first year after birth.

Expected Results:

Improvements in risk assessment include identification of individuals with the greatest susceptibility for developing hypospadias with antiandrogenic exposure, and determination of the contribution of genetic and environmental factors to the occurrence of this malformation.

Publications and Presentations:

Publications have been submitted on this project: View all 39 publications for this project

Journal Articles:

Journal Articles have been submitted on this project: View all 7 journal articles for this project

Supplemental Keywords:

epidemiology, genetic,, RFA, Health, Scientific Discipline, Environmental Chemistry, Health Risk Assessment, Susceptibility/Sensitive Population/Genetic Susceptibility, Biochemistry, Children's Health, genetic susceptability, Biology, male infants, infants, prenatal exposure, children, endocrine disruptors, Human Health Risk Assessment, hyposadias, children's vulnerablity, assessment of exposure, environmental toxicant, epidemeology, human susceptibility, pregnancy, developmental disorders, toxics, maternal exposure

Progress and Final Reports:

  • 2003 Progress Report
  • 2004 Progress Report
  • 2005 Progress Report
  • 2006 Progress Report
  • 2007
  • Final Report