title: Genetic polymorphisms in ESR1 and ESR2 genes, and risk of hypospadias in a multiethnic study population.
abstract: OBJECTIVE
  Estrogenic endocrine disruptors acting via estrogen receptors α (ESR1) and β (ESR2) have been implicated in the etiology of hypospadias, a common congenital malformation of the male external genitalia. We determined the association of single nucleotide polymorphisms in ESR1 and ESR2 genes with hypospadias in a racially/ethnically diverse study population of California births.
  
  
  METHODS
  We investigated the relationship between hypospadias and 108 ESR1 and 36 ESR2 single nucleotide polymorphisms in 647 cases and 877 population based nonmalformed controls among infants born in selected California counties from 1990 to 2003. Subgroup analyses were performed by race/ethnicity (nonHispanic white and Hispanic subjects) and by hypospadias severity (mild to moderate and severe).
  
  
  RESULTS
  Odds ratios for 33 of the 108 ESR1 single nucleotide polymorphisms had p values less than 0.05 (p = 0.05 to 0.007) for risk of hypospadias. However, none of the 36 ESR2 single nucleotide polymorphisms was significantly associated. In stratified analyses the association results were consistent by disease severity but different sets of single nucleotide polymorphisms were significantly associated with hypospadias in nonHispanic white and Hispanic subjects. Due to high linkage disequilibrium across the single nucleotide polymorphisms, haplotype analyses were conducted and identified 6 haplotype blocks in ESR1 gene that had haplotypes significantly associated with an increased risk of hypospadias (OR 1.3 to 1.8, p = 0.04 to 0.00001). Similar to single nucleotide polymorphism analysis, different ESR1 haplotypes were associated with risk of hypospadias in nonHispanic white and Hispanic subjects. No significant haplotype association was observed for ESR2.
  
  
  CONCLUSIONS
  The data provide evidence that ESR1 single nucleotide polymorphisms and haplotypes influence the risk of hypospadias in white and Hispanic subjects, and warrant further examination in other study populations.
authors.affiliation: Department of Urology, University of California, San Francisco, California. Electronic address: choudhrys@urology.ucsf.edu.
authors.forename: Shweta
authors.initials: S
authors.lastname: Choudhry
authors.affiliation: Department of Urology, University of California, San Francisco, California.
authors.forename: Laurence S
authors.initials: LS
authors.lastname: Baskin
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, California.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Lammer
authors.affiliation: Department of Epidemiology and Biostatistics, and Institute of Human Genetics, University of California, San Francisco, California.
authors.forename: John S
authors.initials: JS
authors.lastname: Witte
authors.affiliation: Department of Urology, University of California, San Francisco, California.
authors.forename: Sudeshna
authors.initials: S
authors.lastname: Dasgupta
authors.affiliation: Department of Pediatrics, Division of Neonatology, Stanford University School of Medicine, Stanford, California.
authors.forename: Chen
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Urology, University of California, San Francisco, California.
authors.forename: Abhilasha
authors.initials: A
authors.lastname: Surampalli
authors.affiliation: Department of Urology, University of California, San Francisco, California.
authors.forename: Joel
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Pediatrics, Division of Neonatology, Stanford University School of Medicine, Stanford, California.
authors.forename: Gary M
authors.initials: GM
authors.lastname: Shaw
authors.affiliation: Department of Pediatrics, Division of Neonatology, Stanford University School of Medicine, Stanford, California.
authors.forename: Suzan L
authors.initials: SL
authors.lastname: Carmichael
mesh_terms: D002140:California; D016022:Case-Control Studies; D047628:Estrogen Receptor alpha / Q000235:genetics*; D047629:Estrogen Receptor beta / Q000235:genetics*; D006801:Humans; D007021:Hypospadias / Q000453:epidemiology* / Q000235:genetics*; D007231:Infant, Newborn; D008297:Male; D020641:Polymorphism, Single Nucleotide; D044469:Racial Groups; D012306:Risk
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta
keywords: case-control studies; estrogen; genetic; hypospadias; polymorphism; receptors; urogenital abnormalities