title: Association of cryptorchidism with a specific haplotype of the estrogen receptor alpha gene: implication for the susceptibility to estrogenic environmental endocrine disruptors.
abstract: BACKGROUND
  The prevalence of cryptorchidism (CO) has increased during the past few decades in several countries, and this event has primarily been ascribed to the estrogenic effects of environmental endocrine disruptors (EEDs). Little is known, however, about the role of genetic susceptibility to EEDs in this phenomenon.
  
  
  OBJECTIVE
  The objective of this study was to determine whether CO is associated with a specific haplotype of the gene for estrogen receptor alpha (ESR1) that mediates the estrogenic effects of EEDs.
  
  
  METHODS
  This was a case-control study.
  
  
  METHODS
  The study was performed at the National Research Institute and University Hospitals.
  
  
  METHODS
  Sixty-three cryptorchid males, aged 1-13 yr, and 47 control males, aged 4-12 yr, were studied.
  
  
  METHODS
  After genotyping 15 single nucleotide polymorphisms widely distributed in the greater than 300-kb genomic sequences of ESR1, haplotype analysis was performed.
  
  
  METHODS
  Identification of a specific ESR1 haplotype associated with CO was the main outcome measure.
  
  
  RESULTS
  A haplotype block was identified for an approximately 50-kb region encompassing single nucleotide polymorphisms 10-14 in the 3' region of ESR1 in both groups. The frequency of the estimated AGATA haplotype within the block was higher in the patients than in the control males (34.0% vs. 21.3%; P = 0.037), and the association of this haplotype with CO phenotype was significant in a recessive mode (P = 0.0060). The homozygosity for this haplotype was identified only in the patients, and the frequency of the homozygotes was significantly different between the two groups (10 of 63 vs. zero of 47; P = 0.0042).
  
  
  CONCLUSIONS
  The association of CO with homozygosity for the specific ESR1 haplotype suggests the relevance of genetic susceptibility to EEDs in the development of CO.
authors.affiliation: Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, 2-10-1 Ohkura, Setagaya, Tokyo 157-8535, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Yoshida
authors.forename: Maki
authors.initials: M
authors.lastname: Fukami
authors.forename: Isoji
authors.initials: I
authors.lastname: Sasagawa
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Hasegawa
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
mesh_terms: D000293:Adolescent; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003456:Cryptorchidism / Q000209:etiology / Q000235:genetics*; D004781:Environmental Exposure; D047628:Estrogen Receptor alpha / Q000235:genetics*; D004967:Estrogens; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007223:Infant; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens