Association of cryptorchidism with a specific haplotype of the estrogen receptor α gene: Implication for the susceptibility to estrogenic environmental endocrine disruptors

Context: 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 α (ESR1) that mediates the estrogenic effects of EEDs. Design: This was a case-control study. Setting: The study was performed at the National Research Institute and University Hospitals. Subjects: Sixty-three cryptorchid males, aged 1-13 yr, and 47 control males, aged 4-12 yr, were studied. Intervention: After genotyping 15 single nucleotide polymorphisms widely distributed in the greater than 300-kb genomic sequences of ESR1, haplotype analysis was performed. Main Outcome Measure: 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.