Hum. Reprod. Advance Access originally published online on February 5, 2007
Human Reproduction 2007 22(5):1279-1284; doi:10.1093/humrep/del513
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Haplotype analysis of the estrogen receptor 1 gene in male genital and reproductive abnormalities
1 Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, Tokyo, Japan 2 Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan 3 Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan 4 Division of Urology, National Center for Child Health and Development, Tokyo, Japan 5 Department of Urology, Yamagata University School of Medicine and Yamagata Tokushukai Hospital, Yamagata, Japan 6 Division of Statistical Genetics and Genomic Medicine, Department of Applied Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan
7 To whom correspondence should be addressed at: Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan. Fax: +81-3-5494-7026; E-mail: tomogata{at}nch.go.jp
BACKGROUND: We have recently suggested that homozygosity for a specific ‘AGATA’ haplotype within a 
50 kb linkage disequilibrium (LD) block of the gene for estrogen receptor 
(ESR1) may raise the susceptibility to cryptorchidism by enhancing estrogenic effects of environmental endocrine disruptors (EEDs).
METHODS: Haplotype analysis of ESR1 was performed in 328 Japanese subjects, i.e. 70 patients with micropenis (MP), 43 patients with hypospadias (HS), 80 patients with spermatogenic failure (SF) and 135 control males. Genotyping was performed by the 5' nuclease assay.
RESULTS: The LD block was identified in each of the patient groups and in the control males. The frequency of homozygotes for the specific ‘AGATA’ haplotype was markedly higher in the HS patients [P = 0.0000033, odds ratio [OR] = 11.26] and slightly higher in the MP patients (P = 0.034, OR = 3.64) than in the control males, and the ‘AGATA’ haplotype was strongly associated with HS (P = 0.0000022, OR = 11.26) and weakly associated with MP (P = 0.040, OR = 3.64) in a recessive mode. There was no significant difference between the SF patients and the control males.
CONCLUSIONS: Our results support the hypothesis that homozygosity for the specific ESR1 ‘AGATA’ haplotype may increase the susceptibility to the development of male genital abnormalities in response to estrogenic EEDs.
Key words: environmental endocrine disruptors/estrogen receptor 1/haplotype analysis/susceptibility/undermasculinization
8 The first and the second authors equally contributed to this work.
Submitted on May 29, 2006; resubmitted on October 30, 2006; accepted on December 14, 2006.
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