This Article Full Text Full Text (PDF) All Versions of this Article: 92/9/3712    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Beleza-Meireles, A. Articles by Nordenskjöld, A. Search for Related Content PubMed PubMed Citation Articles by Beleza-Meireles, A. Articles by Nordenskjöld, A. Related Collections Male Endocrinology

Risk Factors for Hypospadias in the Estrogen Receptor 2 Gene

Departments of Molecular Medicine and Surgery (A.B.-M., F.L., C.S., A.N.) and Clinical Neurosciences (I.K.), Karolinska Institutet, SE 171 76 Stockholm, Sweden; and Department of Women and Child Health (A.N.), Astrid Lindgren Children Hospital, Karolinska University Hospital, 171 76 Stockholm, Sweden

Address all correspondence and requests for reprints to: Ana Beleza-Meireles, Department of Molecular Medicine and Surgery, Building CMM 00, Karolinska University Hospital, Solna, SE 171 76 Stockholm, Sweden. E-mail: Ana.Beleza{at}ki.se; or Agneta.Nordenskjold{at}ki.se.

Context: Hypospadias is a common inborn error of the male genitalia of complex, and still elusive, etiology. The presence of active estrogen receptors (ESRs) in the developing male urethra, predominantly the ESR2, has suggested a role of estrogens in the otherwise androgen-dependent male genital differetiation. Moreover, imbalances between these two steroid hormones have been suggested to disturb the external genital development. This has been supported by the association between longer (CA)n variants in the ESR2 gene with lower androgen levels as well as with hypospadias.

Objective: The aim of this study was to analyze the effect of ESR2 gene variants on the risk to hypospadias.

Design, Participants, and Methods: Four haplotype-tagging single nucleotide polymorphisms (rs2987983, rs1887994, rs1256040, and rs1256062), the (CA)n polymorphism, and two additional promoter single nucleotide polymorphisms (rs10483774 and rs1271572), mapping to a transcription factor binding region, were typed and analyzed in a Swedish cohort of 354 boys with nonsyndromic hypospadias and 380 healthy controls.

Results: Association was identified with longer variants of the (CA)n polymorphism in intron 6 and with a region of intense transcription factor binding, in the putative promoter region, mapping to rs2987983 and rs10483774. The two regions are in low-linkage disequilibrium, meaning that they are not necessarily inherited together as a haplotype; logistic regression analysis indicates that these two risk effects are not independent.

Conclusions: The present study evidences two nonindependent risk factors for hypospadias in the ESR2 gene. We discuss possible mechanisms that explain how these variants may affect male urethral development.

This article has been cited by other articles:

				S. Ban, F. Sata, N. Kurahashi, S. Kasai, K. Moriya, H. Kakizaki, K. Nonomura, and R. Kishi Genetic polymorphisms of ESR1 and ESR2 that may influence estrogen activity and the risk of hypospadias Hum. Reprod., June 1, 2008; 23(6): 1466 - 1471. [Abstract] [Full Text] [PDF]

				A. Beleza-Meireles, V. Tohonen, C. Soderhall, C. Schwentner, C. Radmayr, I. Kockum, and A. Nordenskjold Activating transcription factor 3: a hormone responsive gene in the etiology of hypospadias Eur. J. Endocrinol., May 1, 2008; 158(5): 729 - 739. [Abstract] [Full Text] [PDF]