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Association of variants in genes involved in environmental chemical metabolism and risk of cryptorchidism and hypospadias

Journal of Human Genetics volume 57, pages 434–441 (2012)Cite this article

Abstract

We hypothesized that single-nucleotide polymorphisms (SNPs) of genes involved in environmental endocrine disruptors (EEDs) metabolism might influence the risk of male genital malformations. In this study, we explored for association between 384 SNPs in 15 genes (AHR, AHRR, ARNT, ARNT2, NR1I2, RXRA, RXRB, RXRG, CYP1A1, CYP1A2, CYP1B1, CYP2B6, CYP3A4, CYP17A1 and CYP19A1) and risk of cryptorchidism (CO) and hypospadias (HS) in 334 Japanese (JPN) males (141 controls, 95 CO and 98 HS) and 187 Italian (ITA) males (129 controls and 58 CO). In the JPN study group, five SNPs from ARNT2 (rs2278705 and rs5000770), CYP1A2 (rs2069521), CYP17A1 (rs4919686) and NR1I2 (rs2472680) were significantly associated at both allelic and genotypic levels with risk of at least one genital malformation phenotype. In the ITA study group, two SNPs in AHR (rs3757824) and ARNT2 (rs1020397) were significantly associated with risk of CO. Interaction analysis of the positive SNPs using multifactor dimensionality reduction demonstrated that synergistic interaction between rs2472680, rs4919686 and rs5000770 had 62.81% prediction accuracy for CO (P=0.011) and that between rs2069521 and rs2278705 had 69.98% prediction accuracy for HS (P=0.001) in JPN population. In a combined analysis of JPN and ITA population, the most significant multi-locus association was observed between rs5000770 and rs3757824, which had 65.70% prediction accuracy for CO (P=0.055). Our findings indicate that genetic polymorphisms in genes involved in EED metabolism are associated with risk of CO and HS.

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Acknowledgements

This study was partly supported by the Environment Research and Technology Development Fund from the Ministry of the Environment, Japan, and by a grant for Research on Risk on Chemical Substances (H20-004) from the Ministry of Health, Labor, and Welfare of Japan. There is no other source of funding that has supported this study. We thank Dr Rie Taniguchi (Institute of Medicinal Molecular Design Inc., Tokyo, Japan) for technical support in gene target selection with KeyMolnet.

Author information

Authors and Affiliations

  1. Research Center for Environmental Risk, National Institute for Environmental Studies, Tsukuba, Ibaraki, Japan

    Xian-Yang Qin, Hiroko Zaha, Masahiro Okura, Junzo Yonemoto & Hideko Sone

  2. Department of Environmental Studies, University of Tokyo, Kashiwa, Chiba, Japan

    Xian-Yang Qin & Jun Yoshinaga

  3. Department of Nephro-Urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan

    Yoshiyuki Kojima, Kentaro Mizuno, Kenjiro Kohri & Yutaro Hayashi

  4. Department of Surgical Subspecialties, National Research Center for Child Health and Development, Tokyo, Japan

    Katsuhiko Ueoka

  5. Department of Pediatrics, University of Pisa, Pisa, Italy

    Francesco Massart

  6. Department of Surgery, University of Pisa, Pisa, Italy

    Claudio Spinelli

  7. Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, Tokyo, Japan

    Tsutomu Ogata

  8. Department of Pediatrics, University Hospital, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan

    Tsutomu Ogata

Authors
  1. Xian-Yang Qin
  2. Yoshiyuki Kojima
  3. Kentaro Mizuno
  4. Katsuhiko Ueoka
  5. Francesco Massart
  6. Claudio Spinelli
  7. Hiroko Zaha
  8. Masahiro Okura
  9. Jun Yoshinaga
  10. Junzo Yonemoto
  11. Kenjiro Kohri
  12. Yutaro Hayashi
  13. Tsutomu Ogata
  14. Hideko Sone

Corresponding author

Correspondence to Hideko Sone.

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Competing interests

The authors declare no conflict of interest.

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Qin, XY., Kojima, Y., Mizuno, K. et al. Association of variants in genes involved in environmental chemical metabolism and risk of cryptorchidism and hypospadias. J Hum Genet 57, 434–441 (2012). https://doi.org/10.1038/jhg.2012.48

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  • DOI: https://doi.org/10.1038/jhg.2012.48

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