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A novel polymorphism in the 17β-hydroxysteroid dehydrogenase type 5 (aldo-keto reductase 1C3) gene is associated with lower serum testosterone levels in caucasian men

Abstract

Genetic variation in the androgen metabolizing enzymes is important to identify and feature as they may influence the risk of prostate cancer and help clarify the etiology of the disease. Human 17β-hydroxysteroid dehydrogenase type 5 (AKR1C3) is highly expressed in the prostate gland and plays a major role in the formation and metabolism of androgens. We identified five novel polymorphisms in the AKR1C3 gene. One of those an A>G substitution in exon 2 that confers a Glu77Gly change occurred in 4.8% in Caucasians but was completely absent in Orientals. Interestingly, the testosterone level in serum was significantly lower in subjects with the Gly77 allele. A promoter A>G polymorphism was associated with significantly altered promoter activity in reporter constructs, but was not associated with any change in testosterone levels. In conclusion, the Glu77Gly polymorphism is associated with lower testosterone levels in serum.

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Notes

  1. Cancer Incidence in Sweden 1992. National Board of Health and Welfare. The Cancer Registry. Center for Epidemiology. Stockholm, 1995.

Abbreviations

AKR:

aldoketoreductase

3α-HSD:

3α-hydroxysteroid dehydrogenase

17β-HSD:

17β-hydroxysteroid dehydrogenase

PGFS:

prostaglandin F synthase

SSCP:

single-strand conformation polymorphism

3α-diol:

5α-androstane-3α,17β-diol

EpiT:

epitestosterone

5α-DHT:

5α-dihydrotestosterone

USF:

upstream stimulating factor

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Acknowledgements

This work was supported by grants from the World Anti-Doping Agency (WADA) and from the Swedish Cancer Society. Professor Åke Pousette, Department of Medicine, Karolinska Institutet kindly provided LNCaP cells. The technical assistance of Birgitta Ask is gratefully acknowledged.

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Correspondence to L Ekström.

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Jakobsson, J., Palonek, E., Lorentzon, M. et al. A novel polymorphism in the 17β-hydroxysteroid dehydrogenase type 5 (aldo-keto reductase 1C3) gene is associated with lower serum testosterone levels in caucasian men. Pharmacogenomics J 7, 282–289 (2007). https://doi.org/10.1038/sj.tpj.6500419

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