Identification of a functional polymorphism of the human type 5 17 beta-hydroxysteroid dehydrogenase gene associated with polycystic ovary syndrome

Context: Polycystic ovary syndrome ( PCOS) is characterized by chronic hyperandrogenic anovulation and is associated with insulin resistance. Its pathogenesis is believed to be multifactorial, and abnormal gene regulation could be one contributing factor. Type 5 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD5) appears to be the major testosterone-forming 17 beta-HSD isoenzyme in females. Objective: Our objective was to investigate the role of a potentially activating 17 beta-HSD5 gene (HSD17B5) variant in hyperandrogenism. Design and Setting: We conducted a case study and case-control cohort study in our General Clinical Research Center. Study subjects: Subjects included a case of PCOS who had hyperthecosis associated with profound type B insulin resistance and an unusual, frankly male testosterone response to a GnRH agonist test, as well as 121 PCOS patients and 128 population controls. Interventions: Interventions were diagnostic. Main Outcome Measures: Main outcome measures included sequencing of HSD17B5 5'-flanking region and nine exons, genotype/ phenotype studies, and in vitro functional studies. Results: Our case had a previously undescribed homozygous HSD17B5 variant (G-to-A substitution) - 71 bp in the promoter region. Genotyping controls showed this to be a single-nucleotide polymorphism ( SNP)- 71G. Luciferase activity of a SNP-71G promoter construct was significantly higher than that of the wild type, and EMSAs revealed that SNP-71G possessed significantly increased affinity to nuclear transcription factors. SNP-71G allele frequency (32.2 vs. 22.3%) and SNP-71G allele homozygosity (10.7 vs. 6.25%) were significantly increased in PCOS ( P = 0.012). SNP-71G homozygosity tended to contribute about 20% to the plasma testosterone level. Conclusions: SNP-71G is a functional polymorphism that may contribute to testosterone excess in a subset of PCOS patients.