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Identification of a Functional Polymorphism of the Human Type 5 17ß-Hydroxysteroid Dehydrogenase Gene Associated with Polycystic Ovary Syndrome

Departments of Pediatrics (K.Q., S.R., R.L.R.), Medicine (D.A.E., N.C., S.R., R.L.R.), and Human Genetics (N.C.) and the Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Kenan Qin, M.D., Section of Pediatric Endocrinology, 5839 South Maryland Avenue, MC 5053, Chicago, Illinois 60637. E-mail: kqin{at}peds.bsd.uchicago.edu.

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 17ß-hydroxysteroid dehydrogenase (17ß-HSD5) appears to be the major testosterone-forming 17ß-HSD isoenzyme in females.

Objective: Our objective was to investigate the role of a potentially activating 17ß-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.

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