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This version published online on August 9, 2005
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0942
A more recent version of this article appeared on October 1, 2005
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Submitted on April 29, 2005
Accepted on July 29, 2005

GENOTYPES AT HSD11B1 AND H6PD LOCI ARE NOT RISK FACTORS FOR APPARENT CORTISONE REDUCTASE DEFICIENCY IN A LARGE POPULATION-BASED SAMPLE

Perrin C. White*

Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas 75390-9063, USA

* To whom correspondence should be addressed. E-mail: perrin.white{at}utsouthwestern.edu.

Context: Apparent cortisone reductase deficiency (ACRD) is a rarely ascertained condition characterized by signs of androgen excess in women or children and decreased urinary excretion of cortisol metabolites compared with cortisone metabolites. These findings suggest deficiency of 11{beta}-hydroxysteroid dehydrogenase type 1 (11-HSD1, encoded by the HSD11B1 gene), which normally converts cortisone to cortisol. Common polymorphisms in both HSD11B1 and the H6PD gene encoding hexose-6-phosphate dehydrogenase have been found together in ACRD patients, who carry 3 of a possible 4 minor alleles at the two loci.

Objective: Confirm the postulated digenic inheritance mechanism for ACRD.

Design: Population-based association study (Dallas Heart Study). Subjects were genotyped for the 1971T>G polymorphism in intron 3 of HSD11B1 and the R453Q polymorphism in H6PD.

Subjects: 3551 individuals in a population-based sample (50% black, 35% white, 15% hispanic).

Main outcome measure: Association between genotypes and risk for PCOS.

Results: Both polymorphisms occurred more frequently than previously reported. Thus ACRD genotypes (at least 3 of 4 minor alleles) occurred in 7.0% of subjects. There were no associations between genotype and body mass index, waist-hip ratio, visceral adiposity, measures of insulin sensitivity, levels of testosterone, FSH or LH (in females), or risk of polycystic ovarian syndrome. There was no genotype effect on urinary free cortisol:cortisone or corticosteroid metabolite ratios, which were measured in ten subjects each carrying 0, 3 or 4 minor alleles.

Conclusions: Previously reported associations of ACRD with HSD11B1 and H6PD alleles represent ascertainment bias. However, rare severe mutations in these genes cannot be ruled out.
Key words: Polycystic ovarian syndrome • 11{beta}-hydroxysteroid dehydrogenase • genetic association




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