MODIFIER GENES IN 21 HYDROXYLASE DEFICIENCY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 9/26/2007 The objective of this multi-center, multi-national study in Genetic Steroid Disorders Consortium of the Rare Disease Clinical Research Network will be to identify other genes that contribute to the clinical and biochemical variations in participants with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) despite mutations in the CYP21A2 gene that should uniformly cause a severe, "salt-wasting" phenotype. The production of cortisol, its precursors, and metabolites (as well as other steroids) will be assessed prospectively in a cohort of 99 adults. (25 of whom will be studied at the Mount Sinai GCRC) Adult study participants with severe, "salt-wasting" 21OHD taking low doses of hydrocortisone will be admitted to the GCRC to be observed for 48 hours after one dose of hydrocortisone and no further glucocorticoid therapy. At the end of the 48 hours, participants will have blood drawn for measurement of serum cortisol, aldosterone, and cortisol precursors before and after cosyntropin infusion. They will also collect urine for the last 24 hours of this time for assay of metabolites derived from cortisol, 19-carbon steroids (androgens), and their precursors. DNA will be prepared from peripheral blood leukocytes and sequenced after PCR amplification. Hypothesis: 1. Genetic Polymorphisms in the CYP2C9 and CYP2C19 genes, which encode extra-adrenal 21-hydroxylases, account for the variable cortisol and aldosterone production in adults with 21OHD due to severe mutations in the CYP21A2 gene. 2. The most common CYP2C9 and CYP2C19 alleles are more active as steroid 21-hydroxylases than the less common alleles. Consequently, most participants with severe 21OHD will make significant amounts of cortisol and aldosterone as adults and therefore require less glucocorticoid therapy than as children. 3. Genetic Polymorphisms in the AKR1C1-4 and RODH genes, which largely control peripheral androgen metabolism, account for a significant portion of the variable androgen production in female participants with 21OHD.