MODIFIER GENES IN 21 HYDROXYLASE DEFICIENCY

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 9/26/2007 罕见病临床研究网络遗传类固醇疾病联盟的这项多中心、多国研究的目的是确定其他基因，这些基因导致21-羟化酶缺乏症（21 OHD）所致先天性肾上腺增生（CAH）受试者的临床和生化变异，尽管CYP 21 A2基因突变应一致导致严重的“盐耗”表型。 皮质醇、其前体和代谢物（以及其他类固醇）的产生将在99名成人的队列中进行前瞻性评估。(25其中将在西奈山GCRC研究） 接受低剂量氢化可的松治疗的重度“盐消耗性”21 OHD成人研究受试者将在接受一剂氢化可的松治疗后进入GCRC观察48小时，不再接受糖皮质激素治疗。在48小时结束时，受试者将在促肾上腺素输注前后抽血测量血清皮质醇、醛固酮和皮质醇前体。他们还将收集最后24小时的尿液，用于测定皮质醇、19碳类固醇（雄激素）及其前体的代谢产物。 将从外周血白细胞中制备DNA，并在PCR扩增后进行测序。 假设： 1. 编码肾上腺外21-羟化酶的CYP 2C 9和CYP 2C 19基因中的遗传多态性解释了由于CYP 21 A2基因中的严重突变而导致的21 OHD成人中可变的皮质醇和醛固酮产生。 2. 最常见的CYP 2C 9和CYP 2C 19等位基因作为类固醇21-羟化酶比不太常见的等位基因更活跃。 因此，大多数重度21 OHD患者在成人时会产生大量皮质醇和醛固酮，因此需要的糖皮质激素治疗比儿童少。 3. AKR 1C 1 -4和RODH基因的遗传多态性在很大程度上控制外周雄激素代谢，占21 OHD女性参与者可变雄激素产生的重要部分。

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.