MODIFIER GENES IN 21 HYDROXYLASE DEFICIENCY

21 羟化酶缺乏症的修饰基因

• 批准号: 7718200
• 负责人: MARIA I. NEW
• 金额: $ 1.71万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7718200
• 关键词: Accounting; Adrenal Glands; Adult; Aldosterone; Alleles; Androgen Metabolism; Androgens; Biochemical; Biological Assay; Blood; CYP21A2 gene; CYP2C19 gene; CYP2C9 gene; Carbon; Child; Clinical; Clinical Research; Computer Retrieval of Information on Scientific Projects Database; Congenital adrenal hyperplasia; Cosyntropin; DNA; Disease; Dose; Female; Funding; Genes; Genetic; Genetic Polymorphism; Glucocorticoids; Grant; Hour; Hydrocortisone; Infusion procedures; Institution; Leukocytes; Measurement; Mutation; Participant; Peripheral; Phenotype; Polymerase Chain Reaction; Production; Rare Diseases; Research; Research Personnel; Resources; Serum; Source; Steroid 21-Monooxygenase; Steroids; Time; United States National Institutes of Health; Urine; Variant; cohort; human CYP21A2 protein; peripheral blood; wasting

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 2007年9月26日 罕见疾病临床研究网络遗传类固醇疾病联盟的这项多中心、跨国研究的目的是确定导致先天性肾上腺增生 (CAH) 参与者临床和生化变异的其他基因，该变异是由于 21 -羟化酶缺乏症（21OHD），尽管 CYP21A2 基因发生突变，这应该一致导致严重的“盐浪费”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 名成年人的队列中进行前瞻性评估。 （其中 25 人将在西奈山 GCRC 进行研究） 服用低剂量氢化可的松、患有严重“盐浪费”21OHD 的成人研究参与者将被送入 GCRC，在接受一剂氢化可的松后观察 48 小时，不再接受进一步的糖皮质激素治疗。 48 小时结束时，参与者将在促收缩素输注前后抽血测量血清皮质醇、醛固酮和皮质醇前体。他们还将收集这段时间最后 24 小时的尿液，用于分析源自皮质醇、19 碳类固醇（雄激素）及其前体的代谢物。 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 CYP2C9 和 CYP2C19 基因的遗传多态性解释了由于 CYP21A2 基因的严重突变，21OHD 成人皮质醇和醛固酮产生的变化。 2. 最常见的 CYP2C9 和 CYP2C19 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，大多数患有严重 21OHD 的参与者在成年后会产生大量的皮质醇和醛固酮，因此比儿童时需要更少的糖皮质激素治疗。 3. AKR1C1-4 和 RODH 基因的遗传多态性主要控制外周雄激素代谢，在 21OHD 女性参与者的可变雄激素产生中占很大一部分。