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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 2007年9月26日 这项多中心，跨国研究在遗传类固醇疾病联盟中的目的是确定其他基因，这些基因导致先天性肾上腺增生（CAH）的临床和生物化学变化，但由于21-羟化酶缺乏效率（21OHD），尽管cyp21 A. “浪费盐”表型。 皮质醇，其前体和代谢产物（以及其他类固醇）的生产将在99名成年人的队列中进行前瞻性评估。 （其中25个将在西奈山GCRC进行研究） 成人研究参与者患有低剂量的氢化可的松的严重“饮用盐” 21OHD将在一剂氢化可的松后48小时观察到GCRC，而无需进一步的糖皮质激素治疗。在48小时结束时，参与者将有血液来测量血清皮质醇，醛固酮和皮质醇前体，并在cosyntropin输注前后。他们还将在这段时间的最后24小时内收集尿液，以分析源自皮质醇，19碳类固醇（雄激素）及其前体的代谢产物。 DNA将从外周血白细胞制备，并在PCR扩增后测序。 假设： 1。编码CYP2C9和CYP2C19基因中的遗传多态性，它们编码外肾上腺外21-羟化酶，这是由于CYP21A2基因的严重突变而导致的21OHD的可变皮质醇和醛固酮产生的可变皮质醇和醛固酮。 2。最常见的CYP2C9和CYP2C19等位基因比较不常见的等位基因更活跃。 因此，大多数患有重度21OHD的参与者将使大量的皮质醇和醛固酮成为成年人，因此与儿童相比，糖皮质激素治疗所需的糖皮质激素治疗较少。 3。AKR1C1-4和RODH基因中的遗传多态性很大程度上控制了外周雄激素代谢，占21OHD女性参与者可变雄激素产生的很大一部分。