CYP19A1 gene and Pharmacogenetics of Response

CYP19A1 基因和反应的药物遗传学

• 批准号: 8046813
• 负责人: REINA C VILLAREAL
• 金额: --
• 依托单位: ALBUQUERQUE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046813
• 关键词: Adipose tissue; Adverse effects; Adverse event; Affect; Age-Related Bone Loss; Aging; Alleles; Androgen Therapy; Androgens; Aromatase; Aromatase Inhibitors; Biological Assay; Biopsy; Bone Density; Bone Resorption; CYP19A1 gene; Caring; Clinic; Data; Dual-Energy X-Ray Absorptiometry; Elderly; Enzymes; Epidemiologic Studies; Estradiol; Estrogens; Event; Exhibits; Fatty acid glycerol esters; Female; Fracture; Future; Gene Expression; Genes; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Gonadal Steroid Hormones; Growth; Hematocrit procedure; Hormonal; Hormones; Hypogonadism; Incidence; Lead; Life Expectancy; Link; Malignant neoplasm of prostate; Measurement; Mediating; Napping; Outcome; Patient Care; Patients; Pharmaceutical Preparations; Pharmacogenetics; Placebos; Population; Postmenopause; Predisposition; Prevention; Production; Prostate; Prostate-Specific Antigen; Randomized; Relative (related person); Replacement Therapy; Reporting; Risk; Role; Sales; Serum; Skeleton; Subgroup; Surrogate Markers; Symptoms; Testing; Testis; Testosterone; Time; Variant; Veterans; Woman; Writing; aging population; base; bone loss; bone metabolism; bone turnover; clinically significant; design; enzyme activity; experience; genetic profiling; hormone related cancer; hormone therapy; male; malignant breast neoplasm; men; prevent; response; sex; skeletal; standard of care; therapy design; treatment duration; trend

DESCRIPTION (provided by applicant): Estrogen has been gaining recognition as the primary hormone that regulates the male skeleton. Estrogen in males is mainly derived from the conversion of testosterone to estradiol by the enzyme aromatase. Polymorphisms of the aromatase gene (CYP19A1) have been reported to result in variable enzyme activity resulting in variable hormonal profile and differences in bone mineral density (BMD) among the variants. These polymorphisms were also found to influence changes in BMD in response to hormone therapy in postmenopausal women and bone loss from aromatase inhibitors in women with breast cancer. It is possible that these same polymorphisms will also influence skeletal response to testosterone therapy in hypogonadal males given testosterone. Among the side effects described for testosterone therapy, prostate-related events and an increase in hematocrit represent as the more common and the potentially more serious side effects. However, these side effects do not affect everybody, suggesting that a certain subgroup of patients is predisposed to these side effects. Because polymorphisms in the CYP19A1 gene result differences in activity among variants leading in variable substrate and product accumulation, we hypothesize that these polymorphisms will influence the skeletal response and perhaps susceptibility to side effects from testosterone therapy. Thus the objectives of this proposal are: (1) To evaluate the influence of polymorphisms in the CYP19A1 gene on the skeletal response to testosterone in male patients with low testosterone, (2) To evaluate the influence of polymorphisms in the CYP19A1 gene on the susceptibility to side effects from testosterone therapy, (3) To evaluate the changes in functional activity of the aromatase enzyme in clinically significant CYP19A1 gene polymorphisms. We propose to randomize 131 patients to either placebo (25% of subjects) or testosterone cypionate 200 mg IM every 2 weeks (75% of subjects) for an 18-month treatment period. We will do serial measurements of BMD by dual energy X-ray absorptiometry, markers of bone turnover, hematocrit, prostate- specific antigen (PSA), prostate volume and hormonal assays. Changes in BMD and markers of bone turnover will be compared between testosterone-treated subjects and placebo and among the different CYP19A1 genotypes in the testosterone-treated group. We will also compare changes in hematocrit, PSA and prostate volume among the different CYP19A1 genotypes. Changes in functional activity among the variants will be evaluated by CYP19 gene expression studies on the adipose tissues obtained from periumbilical fat biopsies, and by changes the in estradiol to testosterone ratio, a surrogate marker for aromatase activity. We anticipate that variants with increase in activity will have relatively higher estradiol levels than less active variants resulting in greater increments in BMD. Meanwhile, less active variants will have relatively higher levels of testosterone than other variants and have greater increments in hematocrit. On the other hand, variants associated with higher estradiol to testosterone ratio will experience greater increases in PSA and prostate volume with therapy. The incidence of testosterone deficiency goes up with aging and the presence of co-morbid conditions making male hypogonadism one of the common problems among patients attending the VA clinics who are for the most part, elderly with various co-morbid conditions. Indeed, a large number of VA patients are already taking testosterone for hyogonadism, some of them primarily to prevent further bone loss. It is possible that some of these patients do not derive benefit from the drug while subjecting them to potential serious side effects. Results from this proposal will identify the genetic profiles of favorable responders from poor responders or those who might be more prone to serious side effects, thus, may impact the future care of male veterans and hypogonadal patients in general, once genetic profiling becomes part of the standard of care.

描述（由申请人提供）： 雌激素已成为调节男性骨骼的主要激素。雄性中的雌激素主要源自睾丸激素蛋白酶向雌二醇的转化。据报道，芳香酶基因的多态性（CYP19A1）导致可变的酶活性，从而导致变体中的激素谱和骨矿物质密度（BMD）的差异。还发现这些多态性会影响绝经后妇女激素治疗的响应，以及乳腺癌女性芳香酶抑制剂的骨丢失。这些相同的多态性可能还会影响给定睾丸激素的性雄性雄性睾丸激素治疗对睾丸激素治疗的骨骼反应。 在描述的睾丸激素治疗所描述的副作用中，前列腺相关事件和血细胞比容的增加表示为更常见和可能更严重的副作用。但是，这些副作用并不影响每个人，这表明某些患者亚组易受这些副作用。由于CYP19A1基因中的多态性导致可变底物和产物积累的变体中的活性差异，因此我们假设这些多态性会影响睾丸激素疗法的骨骼反应以及对副作用的副作用的敏感性。因此，该提案的目的是：（1）评估CYP19A1基因中多态性对睾丸激素低的男性患者对睾丸激素的骨骼反应的影响，（2）评估CYP19A1基因对CYP19A1基因在睾丸激素治疗中的影响的影响（3）的影响（3）显着的CYP19A1基因多态性。我们建议在18个月的治疗期间每2周（75％的受试者）（75％的受试者）随机将131例患者与安慰剂（占受试者的25％）或睾丸激素200 mg IM（占受试者的75％）。我们将通过双能X射线吸收法，骨转换标记，血细胞比容，前列腺特异性抗原（PSA），前列腺体积和激素测定法对BMD进行串行测量。将在经过睾丸激素治疗组中的不同CYP19A1基因型之间比较BMD的变化和BMD的变化和骨转换标记。我们还将比较不同CYP19A1基因型中血细胞比容，PSA和前列腺体积的变化。这些变体之间功能活性的变化将通过CYP19基因表达研究对从pobilical脂肪脂肪活检获得的脂肪组织，以及通过雌二醇与睾丸激素比的变化，这是芳香酶活性的替代标记。我们预计，随着活性增加的变异将比不太活跃的变体具有相对较高的雌二醇水平，从而导致BMD的增长更高。同时，较少的活性变体的睾丸激素水平将比其他变体具有更高的水平，并且血细胞比容的增量更高。另一方面，与雌二醇与睾丸激素比率较高相关的变体将经历PSA和前列腺量的增加，并通过治疗增加。 睾丸激素缺乏症的发病率与衰老和合并症的存在有关，这使得男性异常症成为参加VA诊所的患者中常见的问题之一，这些患者大部分是老年人，患有各种联合性疾病。实际上，许多VA患者已经服用了睾丸激素来进行卫生症，其中一些患者主要是为了防止进一步的骨质流失。这些患者中的一些人可能不会从药物中获得受益，同时使他们遭受潜在的严重副作用。该提案的结果将确定较差的反应者或可能更容易出现严重副作用的人的遗传概况，因此，一旦遗传分析成为护理标准的一部分，可能会影响男性退伍军人和降压体患者的未来护理。