CYP19A1 gene and Pharmacogenetics of Response

CYP19A1 基因和反应的药物遗传学

• 批准号: 8391094
• 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/8391094
• 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）： 雌激素作为调节男性骨骼的主要激素已得到认可。男性的雌激素主要来自于芳香酶将睾酮转化为雌二醇。据报道，芳香酶基因 (CYP19A1) 的多态性会导致不同的酶活性，从而导致不同变体之间不同的激素分布和骨矿物质密度 (BMD) 差异。还发现这些多态性会影响绝经后女性激素治疗引起的骨密度变化，以及乳腺癌女性芳香酶抑制剂引起的骨质流失。这些相同的多态性也可能会影响接受睾酮治疗的性腺功能减退男性的骨骼对睾酮治疗的反应。 在睾酮治疗描述的副作用中，前列腺相关事件和血细胞比容增加是更常见且可能更严重的副作用。然而，这些副作用并不影响所有人，这表明某些患者亚群容易出现这些副作用。由于 CYP19A1 基因的多态性导致变异体之间的活性差异，从而导致底物和产物积累可变，因此我们假设这些多态性将影响骨骼反应，并可能影响对睾酮治疗副作用的敏感性。因此，本提案的目的是：（1）评估 CYP19A1 基因多态性对低睾酮男性患者骨骼对睾酮反应的影响，（2）评估 CYP19A1 基因多态性对易感性的影响睾酮治疗的副作用，(3) 评估具有临床意义的 CYP19A1 基因中芳香酶功能活性的变化多态性。我们建议将 131 名患者随机分为安慰剂组（25% 的受试者）或环戊丙酸睾酮 200 mg 肌肉注射，每 2 周一次（75% 的受试者），治疗期为 18 个月。我们将通过双能 X 射线吸收测定法、骨转换标记物、血细胞比容、前列腺特异性抗原 (PSA)、前列腺体积和激素测定对 BMD 进行系列测量。将比较睾酮治疗组和安慰剂组以及睾酮治疗组不同 CYP19A1 基因型之间 BMD 和骨转换标志物的变化。我们还将比较不同 CYP19A1 基因型之间的血细胞比容、PSA 和前列腺体积的变化。将通过对脐周脂肪活检获得的脂肪组织进行 CYP19 基因表达研究，并通过雌二醇与睾酮比率（芳香酶活性的替代标记）的变化来评估变体之间功能活性的变化。我们预计活性增加的变体将比活性较低的变体具有相对更高的雌二醇水平，从而导致 BMD 增加更大。同时，较不活跃的变体将比其他变体具有相对更高的睾酮水平，并且血细胞比容具有更大的增量。另一方面，与较高雌二醇与睾酮比率相关的变异体在治疗过程中 PSA 和前列腺体积会出现更大的增加。 睾酮缺乏症的发病率随着年龄的增长和合并症的存在而增加，这使得男性性腺功能减退症成为 VA 诊所就诊的患者的常见问题之一，这些患者大部分是患有各种合并症的老年人。事实上，大量 VA 患者已经在服用睾酮来治疗性腺功能减退症，其中一些主要是为了防止进一步的骨质流失。其中一些患者可能无法从该药物中获益，同时面临潜在的严重副作用。该提案的结果将识别出良好反应者和不良反应者或可能更容易出现严重副作用的人的基因谱，因此，一旦基因谱成为研究的一部分，可能会影响男性退伍军人和性腺功能减退症患者的未来护理。护理标准。