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承认。男性体内的雌激素主要来源于芳香化酶将睾酮转化为雌二醇。芳香化酶基因（CYP 19 A1）的多态性已被报道导致可变的酶活性，导致可变的激素谱和变异体之间骨矿物质密度（BMD）的差异。这些多态性也被发现影响绝经后妇女对激素治疗的BMD变化和乳腺癌妇女芳香化酶抑制剂引起的骨丢失。这些相同的多态性也可能影响给予睾酮的性腺功能减退男性对睾酮治疗的骨骼反应。 在睾酮治疗的副作用中，前列腺相关事件和红细胞压积增加是更常见和可能更严重的副作用。然而，这些副作用并不会影响所有人，这表明某些亚组的患者容易出现这些副作用。由于CYP 19 A1基因的多态性导致变异体之间活性的差异，导致可变的底物和产物积累，我们假设这些多态性将影响骨骼反应，并可能影响睾酮治疗副作用的易感性。因此，本提案的目标是：（1）评估CYP 19 A1基因多态性对低睾酮男性患者对睾酮的骨骼反应的影响，（2）评估CYP 19 A1基因多态性对睾酮治疗副作用易感性的影响，（3）研究CYP 19 A1基因多态性对芳香化酶功能活性的影响。我们建议将131例患者随机分为安慰剂组（25%的受试者）或环戊丙酸睾酮200 mg IM组（75%的受试者），每2周一次，治疗期为18个月。我们将通过双能X线吸收法、骨转换标志物、血细胞比容、前列腺特异性抗原（PSA）、前列腺体积和激素测定进行BMD的系列测量。将比较睾酮治疗受试者和安慰剂之间以及睾酮治疗组中不同CYP 19 A1基因型之间的BMD和骨转换标志物的变化。我们还将比较不同CYP 19 A1基因型之间红细胞压积、PSA和前列腺体积的变化。通过对从脐周脂肪活检获得的脂肪组织进行CYP 19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志物）的变化，评价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较高的雌二醇水平，从而导致BMD的更大增量。同时，活性较低的变体将具有比其他变体相对更高的睾酮水平，并且具有更大的血细胞比容增量。另一方面，与较高雌二醇/睾酮比值相关的变异体在治疗后将经历PSA和前列腺体积的更大增加。 睾酮缺乏症的发生率随着年龄的增长和共病的存在而上升，使得男性性腺功能减退症成为参加VA诊所的患者中的常见问题之一，这些患者大多数是患有各种共病的老年人。事实上，大量的VA患者已经在服用睾酮治疗舌骨腺症，其中一些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没有从药物中获益，同时使他们遭受潜在的严重副作用。该提案的结果将确定不良反应者或更容易发生严重副作用的人的有利反应者的遗传特征，因此，一旦遗传特征成为护理标准的一部分，可能会影响男性退伍军人和性腺功能减退患者的未来护理。