CYP19A1 gene and Pharmacogenetics of Response

描述(由申请人提供)： 雌激素已经被公认为是调节男性骨骼的主要荷尔蒙。男性体内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)的多态导致酶活性变化，导致激素谱不同，不同变异体之间的骨密度(BMD)存在差异。这些基因多态也被发现影响绝经后妇女激素治疗后骨密度的变化，以及乳腺癌妇女芳香酶抑制剂导致的骨丢失。在给予睾酮的性腺功能低下的男性中，这些相同的基因多态也可能会影响骨骼对睾酮治疗的反应。在所描述的睾酮治疗的副作用中，与前列腺相关的事件和红细胞压积的增加是更常见的，也是潜在的更严重的副作用。然而，这些副作用并不影响每个人，这表明某些患者容易受到这些副作用的影响。由于CYP19A1基因的多态导致不同变异体的活性差异，从而导致不同底物和产物的积累，我们假设这些多态将影响骨骼反应，并可能影响对睾酮治疗副作用的易感性。因此，本研究的目的是：(1)评估CYP19A1基因多态性对睾酮水平低下男性患者骨骼组织对睾酮反应的影响；(2)评估CYP19A1基因多态性对睾酮治疗副作用易感性的影响；(3)评估临床上有意义的CYP19A1基因多态性对芳香化酶功能活性的影响。我们建议将131名患者随机分为安慰剂(25%的受试者)或西比亚酸睾丸酮200 mg肌注，每两周(75%的受试者)进行为期18个月的治疗。采用双能X线骨密度仪、骨转换标志物、红细胞压积、前列腺特异性抗原(PSA)、前列腺体积和激素测定等方法进行系列骨密度测定。研究人员将比较接受睾丸素治疗的受试者和安慰剂组的骨密度和骨转换指标的变化，以及接受睾丸酮治疗的受试者中不同的CYP19A1基因型间的变化。我们还将比较不同CYP19A1基因型之间的红细胞压积、PSA和前列腺体积的变化。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，以及通过雌二醇与睾酮比率的变化(芳香酶活性的替代标记物)，来评估突变体之间的功能活性变化。我们预计，活性增加的变体将比活性较低的变体有相对更高的雌二醇水平，从而导致更大的骨密度增量。同时，活性较低的变种会比其他变种的睾酮水平相对较高，红细胞压积的增量也更大。另一方面，与更高的雌二醇/睾酮比率相关的变体将在治疗后经历更大的PSA和前列腺体积的增加。睾酮缺乏症的发生率随着年龄的增长而上升，并伴随疾病的存在，这使得男性性腺功能减退成为退伍军人管理局诊所患者中常见的问题之一，这些患者大多是患有各种共同疾病的老年人。事实上，大量的VA患者已经在服用睾丸素来治疗扁桃体增生症，其中一些主要是为了防止进一步的骨丢失。有可能的是，这些患者中的一些人并没有从药物中受益，而是受到潜在的严重副作用的影响。这项提案的结果将确定来自较差应答者或那些可能更容易出现严重副作用的有利应答者的基因图谱，因此，一旦基因图谱成为护理标准的一部分，可能会影响未来对男性退伍军人和性腺功能低下患者的护理。

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.