Influence of genetic variants on steroid hormone metabolism and progestin-related side effects in contraceptive implant users

项目总结 类固醇激素是最常见的处方药之一，但人们对其知之甚少 它们的处置、反应和毒性的决定因素。药物基因组学研究的是两者之间的关系。 在药物疗效、新陈代谢和安全性方面的遗传变异和个体间变异之间的关系。结果是 药物基因组学研究导致了临床药物遗传学实施联盟 为超过35个药物-基因对制定可操作的临床指南。尽管在以下方面取得了快速进展 药物基因组学对于医学的许多领域来说，关于疾病的遗传决定因素的信息很少 类固醇激素(即雌激素和孕激素)的有效性、新陈代谢和安全性。使用类固醇激素 在妇女的一生中，有许多适应症，包括避孕、早产预防、 激素替代疗法，以及许多其他疗法。考虑到类固醇激素的高处方率 对于药物，我们必须了解个体基因变异与这些 药物。我们的目标是确定人类基因组中与类固醇激素相关的新区域。 代谢，并与临床相关的副作用有关。我们计划使用依托诺孕酮避孕药 本研究的植入物使用者给出了避孕药植入物的稳定释放药理学及其 独立于遵守协议的问题。我们还有一项候选基因研究的初步数据 这表明基因变异与两种血清之间的关系 依托诺孕酮浓度和孕激素相关副作用。然而，大多数药理学 变异性仍未被解释，我们的候选基因方法不能包括所有的遗传区域。 与类固醇激素代谢和功能有关。我们计划丰富我们现有的基因组生物库 来自339名避孕植入物使用者的样本，另有561名在其 12-36个月的稳定期，用于创建700名植入物用户的发现队列和复制 其余200名女性的队列。我们目前已招募了101名新参与者，需要460名 额外的参与者以满足我们计划的样本量。然后我们将执行基因组范围的关联 与我们的发现队列一起研究，并检查与血清雌二醇浓度的相关性 表示新陈代谢可能增加或减少的。所有参与者还将完成一份调查问卷，以 收集相关的生活方式因素和副作用数据，我们将分析它们与我们的基因组之间的关联 结果。我们将利用我们的复制队列来复制最多五个单核苷酸的关联 发现队列中发现的具有最强关联性的多态。这项研究将确定小说 基因靶标可以直接为未来的研究工作提供信息，并为最终的创造提供数据 精准医学临床工具。这些临床工具有一天可能会允许更精确的咨询 考虑服用类固醇激素药物的妇女对这些药物的个人疗效和副作用 常用的处方药。

PROJECT SUMMARY Steroid hormones are some of the most commonly prescribed medications, yet little is known about the determinants of their disposition, response, and toxicity. Pharmacogenomics is the study of the relationship between genetic variations and interindividual variability in drug efficacy, metabolism, and safety. The results of pharmacogenomic investigations have led to the Clinical Pharmacogenetics Implementation Consortium developing actionable clinical guidelines for over 35 drug-gene pairs. Despite rapid progress in pharmacogenomics for many areas of medicine, there is scant information about genetic determinants of steroid hormone (i.e. estrogens and progestins) efficacy, metabolism, and safety. Steroid hormones are used throughout a woman's life-span for a multitude of indications including contraception, preterm birth prevention, hormone replacement therapy, and many others. Given the high prescription rate of steroid hormone medications, it is imperative that we understand the relationship between individual genetic variation and these medications. We aim to identify novel areas of the human genome that are associated with steroid hormone metabolism and associated with clinically relevant side effects. We plan to use etonogestrel contraceptive implant users for this study given the steady-release pharmacology of the contraceptive implant and its independence from issues of protocol adherence. We also have preliminary data from a candidate gene study of etonogestrel implant users, which demonstrated associations between genetic variants and both serum etonogestrel concentrations and progestin related side effects. However, the majority of pharmacologic variability remains unaccounted for and our candidate gene approach could not include all genetic regions pertinent to steroid hormone metabolism and function. We plan to enrich our existing biobank of genomic samples from 339 contraceptive implant users with another 561 using a contraceptive implant during its steady-state period of 12-36 months of use to create a discovery cohort of 700 implant users and a replication cohort of the remaining 200 women. We have currently enrolled 101 new participants and require 460 additional participants to meet our planned sample size. We will then perform a Genome Wide Association Study with our discovery cohort and examine for associations with serum etonogestrel concentrations that are indicative of possible increased or decreased metabolism. All participants will also complete a questionnaire to gather pertinent lifestyle factors and side-effect data that we will analyze for associations with our genomic results. We will utilize our replication cohort to duplicate associations for up to five single nucleotide polymorphisms with the strongest associations identified in the discovery cohort. This study will identify novel genetic targets that can directly inform future research endeavors and contribute data to the eventual creation of precision medicine clinical tools. These clinical tools may one day allow for more precise counseling of women considering steroid hormone medications regarding their individual efficacy and side effects with these commonly prescribed medications.