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

遗传变异对避孕埋植剂使用者类固醇激素代谢和孕激素相关副作用的影响

• 批准号: 10356154
• 负责人: Aaron Lazorwitz
• 金额: $ 7.78万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-18 至 2024-02-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356154
• 关键词: Adherence; Affect; Area; Candidate Disease Gene; Clinical; Clinical Medicine; Codeine; Contraceptive Agents; Contraceptive Usage; Contraceptive methods; Counseling; Country; Custom; Data; Development; Drug Kinetics; Drug Prescriptions; Enrollment; Enzymes; Estrogens; Etonogestrel; Formulation; Future; Genes; Genetic; Genetic Determinism; Genetic Variation; Genomics; Guidelines; Health; Healthcare Systems; Hemorrhage; Hormonal; Hormone replacement therapy; Hormone use; Hormones; Human; Human Genome; Implant; Individual; Individual Differences; Investigation; Lead; Literature; Longevity; Medical; Medicine; Menopausal Symptom; Metabolism; Modality; Oral Contraceptives; Participant; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Pharmacology; Physiological; Population; Premature Birth; Prevention; Progestins; Protocols documentation; Questionnaires; Research Design; Risk; Safety; Sample Size; Sampling; Serum; Single Nucleotide Polymorphism; Tacrolimus; Testing; Testosterone; Toxic effect; Translating; Warfarin; Woman; Women' s Health; Work; base; biobank; birth control; clinical application; clinically actionable; clinically relevant; clopidogrel; cohort; dehydroepiandrosterone; design; drug disposition; drug efficacy; genetic regulatory protein; genetic variant; genome wide association study; genomic locus; hormonal contraception; improved; inter-individual variation; lifestyle factors; male; novel; personalized management; personalized medicine; pill; precision medicine; premature; response; side effect; steroid hormone; steroid hormone metabolism; symptom management; tool

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.

项目摘要 类固醇激素是一些最常见的药物，但对 其处置，反应和毒性的决定因素。药物基因组学是对关系的研究 在药物疗效，代谢和安全性的遗传变异与个体差异之间。结果 药物基因组学调查导致了临床药物遗传学实施联盟 制定了35多个药物对的可行临床指南。尽管进展迅速 对于许多医学领域的药物基因组学，关于遗传决定因素的信息很少 类固醇激素（即雌激素和孕激素）功效，代谢和安全性。使用类固醇激素 在一个女人的生命中，有多种适应症，包括避孕，预防早产， 激素替代疗法以及许多其他疗法。鉴于类固醇激素的高处方率 药物，我们必须了解单个遗传变异与这些差异之间的关系 药物。我们旨在确定与类固醇激素相关的人类基因组的新领域 代谢，与临床相关的副作用相关。我们计划使用Etonogestel避孕药 鉴于避孕植入物的稳定释放药理学及其植入用户 独立于协议依从性问题。我们也有来自候选基因研究的初步数据 Etonogestel植入物的使用者，证明了遗传变异与血清之间的关联 Etonogestel浓度和孕激素相关的副作用。但是，大多数药理学 可变性仍然没有责任，我们的候选基因方法不能包括所有遗传区域 与类固醇激素的代谢和功能有关。我们计划丰富我们现有的基因组生物库 来自339种避孕植入物的样品在其期间使用避孕植入物使用另外561 稳态时期为12-36个月，用于创建700种植入用户的发现队列和复制 剩下的200名妇女队列。我们目前已经注册了101名新参与者，需要460 其他参与者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 通过我们的发现队列进行研究，并检查与血清EtonogeTrel浓度的关联 表示可能增加或减少新陈代谢。所有参与者还将完成问卷调查 收集相关的生活方式因素和副作用数据，我们将分析与基因组的关联 结果。我们将利用复制队列来复制多达五个单核苷酸 在发现队列中确定的最强关联的多态性。这项研究将确定新颖 可以直接告知未来研究努力并为最终创建贡献数据的遗传目标 精密医学临床工具。这些临床工具可能有一天可以提供更精确的咨询 考虑类固醇激素药物有关其个体功效和副作用的女性 通常处方药。