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用的处方药，但鲜为人知的是， 它们的处置、反应和毒性的决定因素。药物基因组学是研究 遗传变异与个体间药物疗效、代谢和安全性变异之间的关系。的结果 药物基因组学研究已经导致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。尽管取得了快速进展， 药物基因组学对于许多医学领域来说，关于药物基因组学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）的功效、代谢和安全性。使用类固醇激素 在妇女的整个生命周期中，用于多种适应症，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 因此，我们必须了解个体遗传变异与这些疾病之间的关系。 药物治疗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 代谢和临床相关的副作用。我们计划使用依托孕烯避孕药 考虑到避孕植入剂的稳定释放药理学及其 独立于方案遵守问题。我们也有候选基因研究的初步数据 依托孕烯植入物使用者的研究，证明了遗传变异与血清 依托孕烯的浓度和维生素B1相关的副作用。然而，大多数药理学 变异性仍然是未知的，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， 样本来自339名避孕植入物使用者，另有561名在其治疗期间使用避孕植入物。 使用12-36个月的稳态期，以创建700名植入用户的发现队列和一个复制 剩下的200名女性。我们目前已经招募了101名新参与者，需要460名 以满足我们计划的样本量。然后我们将进行全基因组关联 与我们的发现队列研究，并检查与血清依托孕烯浓度的相关性， 表明可能的代谢增加或减少。所有参与者还将填写一份问卷， 收集相关的生活方式因素和副作用数据，我们将分析这些数据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多达五个单核苷酸的关联， 在发现队列中鉴定的具有最强关联的多态性。这项研究将确定新的 基因靶点，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 精准医疗临床工具的一部分这些临床工具有一天可能会允许更精确的咨询， 考虑类固醇激素药物治疗的女性，考虑其个体疗效和副作用， 常用的处方药。