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 preci...