Variant allele frequencies were 69.4%, 84.9%, and 5.1%, respectively. associated with serum ENG concentrations: rs2461817 (= 13.36, p=0.005), rs537681 (= ?29.77, p=0.007), and (= ?35.06, p=0.025). Variant allele frequencies were 69.4%, 84.9%, and 5.1%, respectively. Our linear model also contained two nongenetic factors associated with etonogestrel concentrations: body-mass index (= ?3.08, p=7.010?7) and duration of implant use (= ?1.60, p=5.810?5); R2 for the model = 0.17. Conclusion: Only body-mass index and duration of implant use remained significantly associated with steady-state etonogestrel concentrations. Of the three novel genetic associations found, one variant associated with increased etonogestrel metabolism (carriers had serum etonogestrel concentrations that fell below Entacapone sodium salt the threshold for consistent ovulatory suppression ( 90pg/mL). More pharmacogenomic investigations are needed to advance our understanding of how genetic variation can influence the effectiveness and safety of hormonal contraception, and lay the groundwork for personalized medicine approaches in womens health. Clinical Trial Registration: ClinicalTrials.gov, “type”:”clinical-trial”,”attrs”:”text”:”NCT03092037″,”term_id”:”NCT03092037″NCT03092037. Prcis Some genetic variants, such as those influencing cytochrome P450 enzyme function, can affect steroid hormone drug concentrations and may decrease the efficacy of hormonal contraceptive methods. Introduction In this era of precision and personalized medicine, as the field of pharmacogenomics and our understanding of the human genome advance, the potential to customize medical treatments based on an individuals genetic profile is becoming a reality (1, 2). Pharmacogenomics is the study of the relationship between genetic variations and interindividual variability in drug disposition, response, and toxicity. Some of these genetic variations significantly affect the function of drug metabolizing enzymes and their regulatory proteins, leading to altered metabolism of medications including clopidogrel, warfarin, codeine, tacrolimus, and many others (3C5). The Clinical Pharmacogenetics Implementation Consortium currently provides clinical guidelines for over 35 medications (1). Drug-gene research often consists of both candidate gene approaches, selecting specific genetic variants to study based on physiologic plausibility, and genome wide association studies, searching for novel associations across the whole genome. If well-designed, both of these approaches can provide high quality evidence for the development of clinical guidelines (6). However, there is a dearth of information about genetic determinants of hormonal contraceptive disposition, response, and toxicity, which is surprising given that these are some of the most commonly prescribed medications in the United States (7). Pharmacogenomics is particularly useful for medications with large interindividual Entacapone sodium salt differences in drug pharmacokinetics or pharmacodynamics. Pharmacokinetic data already demonstrate that there is a wide range ( 12 fold difference) in drug concentrations for women using the exact same hormonal contraceptive method (8C10). This wide inter-individual variability can be beyond the accepted criteria for bioequivalence (95% confidence interval of the mean parameter values within 80C125% of the accepted standard), which may put some women outside the therapeutic range of their hormonal contraceptive method (11, 12). Estrogens and progestins Bnip3 are primarily metabolized Entacapone sodium salt by cytochrome P-450 (CYP) 3A enzymes, predominantly through CYP3A4 (13). Previous studies with other CYP3A substrates have shown that genetic variants significantly affect drug metabolism and concentrations (14, 15). However, the influence of variation in and related genes on steroid hormone medication pharmacokinetics is not known. According to the Guttmacher Institute, 27.6% of women have used a hormonal contraceptive method in the past month and four out of five sexually experienced women report current or past usage of an oral hormonal contraceptive method (7, 16). Given the personal and public health implications of unintended pregnancies from contraceptive failures, there is an urgent need to better understand the role of genetic variations on hormonal contraceptive serum concentrations, efficacy, and toxicity. The etonogestrel contraceptive implant (Nexplanon?, formerly Implanon?, Merck & Co., Whitehouse Station NJ) has a well-described pharmacokinetic profile and represents an ideal model for pharmacogenomic studies of exogenous steroid hormones given its steady-state drug release and independence from issues of protocol adherence (17). To address current gaps in knowledge, we used a candidate gene approach to identify genetic variants that influence steady-state etonogestrel concentrations among a large, racially Entacapone sodium salt and ethnically diverse group of contraceptive implant users. We hypothesized that variants in genes encoding proteins involved in steroid hormone (i.e. estrogens, progestins) metabolism, regulation, and function would be associated with serum etonogestrel concentrations in contraceptive implant users and account for some of the known interindividual pharmacokinetic variability of this contraceptive method. Materials and Methods Entacapone sodium salt In this pharmacogenomic study, we recruited English or Spanish speaking reproductive aged women (18C45 years old) with an etonogestrel contraceptive implant in place for at least 12 and no more than 36 months. We chose this duration of implant use because the etonogestrel implant has a pharmacokinetic.