Browsing by Author "Swart, Marelize"
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Item Analytical Validation of Variants to Aid in Genotype-Guided Therapy for Oncology(Elsevier, 2019) Swart, Marelize; Stansberry, Wesley M.; Pratt, Victoria M.; Medeiros, Elizabeth B.; Kiel, Patrick J.; Shen, Fei; Schneider, Bryan P.; Skaar, Todd C.; Medical and Molecular Genetics, School of MedicineThe Clinical Laboratory Improvement Amendments (CLIA) of 1988 requires that pharmacogenetic genotyping methods need to be established according to technical standards and laboratory practice guidelines before testing can be offered to patients. Testing methods for variants in ABCB1, CBR3, COMT, CYP3A7, C8ORF34, FCGR2A, FCGR3A, HAS3, NT5C2, NUDT15, SBF2, SEMA3C, SLC16A5, SLC28A3, SOD2, TLR4, and TPMT were validated in a CLIA-accredited laboratory. As no known reference materials were available, DNA samples that were from Coriell Cell Repositories (Camden, NJ) were used for the analytical validation studies. Pharmacogenetic testing methods developed here were shown to be accurate and 100% analytically sensitive and specific. Other CLIA-accredited laboratories interested in offering pharmacogenetic testing for these genetic variants, related to genotype-guided therapy for oncology, could use these publicly available samples as reference materials when developing and validating new genetic tests or refining current assays.Item Analytical validity of a genotyping assay for use with personalized antihypertensive and chronic kidney disease therapy(Wolters Kluwer, 2019-01) Collins, Kimberly; Pratt, Victoria; Stansberry, Wesley; Medeiros, Elizabeth; Kannegolla, Karthik; Swart, Marelize; Skaar, Todd C.; Chapman, Arlene; Decker, Brian; Moorthi, Ranjani; Eadon, Michael; Medicine, School of MedicineHypertension and chronic kidney disease are inextricably linked. Hypertension is a well-recognized contributor to chronic kidney disease progression and, in turn, renal disease potentiates hypertension. A generalized approach to drug selection and dosage has not proven effective in managing these conditions, in part, because patients with heterogeneous kidney disease and hypertension etiologies are frequently grouped according to functional or severity classifications. Genetic testing may serve as an important tool in the armamentarium of clinicians who embrace precision medicine. Increasing scientific evidence has supported the utilization of genomic information to select efficacious antihypertensive therapy and understand hereditary contributors to chronic kidney disease progression. Given the wide array of antihypertensive agents available and diversity of genetic renal disease predictors, a panel-based approach to genotyping may be an efficient and economic means of establishing an individualized blood pressure response profile for patients with various forms of chronic kidney disease and hypertension. In this manuscript, we discuss the validation process of a Clinical Laboratory Improvement Amendments (CLIA)-approved genetic test to relay information on 72 genetic variants associated with kidney disease progression and hypertension therapy. These genomic-based interventions, in addition to routine clinical data, may help inform physicians to provide personalized therapy.Item Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6 and Efavirenz-Containing Antiretroviral Therapy(Wiley, 2019-04-21) Desta, Zeruesenay; Gammal, Roseann S.; Gong, Li; Whirl-Carrillo, Michelle; Gaur, Aditya H.; Sukasem, Chonlaphat; Hockings, Jennifer; Myers, Alan; Swart, Marelize; Tyndale, Rachel F.; Masimirembwa, Collen; Iwuchukwu, Otito F.; Chirwa, Sanika; Lennox, Jeffrey; Gaedigk, Andrea; Klein, Teri E.; Haas, David W.; Medicine, School of MedicineThe human immunodeficiency virus (HIV) type-1 non-nucleoside reverse transcriptase inhibitor, efavirenz, is widely used to treat HIV-1 infection. Efavirenz is predominantly metabolized into inactive metabolites by CYP2B6, and patients with certain CYP2B6 genetic variants may be at increased risk for adverse effects, particularly central nervous system toxicity and treatment discontinuation. We summarize the evidence from the literature and provide therapeutic recommendations for efavirenz prescribing based on CYP2B6 genotypes.Item Pharmacogenetics and Practice: Tailoring Prescribing for Safety and Effectiveness(Elsevier, 2018) Fulton, Cathy R.; Swart, Marelize; De Luca, Thomas; Liu, Stephanie N.; Collins, Kimberly S.; Desta, Zeruesenay; Gufford, Brandon T.; Eadon, Michael T.; Medicine, School of MedicineThe promise of pharmacogenomics testing, to find the right medication at the right dose for the right patient at the right time, sits at the heart of precision medicine. Identifying genetic variants that contribute to inter-patient variability in drug disposition and effect allows clinicians to select a more appropriate medication for a patient’s condition by limiting adverse drug events and maximizing beneficial effects. However, as pharmacogenomics is increasingly integrated into prevention-based healthcare, a major obstacle to effective implementation of pharmacogenomics testing is the lack of adequate knowledge of healthcare providers on interpretation of these test results.Item Report of Confirmation of the rs7853758 and rs885004 Haplotype in SLC28A3(Mary Ann Liebert, 2018-11) Stansberry, Wesley M.; Swart, Marelize; Medeiros, Elizabeth B.; Skaar, Todd C.; Pratt, Victoria M.; Medical and Molecular Genetics, School of MedicineAIMS: To validate a laboratory-developed test for the nucleoside transporter, SLC28A3, which has been associated with an increased risk of anthracycline-induced cardiomyopathy. METHODS: We used Taqman® allele discrimination to test for two variants of the SLC28A3 gene: rs7853758 (c.1381C>T) and rs885004 (c.862-360C>T). RESULTS: During the validation process, we noted that several DNA samples obtained from the Coriell Cell Repository (Camden, NJ) were positive for both the c.1381 C > T and c.862-360C>T variants and another variant allele for either c.1381 C > T or c.862-360C>T (e.g., c.1381C>T homozygous/c.862-360C>T heterozygous, c.1381C>T homozygous/c.862-360C>T homozygous). We used de-identified DNA samples from trios of family members (mother, father, and child) to establish that the c.1381 C > T and c.862-360C>T variant alleles could be inherited in cis on the same chromosome. CONCLUSIONS: Samples containing three variant alleles suggest that the c.1381 C > T and c.862-360C>T are in cis on the chromosome in some individuals and may have implications when calculating anthracycline-induced cardiomyopathy risk. In this study, we confirm a novel haplotype of SLC28A3 using familial studies.Item Variants in the CYP2B6 3′UTR Alter In Vitro and In Vivo CYP2B6 Activity: Potential Role of MicroRNAs(Wiley, 2017) Burgess, Kimberly S.; Ipe, Joseph; Swart, Marelize; Metzger, Ingrid F.; Lu, Jessica; Gufford, Brandon T.; Thong, Nancy; Desta, Zeruesenay; Gaedigk, Roger; Pearce, Robin; Gaedigk, Andrea; Liu, Yunlong; Skaar, Todd C.; Medicine, School of MedicineCYP2B6*6 and CYP2B6*18 are the most clinically important variants causing reduced CYP2B6 protein expression and activity. However, these variants do not account for all variability in CYP2B6 activity. Emerging evidence has shown that genetic variants in the 3′UTR may explain variable drug response by altering microRNA regulation. Five 3′UTR variants were associated with significantly altered efavirenz AUC0-48 (8-OH-EFV/EFV) ratios in healthy human volunteers. The rs70950385 (AG>CA) variant, predicted to create a microRNA binding site for miR-1275, was associated with a 33% decreased CYP2B6 activity among normal metabolizers (AG/AG vs. CA/CA (P < 0.05)). In vitro luciferase assays were used to confirm that the CA on the variant allele created a microRNA binding site causing an 11.3% decrease in activity compared to the AG allele when treated with miR-1275 (P = 0.0035). Our results show that a 3′UTR variant contributes to variability in CYP2B6 activity.