Extreme phenotype sampling and next generation sequencing to identify genetic variants associated with tacrolimus in African American kidney transplant recipients.

African American (AA) kidney transplant recipients (KTRs) have poor outcomes, which may in-part be due to tacrolimus (TAC) sub-optimal immunosuppression. We previously determined the common genetic regulators of TAC pharmacokinetics in AAs which were CYP3A5 *3, *6, and *7. To identify low-frequency variants that impact TAC pharmacokinetics, we used extreme phenotype sampling and compared individuals with extreme high (n = 58) and low (n = 60) TAC troughs (N = 515 AA KTRs).

Limited Sampling Strategies Fail to Accurately Predict Mycophenolic Acid Area Under the Curve in Kidney Transplant Recipients and the Impact of Enterohepatic Recirculation.

Background: Therapeutic drug monitoring for mycophenolic acid (MPA) is challenging due to difficulties in measuring the area under the curve (AUC). Limited sampling strategies (LSSs) have been developed for MPA therapeutic drug monitoring but come with risk of unacceptable performance. The authors hypothesized that the poor predictive performance of LSSs were due to the variability in MPA enterohepatic recirculation (EHR).

Steroid-tacrolimus drug-drug interaction and the effect of CYP3A genotypes.

Aims: Tacrolimus, metabolized by CYP3A4 and CYP3A5 enzymes, is susceptible to drug-drug interactions (DDI). Steroids induce CYP3A genes to increase tacrolimus clearance, but the effect is variable. We hypothesized that the extent of the steroid-tacrolimus DDI differs by CYP3A4/5 genotypes.

Polygenic risk score for acute rejection based on donor-recipient non-HLA genotype mismatch.

Background: Acute rejection (AR) after kidney transplantation is an important allograft complication. To reduce the risk of post-transplant AR, determination of kidney transplant donor-recipient mismatching focuses on blood type and human leukocyte antigens (HLA), while it remains unclear whether non-HLA genetic mismatching is related to post-transplant complications.

Methods: We carried out a genome-wide scan (HLA and non-HLA regions) on AR with a large kidney transplant cohort of 784 living donor-recipient pairs of European ancestry.

Donor genetic burden for cerebrovascular risk and kidney transplant outcome.

Background And Hypothesis: Kidney grafts from donors who died of stroke and related traits have worse outcomes relative to grafts from both living donors and those who died of other causes. We hypothesise that deceased donors, particularly those who died of stroke, have elevated polygenic burden for cerebrovascular traits. We further hypothesise that this donor polygenic burden is associated with inferior graft outcomes in the recipient.

Assessing the Utility of a Genotype-Guided Tacrolimus Equation in African American Kidney Transplant Recipients: A Single Institution Retrospective Study.

Tacrolimus metabolism is heavily influenced by the CYP3A5 genotype, which varies widely among African Americans (AA). We aimed to assess the performance of a published genotype-informed tacrolimus dosing model in an independent set of adult AA kidney transplant (KTx) recipients. CYP3A5 genotypes were obtained for all AA KTx recipients (n = 232) from 2010 to 2019 who met inclusion criteria at a single transplant center in Philadelphia, Pennsylvania, USA.

Extreme Phenotype Sampling and Next Generation Sequencing to Identify Genetic Variants Associated with Tacrolimus in African American Kidney Transplant Recipients.

African American (AA) kidney transplant recipients (KTRs) have poor outcomes, which may in-part be due to tacrolimus (TAC) sub-optimal immunosuppression. We previously determined the common genetic regulators of TAC pharmacokinetics in AAs which were CYP3A5 *3, *6, and *7. To identify low-frequency variants that impact TAC pharmacokinetics, we used extreme phenotype sampling and compared individuals with extreme high (n=58) and low (n=60) TAC troughs (N=515 AA KTRs).

Meeting the New AACP Competencies in Genetics and Clinical Pharmacogenomics at the University of Minnesota.

: Pharmacogenomics (PGx) is increasingly being used for creating individualized treatments for patient care. Healthcare professionals, especially pharmacists, need to understand how genetic variation impacts the efficacy and toxicity of medications. Due to the breadth and complexity of PGx-related information, it has been challenging to determine what information should be included in pharmacy curricula and how best to educate students.

Phase II, Open-Label Clinical Trial of Urinary-Derived Human Chorionic Gonadotropin/Epidermal Growth Factor for Life-Threatening Acute Graft-versus-Host Disease.

Treatments that aid inflammation resolution, immune tolerance, and epithelial repair may improve outcomes beyond high-dose corticosteroids and other broad immunosuppressants for life-threatening acute graft-versus-host disease (aGVHD). We studied the addition of urinary-derived human chorionic gonadotropin/epidermal growth factor (uhCG/EGF; Pregnyl; Organon, Jersey City, NJ) to standard aGVHD therapy in a prospective Phase II clinical trial (ClinicalTrials.gov identifier NCT02525029).

Addressing disparities in pharmacogenomics through rural and underserved workforce education.

While pharmacogenomic (PGx) testing is routine in urban healthcare institutions or academic health centers with access to existing expertise, uptake in medically-underserved areas is lagging. The primary objective of this workforce education program is to extend access to didactic, case-based and clinical PGx training for pharmacists serving rural Minnesota and populations experiencing health disparities in Minnesota. A PGx workforce training program funded through the Minnesota Department of Health was offered through the University of Minnesota College of Pharmacy (COP) to pharmacists working in rural and/or underserved areas in the state of Minnesota.

Higher number of tacrolimus dose adjustments in kidney transplant recipients who are extensive and intermediate CYP3A5 metabolizers.

Kidney transplant recipients carrying the CYP3A5*1 allele have lower tacrolimus troughs, and higher dose requirements compared to those with the CYP3A5*3/*3 genotype. However, data on the effect of CYP3A5 alleles on post-transplant tacrolimus management are lacking. The effect of CYP3A5 metabolism phenotypes on the number of tacrolimus dose adjustments and troughs in the first 6 months post-transplant was evaluated in 78 recipients (64% Caucasians).

Public Attitudes toward Pharmacogenomic Testing and Establishing a Statewide Pharmacogenomics Database in the State of Minnesota.

The clinical adoption and implementation of pharmacogenomics (PGx) beyond academic medical centers remains slow, restricting the general population from benefitting from this important component of personalized medicine. As an initial step in the statewide initiative of PGx implementation in Minnesota, we engaged community members and assessed attitudes towards PGx testing and acceptability of establishing a secure statewide PGx database for clinical and research use among Minnesota residents. Data was collected from 808 adult attendees at the 2021 Minnesota State Fair through an electronic survey.

Comparison of Dose Adjustment Strategies for Obesity in High-dose Cyclophosphamide Among Adult Hematopoietic Cell Transplantation Recipients: Pharmacokinetic Analysis.

Cyclophosphamide (CY) is an alkylating agent widely used in the field of oncology and hematopoietic cell transplantation (HCT). It is recommended to use an adjusted body weight with an adjustment factor of 0.25 (ABW25) for dosing of CY in obese patients undergoing HCT.

Development and Validation of the Minnesota Assessment of Pharmacogenomic Literacy (MAPL).

Ensuring that patients have an adequate understanding of pharmacogenomic (PGx) test results is a critical component of implementing precision medicine into clinical care. However, no PGx-specific validated literacy assessment has yet been developed. To address this need, we developed and validated the Minnesota Assessment of Pharmacogenomic Literacy (MAPLTM).

Influence of Renal Function on Phosphoramide Mustard Exposure: A Nonlinear Mixed-Effects Analysis.

Phosphoramide mustard (PM) is the final cytotoxic metabolite formed from the parent compound cyclophosphamide through a complex metabolic pathway, primarily through hepatic metabolism. Little is known about the effect of renal elimination on the disposition of PM. We evaluated the effect of renal function on PM exposure after single doses of cyclophosphamide in 85 patients undergoing allogeneic hematopoietic cell transplantation using nonlinear mixed-effects modeling.

Fecal β-glucuronidase activity differs between hematopoietic cell and kidney transplantation and a possible mechanism for disparate dose requirements.

The intestinal microbiota produces β-glucuronidase that plays an essential role in the metabolism of the immunosuppressant mycophenolate mofetil (MMF). This drug is commonly used in organ and hematopoietic cell transplantation (HCT), with variations in dosing across transplant types. We hypothesized that β-glucuronidase activity differs between transplant types, which may account for differences in dosing requirements.

Perceptions of pharmacogenetic exceptionalism and the implications for clinical management within an electronic health record.

Genetic exceptionalism refers to a concept that genetic information is distinct from other health data and therefore should have additional safety guards in place. The objective of this study was to establish perceptions of pharmacogenetic (PGx) exceptionalism and genetic information privacy and management within the electronic health record (EHR) from individuals who attended a PGx-focused conference. A 47-question survey was distributed to 370 attendees at a PGx conference in September 2020.

Exploring Potential for a Personalized Medicine Approach to Smoking Cessation With an American Indian Tribe.

Introduction: A potential precision medicine approach to smoking cessation is tailoring pharmacotherapy to a biomarker known as the nicotine metabolite ratio (NMR). Little is known about the potential impact and acceptability of this approach for American Indian (AI) persons.

Aims And Methods: Tribal-academic collaboration was formed and during 2019-2020 AI adults who smoke(N = 54) were recruited to (1) examine correlations between NMR, dependence, and smoking exposure; (2) assess the extent to which pharmacotherapy preference aligned with NMR-informed recommendations; (3) explore acceptability of NMR-informed pharmacotherapy selection.

Reduced Enterohepatic Recirculation of Mycophenolate and Lower Blood Concentrations Are Associated with the Stool Bacterial Microbiome after Hematopoietic Cell Transplantation.

Mycophenolate mofetil (MMF) is an important immunosuppressant used after allogeneic hematopoietic cell transplantation (HCT). MMF has a narrow therapeutic index, and blood concentrations of mycophenolic acid (MPA), the active component of MMF, are highly variable. Low MPA concentrations are associated with the risk of graft-versus-host disease (GVHD), whereas high concentrations are associated with toxicity.

Donor and recipient polygenic risk scores influence the risk of post-transplant diabetes.

Post-transplant diabetes mellitus (PTDM) reduces allograft and recipient life span. Polygenic risk scores (PRSs) show robust association with greater risk of developing type 2 diabetes (T2D). We examined the association of PTDM with T2D PRS in liver recipients (n = 1,581) and their donors (n = 1,555), and kidney recipients (n = 2,062) and their donors (n = 533).

Opportunities for personalizing colorectal cancer care: an analysis of SEER-medicare data.

United States clinical practice guidelines for metastatic colorectal cancer recommend use of medications impacted by genetic variants but do not recommend testing. We analyzed real-world treatment using a cancer registry and claims dataset to explore pharmacogenomic (PGx) medication treatment patterns and characterize exposure. In a cohort of 6957 patients, most (86.