Response to medications, the principal treatment modality for acute and chronic diseases, is highly variable, with 40–70% of patients exhibiting lack of efficacy or adverse drug reactions. With ...~ 15–30% of this variability explained by genetic variants, pharmacogenomics has become a valuable tool in our armamentarium for optimizing treatments and is poised to play an increasing role in clinical care. This review presents the progress made toward elucidating genetic underpinnings of drug response including discovery of race/ancestry‐specific pharmacogenetic variants and discusses the current evidence and evidence framework for actionability. The review is framed in the context of changing demographics and evolving views related to race and ancestry. Finally, it highlights the vital role played by cohort studies in elucidating genetic differences in drug response across race and ancestry and the informal collaborations that have enabled the field to bridge the “bench to bedside” translational gap.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Myocardial microRNAs (myo-miRs) are released into the circulation after acute myocardial infarction (AMI). How they impact remote organs is however largely unknown. Here we show that circulating ...myo-miRs are carried in exosomes and mediate functional crosstalk between the ischemic heart and the bone marrow (BM). In mice, we find that AMI is accompanied by an increase in circulating levels of myo-miRs, with miR-1, 208, and 499 predominantly in circulating exosomes and miR-133 in the non-exosomal component. Myo-miRs are imported selectively to peripheral organs and preferentially to the BM. Exosomes mediate the transfer of myo-miRs to BM mononuclear cells (MNCs), where myo-miRs downregulate CXCR4 expression. Injection of exosomes isolated from AMI mice into wild-type mice downregulates CXCR4 expression in BM-MNCs and increases the number of circulating progenitor cells. Thus, we propose that myo-miRs carried in circulating exosomes allow a systemic response to cardiac injury that may be leveraged for cardiac repair.
Despite the introduction of direct acting oral anticoagulants, warfarin remains the most commonly prescribed oral anticoagulant. However, warfarin therapy is plagued by the large inter- and ...intrapatient variability. The variability in dosing fueled research to identify clinical and genetic predictors and develop more accurate dosing algorithms. Observational studies have demonstrated the significant impact of single nucleotide polymorphisms in
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on warfarin dose in patients of European ancestry and African-Americans. This evidence supported the design and conduct of clinical trials to assess whether genotype-guided dosing results in improved anticoagulation control and outcomes. The trial results have shown discordance by race, with pharmacogenetic algorithms improving dose and anticoagulation control among European ancestry patients compared with African-American patients. Herein, we review the evidence from observational and interventional studies, highlight the need for inclusion of minority race groups and propose the need to develop race specific dosing algorithms.
CYP2C19 catalyzes the bioactivation of the antiplatelet prodrug clopidogrel, and CYP2C19 genotype impacts clopidogrel active metabolite formation. CYP2C19 intermediate and poor metabolizers who ...receive clopidogrel experience reduced platelet inhibition and increased risk for major adverse cardiovascular and cerebrovascular events. This guideline is an update to the 2013 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for the use of clopidogrel based on CYP2C19 genotype and includes expanded indications for CYP2C19 genotype‐guided antiplatelet therapy, increased strength of recommendation for CYP2C19 intermediate metabolizers, updated CYP2C19 genotype to phenotype translation, and evidence from an expanded literature review (updates at www.cpicpgx.org).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Arachidonate 5-lipoxygenase (ALOX5)-derived leukotrienes are primary signals of leukocyte activation and inflammation in response to ischemic cardiac injury (MI; myocardial infarction). Using ...risk-free male C57BL/6J and ALOX5-null mice (8-12 wk), we quantitated leukocytes and ALOX5-derived bioactive lipids of the infarcted left ventricle (LV) and spleen to measure the physiological inflammation and cardiac repair. Our results showed that ALOX5 endogenously generates specialized pro-resolving mediators (SPMs) that facilitate cardiac repair post-MI. Deficiency of ALOX5 leads to increase in cyclooxygenase gene expression, 6-keto prostaglandin F1α, and delayed neutrophil clearance with signs of unresolved inflammation post-MI. Consequently, ALOX5 deficiency impaired the resolution of inflammation and cardiac repair, including increased myocardium rupture post-MI in acute heart failure. On-time ALOX5 activation is critical for leukocyte clearance from the infarcted heart, indicating an essential role of ALOX5 in the resolution of inflammation. In addition, to balance the inflammatory responses, ALOX5 is also necessary for fibroblast signaling, as the ALOX5-deficient fibroblast are prone to fibroblast-to-myofibroblast differentiation leading to defective scar formation in post-MI cardiac repair. Consistent with these findings, ALOX5-null mice showed an overly inflammatory response, defective fibrotic signaling, and unresolved inflammation. These findings are indicative of a critical role of ALOX5 in myocardium healing, inflammation-resolution signaling, cardiac repair, and fibroblast pathophysiology.
Arachidonate 5-lipoxygenase (ALOX5) is critical in synthesizing specialized pro-resolving mediators that facilitate cardiac repair after cardiac injury. Thus, ALOX5 orchestrates the overlapping phases of inflammation and resolution to facilitate myocardium healing in cardiac repair postmyocardial infarction.
Oral anticoagulants (OACs) are commonly used to reduce the risk of venous thromboembolism and the risk of stroke in patients with atrial fibrillation. Endorsed by the American Heart Association, ...American College of Cardiology, and the European Society of Cardiology, direct oral anticoagulants (DOACs) have displaced warfarin as the OAC of choice for both conditions, due to improved safety profiles, fewer drug–drug and drug–diet interactions, and lack of monitoring requirements. Despite their widespread use and improved safety over warfarin, DOAC‐related bleeding remains a major concern for patients. DOACs have stable pharmacokinetics and pharmacodynamics; however, variability in DOAC response is common and may be attributed to numerous factors, including patient‐specific factors, concomitant medications, comorbid conditions, and genetics. Although DOAC randomized controlled trials included patients of varying ages and levels of kidney function, they failed to include patients of diverse ancestries. Additionally, current evidence to support DOAC pharmacogenetic associations have primarily been derived from European and Asian individuals. Given differences in genotype frequencies and disease burden among patients of different biogeographic groups, future research must engage diverse populations to assess and quantify the impact of predictors on DOAC response. Current under‐representation of patients from diverse racial groups does not allow for proper generalization of the influence of clinical and genetic factors in relation to DOAC variability. Herein, we discuss factors affecting DOAC response, such as age, sex, weight, kidney function, drug interactions, and pharmacogenetics, while offering a new perspective on the need for further research including frequently excluded groups.
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Background In patients with kidney impairment, warfarin, a drug metabolized primarily by the cytochrome P-450 system, is initiated at similar doses and managed similarly as in the general medical ...population. Unfortunately, few data exist to guide dose adjustment in patients with decreased kidney function. Here, we determine the degree of warfarin dose reduction associated with kidney impairment and make recommendations for warfarin dosing. Study Design Cross-sectional analysis. Setting & Participants Long-term warfarin users followed up at anticoagulation clinics (n = 980); 708 participants from the University of Alabama (UAB) and 272 participants from the University of Chicago (UIC). Predictor No/mild (estimated glomerular filtration rate eGFR ≥60 mL/min/1.73 m2 ), moderate (eGFR, 30-59 mL/min/1.73 m2 ), and severe (eGFR <30 mL/min/1.73 m2 ) kidney impairment; CYP2C9 and VKORC1 genotype; age; race; sex; body mass; sociodemographic factors; smoking status; alcohol; vitamin K intake; comorbid conditions (eg, congestive heart failure); and drug interactions (eg, amiodarone and statins). Outcome & Measurement Warfarin dose (milligrams per day) was evaluated using linear regression after adjustment for clinical, demographic, and genetic factors. Results Prevalences of moderate (31.8% and 27.6%) and severe kidney impairment (8.9% and 6.6%) were similar in the UAB and UIC cohorts. Warfarin dose requirements were significantly lower in patients with moderate and severe kidney impairment compared with those with no/mild kidney impairment in the UAB ( P < 0.001) and UIC ( P < 0.001) cohorts. Compared with patients with no/mild kidney impairment, patients with moderate kidney impairment required 9.5% lower doses ( P < 0.001) and patients with severe kidney impairment required 19% lower doses ( P < 0.001). Limitations No measurement of warfarin, serum albumin, vitamin K, and coagulation factors; no evaluation of other markers (eg, cystatin). Conclusion Moderate and severe kidney impairment were associated with a reduction in warfarin dose requirements.
Although major advancements have been made in the therapeutics for people with cystic fibrosis (PwCF), many still require the use of multiple medications to manage acute exacerbations of disease and ...maintain health. Iterative trial and error processes of pharmacotherapeutic management can be optimized by assessing and incorporating pharmacogenetics. For 82 PwCF, we reviewed 2 years of medication use and response history and interrogated metabolizer status for common pharmacogenes, revealing 3336 medication exposure events (MEEs) to 286 unique medications. As expected, the more frequent MEEs were those commonly used to treat cystic fibrosis (CF), such as antibiotics and respiratory medications. Antibiotics also comprised 56.7% of the undesirable drug responses. The impact of gene variants on drug responses was assessed using Pharmacogenomics Knowledgebase (PharmGKB) and Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. Thirty‐three (11.5%) medications have strong evidence of genetic influence on response as evidenced by gene‐based dosing guidelines. 110 (38.5%) unique medications had at least one association with a very important pharmacogene, whereas 143 (50%) were associated with at least one clinical or variant annotation. Over 97% of participants had at least one actionable genotype. Eleven (13.4%) patients with an actionable genotype, taking the impacted medication, had an undesirable drug response described in the CPIC guidelines that could potentially have been mitigated with a priori knowledge of the genotype. PwCF take many medications for disease management, with frequent dose changes to elicit a desired clinical effect. As CF care evolves, implementing pharmacogenetics testing can improve efficiency and safety of prescribing practices using precision selection and dosing at medication initiation.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Background Anticoagulation management is difficult in chronic kidney disease, with frequent supratherapeutic international normalized ratios (INRs ≥ 4) increasing hemorrhagic risk. We evaluated ...whether the interaction of INR and lower estimated glomerular filtration rate (eGFR) increases hemorrhage risk and whether patients with lower eGFRs experience slower anticoagulation reversal. Study Design Prospective cohort study. Setting & Participants Warfarin pharmacogenetics cohort (1,273 long-term warfarin users); warfarin reversal cohort (74 warfarin users admitted with INRs ≥ 4). Predictor eGFR, INR as time-dependent covariate, and their interaction in the pharmacogenetics cohort; eGFR in the reversal cohort. Outcomes & Measurements In the pharmacogenetics cohort, hemorrhagic (serious, life-threatening, and fatal bleeding) risk was assessed using proportional hazards regression. In the reversal cohort, anticoagulation reversal was assessed from changes in INR, warfarin and metabolite concentrations, clotting factors (II, VII, IX, and X), and PIVKA-II (protein induced by vitamin K absence or antagonist II) levels at presentation and after reversal, using linear regression and path analysis. Results In the pharmacogenetics cohort, 454 (35.7%) had eGFRs < 60 mL/min/1.73 m2 . There were 137 hemorrhages in 119 patients over 1,802 person-years of follow-up (incidence rate, 7.6 95% CI, 6.4-8.9/100 person-years). Patients with lower eGFRs had a higher frequency of INR ≥ 4 ( P < 0.001). Risk of hemorrhage was affected significantly by eGFR-INR interaction. At INR < 4, there was no difference in hemorrhage risk by eGFR (all P ≥ 0.4). At INR ≥ 4, patients with eGFRs of 30 to 44 and <30 mL/min/1.73 m2 had 2.2-fold (95% CI, 0.8-6.1; P = 0.1) and 5.8-fold (95% CI, 2.9-11.4; P < 0.001) higher hemorrhage risks, respectively, versus those with eGFRs ≥ 60 mL/min/1.73 m2 . In the reversal cohort, 35 (47%) had eGFRs < 45 mL/min/1.73 m2 . Patients with eGFRs < 45 mL/min/1.73 m2 experienced slower anticoagulation reversal as assessed by INR ( P = 0.04) and PIVKA-II level ( P = 0.008) than those with eGFRs ≥ 45 mL/min/1.73 m2. Limitations Limited sample size in the reversal cohort, unavailability of antibiotic use and urine albumin data. Conclusions Patients with lower eGFRs have differentially higher hemorrhage risk at INR ≥ 4. Moreover, because the INR reversal rate is slower, hemorrhage risk is prolonged.
Chronic kidney disease is a common comorbidity among patients taking direct‐acting oral anticoagulants (DOACs). Herein, we evaluate the influence of kidney function on stroke or systemic embolism ...(SEE), hemorrhage, and composite end points (stroke/SEE/hemorrhage/death and stroke/SEE/death) among patients on DOACs and warfarin. Baseline kidney function was categorized as glomerular filtration rate (GFR) ≥ 60 (reference), 45–59, and < 45mL/min/1.73 m2 for participants in the Randomized Evaluation of Long‐Term Anticoagulant Therapy (RE‐LY) (n = 18,049), Apixaban for Reduction in Stroke and Other Thromboembolic Events (ARISTOTLE) (n = 18,187), and The Effective Anticoagulation with Factor Xa Next Generation in AF (ENGAGE AF) (n = 20,798) trials. Incidence of events was compared across GFR categories. Hazard ratios for events were estimated using Cox regression using intention‐to‐treat analysis adjusting for known predictors. A large proportion of participants had GFR < 60 (25–29% had 45 ≤ GFR < 60 and 9.5–12.6% with GFR < 45). Compared with patients with GFR ≥ 60, warfarin users across the trials with GFR ≥ 45–59 and GFR < 45 had a higher incidence of hemorrhage (P values < 0.0001) and warfarin users in the ARISTOTLE and ENGAGE trials had higher incidence of stroke/SEE (P values ≤ 0.05). Compared with patients with GFR ≥ 60, dabigatran users with GFR ≥ 45–59 and GFR < 45 had a higher incidence of stroke/SEE (P ≤ 0.02), hemorrhage (P < 0.001), and both composite end points (P < 0.0001). Compared with patients with GFR ≥ 60, apixaban and edoxaban users with GFR ≥ 45–59 and GFR < 45 had a higher incidence of hemorrhage (P values ≤ 0.05) and composite end points (P values ≤ 0.05). After adjustment, compared with patients with GFR ≥ 60, warfarin users with GFR < 60 in the ARISTOTLE and RE‐LY trials had a higher risk of hemorrhage (P < 0.05), as did dabigatran (P < 0.001) and edoxaban (P ≤ 0.005) users, while apixaban users did not exhibit an increased risk (P = 0.08 GFR ≥ 45–59; P = 0.71 GFR < 45). Kidney function significantly influences the safety and efficacy of oral anticoagulants.
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