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Background: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure. Methods: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants. Results: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings ( P -8 ). Among them, a rare intergenic variant at novel locus, LOC100506274 , was associated with lower systolic blood pressure in stage-1 (beta [SE]=−32.6 [6.0]; P =4.99×10 -8 ) but not stage-2 analysis ( P =0.11). Furthermore, a novel common variant at the known INSR locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=−0.36 [0.07]; P =4.18×10 -7 ) and attained genome-wide significance in stage-2 (beta [SE]=−0.29 [0.03]; P =7.28×10 -23 ). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings ( P -6 and P -4 , respectively). Discussion: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.

ContextCanagliflozin has been reported to increase the risk of bone fracture – possibly mediated by decreasing 1,25-dihydroxyvitamin D [1,25(OH)2D] and increasing PTH.ObjectiveTo investigate whether baseline vitamin D (VitD) deficiency renders individuals vulnerable to this adverse effect and whether VitD3 supplementation is protective.DesignThis study had a paired design comparing individual participants before and after VitD3 supplementation.SettingCommunity-based outpatient.Patients11 VitD deficient (25-hydroxyvitamin D [25(OH)D] ≤ 20 ng/mL) individuals recruited from the Amish population in Lancaster PA.InterventionsParticipants underwent two canagliflozin challenge protocols (300 mg daily for five days): the first before and the second after VitD3 supplementation. In the VitD3 supplementation protocol, participants received VitD3 supplementation (50,000 IU once or twice a week depending on BMI for 4-6 weeks) to achieve 25(OH)D ≥ 30 ng/mL.Main Outcome MeasuresTwo co-primary endpoints were identified: effects of VitD3 supplementation on canagliflozin-induced changes in 1,25(OH)2D and PTH. Secondary endpoints included effects of VitD3 supplementation on baseline levels of VitD metabolites and PTH.ResultsVitD3 supplementation increased mean 25(OH)D from 16.5±1.6 to 44.3±5.5 ng/mL (p=0.0006) and 24,25-dihydroxyvitamin D [24,25(OH)2D] from 1.0±0.1 to 4.3±0.6 ng/mL (p=0.0002). Mean 1,25(OH)2D and PTH were unchanged. VitD3 supplementation decreased the magnitude of canagliflozin-induced changes in 1,25(OH)2D (from -31.3%±4.7% to -9.3%±8.3%; p=0.04) and PTH (from +36.2%±6.2% to +9.7%±3.7%; p=0.005).ConclusionsVitD deficiency rendered individuals more vulnerable to adverse effects of canagliflozin on biomarkers associated with bone health. VitD3 supplementation was protective against canagliflozin’s short-term adverse effects on 1,25(OH)2D and PTH.

BackgroundSGLT2 inhibitors provide multiple benefits to patients with type 2 diabetes – including improved glycemic control and decreased risks of cardiorenal disease. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses.MethodsCanagliflozin (300 mg) was administered to 30 healthy volunteers. Several endpoints were measured to assess clinically relevant responses – including drug-induced increases in urinary excretion of glucose, sodium, and uric acid.ResultsThis pilot study confirmed that canagliflozin (300 mg) triggered acute changes in mean levels of several biomarkers: fasting plasma glucose (-4.1 mg/dL; p=6×10-5), serum creatinine (+0.05 mg/dL; p=8×10-4), and serum uric acid (-0.90 mg/dL; p=5×10-10). The effects of sex on glucosuria depended upon how data were normalized. Whereas males’ responses were ∼60% greater when data were normalized to body surface area, males and females exhibited similar responses when glucosuria was expressed as grams of urinary glucose per gram-creatinine. The magnitude of glucosuria was not significantly correlated with fasting plasma glucose, estimated GFR, or age in these healthy non-diabetic individuals with estimated GFR>60 mL/min/1.73m2.ConclusionsNormalizing data relative to creatinine excretion will facilitate including data from males and females in a single analysis. Furthermore, because our ongoing pharmacogenomic study (NCT02891954) is conducted in healthy individuals, this will facilitate detection of genetic associations with limited confounding by other factors such as age and renal function.RegistrationNCT02462421 (clinicaltrials.gov)FundingResearch grants from the National Institute of Diabetes and Digestive and Kidney Diseases: R21DK105401, R01DK108942, T32DK098107, and P30DK072488.

Black patients suffer worse outcomes after percutaneous coronary intervention (PCI) than White patients. Inequities in antiplatelet prescribing may contribute to this health disparity. We compared P2Y

The value of utilizing a multigene pharmacogenetic panel to tailor pharmacotherapy is contingent on the prevalence of prescribed medications with an actionable pharmacogenetic association. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has categorized over 35 gene-drug pairs as "level A," for which there is sufficiently strong evidence to recommend that genetic information be used to guide drug prescribing. The opportunity to use genetic information to tailor pharmacotherapy among adult patients was determined by elucidating the exposure to CPIC level A drugs among 11 Implementing Genomics In Practice Network (IGNITE)-affiliated health systems across the US. Inpatient and/or outpatient electronic-prescribing data were collected between January 1, 2011 and December 31, 2016 for patients ≥ 18 years of age who had at least one medical encounter that was eligible for drug prescribing in a calendar year. A median of ~ 7.2 million adult patients was available for assessment of drug prescribing per year. From 2011 to 2016, the annual estimated prevalence of exposure to at least one CPIC level A drug prescribed to unique patients ranged between 15,719 (95% confidence interval (CI): 15,658-15,781) in 2011 to 17,335 (CI: 17,283-17,386) in 2016 per 100,000 patients. The estimated annual exposure to at least 2 drugs was above 7,200 per 100,000 patients in most years of the study, reaching an apex of 7,660 (CI: 7,632-7,687) per 100,000 patients in 2014. An estimated 4,748 per 100,000 prescribing events were potentially eligible for a genotype-guided intervention. Results from this study show that a significant portion of adults treated at medical institutions across the United States is exposed to medications for which genetic information, if available, should be used to guide prescribing.

Purpose. Genotype-guided antiplatelet therapy is increasingly being incorporated into clinical care. The purpose of this study is to determine the extent to which patients initially genotyped for CYP2C19 to guide antiplatelet therapy were prescribed additional medications affected by CYP2C19. Methods. We assembled a cohort of patients from eight sites performing CYP2C19 genotyping to inform antiplatelet therapy. Medication orders were evaluated from time of genotyping through one year. The primary endpoint was the proportion of patients prescribed two or more CYP2C19 substrates. Secondary endpoints were the proportion of patients with a drug-genotype interaction and time to receiving a CYP2C19 substrate. Results. 9,191 genotyped patients (17% non-white) with a mean age of 68 ± 3 years were evaluated. 4,701 (51%) of patients received two or more CYP2C19 substrates. 3,835 (42%) of patients had a drug-genotype interaction. The average time between genotyping and CYP2C19 substrate other than antiplatelet therapy was 25 ± 10 days. Conclusions. More than half of patients genotyped in the setting of CYP2C19-guided antiplatelet therapy received another medication impacted by CYP2C19 in the following year. Given that genotype is stable for a patient’s lifetime, this finding has implications for cost effectiveness, patient care, and treatment outcomes beyond the indication for which it was originally performed.

Genotyping for CYP2C19 no function alleles to guide antiplatelet therapy after percutaneous coronary intervention (PCI) improves clinical outcomes. Although results for the increased function CYP2C19*17 allele are also reported, its clinical relevance in this setting remains unclear. A collaboration across nine sites examined antiplatelet therapy prescribing and clinical outcomes in 3,342 patients after implementation of CYP2C19-guided antiplatelet therapy. Risk of major atherothrombotic and bleeding events over 12 months after PCI were compared across cytochrome P450 2C19 isozyme (CYP2C19) metabolizer phenotype and antiplatelet therapy groups by proportional hazards regression. Clopidogrel was prescribed to a similar proportion of CYP2C19 normal (84.5%), rapid (82.9%), and ultrarapid metabolizers (80.6%) (P = 0.360). Clopidogrel-treated normal metabolizers (20.4 events/100 patient-years; adjusted hazard ratio (HR) 1.00, 95% confidence interval (CI), 0.75-1.33, P = 0.993) and clopidogrel-treated rapid or ultrarapid metabolizers (19.1 events/100 patient-years; adjusted HR 0.95, 95% CI, 0.69-1.30, P = 0.734) exhibited no difference in major atherothrombotic events compared with patients treated with prasugrel or ticagrelor (17.6 events/100 patient-years). In contrast, clopidogrel-treated intermediate and poor metabolizers exhibited significantly higher atherothrombotic event risk compared with prasugrel/ticagrelor-treated patients (adjusted HR 1.56, 95% CI, 1.12-2.16, P = 0.008). When comparing clopidogrel-treated rapid or ultrarapid metabolizers to normal metabolizers, no difference in atherothrombotic (adjusted HR 0.97, 95% CI, 0.73-1.29, P = 0.808) or bleeding events (adjusted HR 1.34, 95% CI, 0.83-2.17, P = 0.224) were observed. In a real-world setting of genotype-guided antiplatelet therapy, the CYP2C19*17 allele did not significantly impact post-PCI prescribing decisions or clinical outcomes. These results suggest the CYP2C19 *1/*17 and *17/*17 genotypes have limited clinical utility to guide antiplatelet therapy after PCI.

The Age, Body mass index, Chronic kidney disease, Diabetes mellitus, and CYP2C19 GENEtic variants (ABCD-GENE) score was developed to identify patients at risk for diminished antiplatelet effects with clopidogrel after percutaneous coronary intervention (PCI). The objective of this study was to validate the ability of the ABCD-GENE score to predict the risk for atherothrombotic events in a diverse, real-world population of clopidogrel-treated patients who underwent PCI and received clinical CYP2C19 genotyping to guide antiplatelet therapy. A total of 2,341 adult patients who underwent PCI, were genotyped for CYP2C19, and received treatment with clopidogrel across four institutions were included (mean age 64 ± 12 years, 35% women, and 20% Black). The primary outcome was major atherothrombotic events, defined as the composite of all-cause death, myocardial infarction, ischemic stroke, stent thrombosis, or revascularization for unstable angina within 12 months following PCI. Major adverse cardiovascular events (MACE), defined as the composite of cardiovascular death, myocardial infarction, ischemic stroke, or stent thrombosis, was assessed as the secondary outcome. Outcomes were compared between patients with an ABCD-GENE score ≥ 10 vs. 10. The risk of major atherothrombotic events was higher in patients with an ABCD-GENE score ≥ 10 (n = 505) vs. 10 (n = 1,836; 24.6 vs. 14.7 events per 100 patient-years, adjusted hazard ratio (HR) 1.66, 95% confidence interval (CI), 1.23-2.25, P 0.001). The risk for MACE was also higher among patients with a score ≥ 10 vs. 10 (16.7 vs. 10.1 events per 100 patient-years, adjusted HR 1.59, 95% CI 1.11-2.30, P = 0.013). Our diverse, real-world data demonstrate diminished clopidogrel effectiveness in post-PCI patients with an ABCD-GENE score ≥ 10.

Summary Sodium-glucose co-transporter-2 (SGLT2) inhibitors have several beneficial effects in patients with type 2 diabetes, including glucose lowering, weight loss, blood pressure lowering, and a reduced risk of major adverse cardiovascular events. To address high unmet medical need via improved glycaemic control, several clinical trials have been done to assess the efficacy and safety of SGLT2 inhibitors in combination with insulin therapy in patients with type 1 diabetes. In this Personal View, we summarise data from eight clinical trials of canagliflozin, dapagliflozin, empagliflozin, and sotagliflozin in patients with type 1 diabetes. HbA1c-lowering efficacy was greatest at 8–12 weeks of therapy, but the magnitude of HbA1c lowering waned with longer duration of treatment (up to 52 weeks). Data are not yet available to establish for how long glycaemic efficacy could be sustained during long-term therapy in patients with type 1 diabetes. Moreover, SGLT2 inhibitor therapy induces serious adverse events, including a roughly six-times increased risk of diabetic ketoacidosis. The US Food and Drug Administration estimated that one additional case of ketoacidosis will occur for every 26 patient-years of exposure of patients with type 1 diabetes to sotagliflozin therapy. Assuming a case mortality of 0·4%, this estimate translates into 16 additional deaths per year per 100 000 patients with type 1 diabetes undergoing treatment. These considerations raise important questions about the risk-to-benefit profile of SGLT2 inhibitors when used as adjunctive therapy in patients with type 1 diabetes.

Purpose: A number of institutions have clinically implemented CYP2D6 genotyping to guide drug prescribing. We compared implementation strategies of early adopters of CYP2D6 testing, barriers faced by both early adopters and institutions in the process of implementing CYP2D6 testing, and approaches taken to overcome these barriers. Methods: We surveyed eight early adopters of CYP2D6 genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned. Results: Among early adopters, CYP2D6 testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy number variation and 9 common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support, CYP2D6 gene complexity, phenotype assignment, and sustainability. Conclusion: There are specific challenges unique to CYP2D6 testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs.

β-Blockers' heart rate (HR)-lowering effect is an important determinant of the effectiveness for this class of drugs, yet it is variable among β-blocker-treated patients. To date, genetic studies have revealed several genetic signals associated with HR response to β-blockers. However, these genetic signals have not been consistently replicated across multiple independent cohorts. Here we sought to use data from 3 hypertension clinical trials to validate single-nucleotide polymorphisms (SNPs) previously associated with the HR response to β-blockers. Using linear regression analysis, we investigated the effects of 6 SNPs in 3 genes, including ADRB1, ADRB2, and GNB3, relative to the HR response following β-blocker used in the PEAR (n = 757), PEAR-2 (n = 368), and INVEST (n = 1401) trials, adjusting for baseline HR, age, sex, and ancestry. Atenolol was used in PEAR and INVEST, and metoprolol was used in PEAR-2. We found that rs1042714 and rs1042713 in ADRB2 were significantly associated with HR response to both β-blockers in whites (rs1042714 C-allele carriers, meta-analysis β = -0.95 beats per minute [bpm], meta-analysis P = 3×10-4 ; rs1042713 A-allele carriers, meta-analysis β = -1.15 bpm, meta-analysis P = 2×10-3 ). In conclusion, the results of our analyses provide strong evidence to support the hypothesis that rs1042714 and rs1042713 in the ADRB2 gene are important predictors of HR response to cardioselective β-blockade in hypertensive patient cohorts.

Sodium–glucose cotransporter 2 (SGLT2) inhibitors are the most recently approved class of diabetes drugs. Unlike other agents, SGLT2 inhibitors act on the kidney to promote urinary glucose excretion. SGLT2 inhibitors provide multiple benefits, including decreased HbA1c, body weight, and blood pressure. These drugs have received special attention because they decrease the risk of major adverse cardiovascular events and slow progression of diabetic kidney disease (1–3). Balanced against these impressive benefits, the U.S. Food and Drug Administration–approved prescribing information describes a long list of side effects: genitourinary infections, ketoacidosis, bone fractures, amputations, acute kidney injury, perineal necrotizing fasciitis, and hyperkalemia. This review provides a physiological perspective to understanding the multiple actions of these drugs complemented by a clinical perspective toward balancing benefits and risks.

Identifying the genetic determinants of inter-individual variation in lipid species (lipidome) may provide deeper understanding and additional insight into the mechanistic effect of complex lipidomic pathways in CVD risk and progression beyond simple traditional lipids. Previous studies have been largely population based and thus only powered to discover associations with common genetic variants. Founder populations represent a powerful resource to accelerate discovery of previously unknown biology associated with rare population alleles that have risen to higher frequency due to genetic drift. We performed a genome-wide association scan of 355 lipid species in 650 individuals from the Amish founder population including 127 lipid species not previously tested. To the best of our knowledge, we report for the first time the lipid species associated with two rare-population but Amish-enriched lipid variants: APOB_rs5742904 and APOC3_rs76353203. We also identified novel associations for 3 rare-population Amish-enriched loci with several sphingolipids and with proposed potential functional/causal variant in each locus including GLTPD2_rs536055318, CERS5_rs771033566, and AKNA_rs531892793. We replicated 7 previously known common loci including novel associations with two sterols: androstenediol with UGT locus and estriol with SLC22A8/A24 locus. Our results show the double power of founder populations and detailed lipidome to discover novel trait-associated variants.

There is growing interest in utilizing pharmacogenetic (PGx) testing to guide antidepressant use, but there is lack of clarity on how to implement testing into clinical practice. We administered two surveys at 17 sites that had implemented or were in the process of implementing PGx testing for antidepressants. Survey 1 collected data on the process and logistics of testing. Survey 2 asked sites to rank the importance of Consolidated Framework for Implementation Research (CFIR) constructs using best‐worst scaling choice experiments. Of the 17 sites, 13 had implemented testing and four were in the planning stage. Thirteen offered testing in the outpatient setting, and nine in both outpatient/inpatient settings. PGx tests were mainly ordered by psychiatry (92%) and primary care (69%) providers. CYP2C19 and CYP2D6 were the most commonly tested genes. The justification for antidepressants selected for PGx guidance was based on Clinical Pharmacogenetics Implementation Consortium guidelines (94%) and US Food and Drug Administration (FDA; 75.6%) guidance. Both institutional (53%) and commercial laboratories (53%) were used for testing. Sites varied on the methods for returning results to providers and patients. Sites were consistent in ranking CFIR constructs and identified patient needs/resources, leadership engagement, intervention knowledge/beliefs, evidence strength and quality, and the identification of champions as most important for implementation. Sites deployed similar implementation strategies and measured similar outcomes. The process of implementing PGx testing to guide antidepressant therapy varied across sites, but key drivers for successful implementation were similar and may help guide other institutions interested in providing PGx‐guided pharmacotherapy for antidepressant management.

Identifying the genetic determinants of inter-individual variation in lipid species (lipidome) may provide deeper understanding and new insight into the mechanistic effect of complex lipidomic pathways in CVD risk and progression beyond simple traditional lipids. Previous studies have been largely population based and thus only powered to discover associations with common genetic variants. Founder populations represent a powerful resource to accelerate discovery of novel biology associated with rare population alleles that have risen to higher frequency due to genetic drift. We performed a GWAS of 355 lipid species in 650 individuals from the Old Order Amish founder population including 127 lipid species not previously tested. We report for the first time the lipid species associated with two rare-population but Amish-enriched lipid variants:APOB_rs5742904 andAPOC3_rs76353203. We also identified novel associations for 3 rare-population Amish-enriched loci with several sphingolipids and with proposed potential functional/causal variant in each locus includingGLPTD2_rs536055318,CERS5_rs771033566, andAKNA_rs531892793. We replicated 7 previously known common loci including novel associations with two sterols: androstenediol withUGTlocus on chromosome 2 and estriol withSLC22A8/A24locus on chromosome 11. Our results show the power of founder populations to discover novel biology due to genetic drift that can increase the frequency of an allele from only few copies in large sample cohorts such as the UK Biobank to dozens of copies in sample size as small as 650.

BackgroundHigh levels of platelet inhibition have been associated with hemorrhagic complications following Pipeline embolization of intracranial aneurysms. We therefore titrate clopidogrel dosing to maintain a moderate level of platelet inhibition using the VerifyNow P2Y12 assay. However, many patients demonstrate dramatic increases in platelet inhibition following treatment despite being on a consistent antiplatelet regimen. We therefore elected to explore the incidence of this phenomenon and possible predisposing factors.MethodsAll successful Pipeline aneurysm treatments performed at our institution from 2011 to 2019 with moderate procedure-day platelet inhibition levels as indicated by a VerifyNow PRU of 60–235 were included. Patients who received glycoprotein IIb/IIIa inhibitors and those treated for ruptured/symptomatic lesions were excluded. The incidence of excessive platelet inhibition defined by a PRUResultsSome 190 treatments were performed in 178 qualifying patients. A post-procedure PRU ConclusionElevations in platelet inhibition were frequently observed following flow diversion with Pipeline.

Purpose: The increased availability of clinical pharmacogenetic (PGx) guidelines and decreasing costs for genetic testing have slowly led to increased utilization of PGx testing in clinical practice. Preemptive PGx testing, where testing is performed in advance of drug prescribing, is one means to ensure results are available at the time of prescribing decisions. However, the most efficient and effective methods to clinically implement this strategy remain unclear. Methods: In this report, we compare and contrast implementation strategies for preemptive PGx testing by 15 early-adopter institutions. We surveyed these groups, collecting data on testing approaches, team composition, and workflow dynamics, in addition to estimated third-party reimbursement rates. Results: We found that while preemptive PGx testing models varied across sites, institutions shared several commonalities, including methods to identify patients eligible for testing, involvement of a precision medicine clinical team in program leadership, and the implementation of pharmacogenes with Clinical Pharmacogenetics Implementation Consortium guidelines available. Lastly, while reimbursement rate data were difficult to obtain, the data available suggested that reimbursement rates for preemptive PGx testing remain low. Conclusion: These findings should inform the establishment of future implementation efforts at institutions considering a preemptive PGx testing program.

Diabetes mellitus is a major public health problem, affecting about 10% of the population. Pharmacotherapy aims to protect against microvascular complications, including blindness, end-stage kidney disease, and amputations. Landmark clinical trials have demonstrated that intensive glycemic control slows progression of microvascular complications (retinopathy, nephropathy, and neuropathy). Long-term follow-up has demonstrated that intensive glycemic control also decreases risk of macrovascular disease, albeit rigorous evidence of macrovascular benefit did not emerge for over a decade. The US FDA's recent requirement for dedicated cardiovascular outcome trials ushered in a golden age for understanding the clinical profiles of new type 2 diabetes drugs. Some clinical trials with sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP1) receptor agonists reported data demonstrating cardiovascular benefit (decreased risk of major adverse cardiovascular events and hospitalization for heart failure) and slower progression of diabetic kidney disease. This Review discusses current guidelines for use of the 12 classes of drugs approved to promote glycemic control in patients with type 2 diabetes. The Review also anticipates future developments with potential to improve the standard of care: availability of generic dipeptidylpeptidase-4 (DPP4) inhibitors and SGLT2 inhibitors; precision medicine to identify the best drugs for individual patients; and new therapies to protect against chronic complications of diabetes.

This cross-sectional study assesses potential opportunities for genotype-guided prescribing in pediatric populations among multiple health systems by examining the prevalence of prescriptions for each drug with the highest level of evidence and estimating the prevalence of potentially actionable prescribing decisions., Key Points Question What is the opportunity for genotype-guided prescribing among pediatric patients in the US? Findings In this serial cross-sectional study of annual prescribing data at 16 health systems representing approximately 2.9 million pediatric patients per year from 2011 to 2017, the annual prevalence of exposure to at least 1 Clinical Pharmacogenetics Implementation Consortium level A drug ranged from 7987 to 10 629 per 100 000 pediatric patients, with increasing prevalence before reaching a plateau in 2014. The medications with the highest potential for actionability were analgesics (oxycodone, codeine, and tramadol), the antiemetic ondansetron, and antidepressants (citalopram, escitalopram, and amitriptyline). Meaning These findings suggest that ample opportunity exists for genotype-guided prescribing among pediatric patients in the US, especially for drugs metabolized by CYP2D6 or CYP2C19., Importance Genotype-guided prescribing in pediatrics could prevent adverse drug reactions and improve therapeutic response. Clinical pharmacogenetic implementation guidelines are available for many medications commonly prescribed to children. Frequencies of medication prescription and actionable genotypes (genotypes where a prescribing change may be indicated) inform the potential value of pharmacogenetic implementation. Objective To assess potential opportunities for genotype-guided prescribing in pediatric populations among multiple health systems by examining the prevalence of prescriptions for each drug with the highest level of evidence (Clinical Pharmacogenetics Implementation Consortium level A) and estimating the prevalence of potential actionable prescribing decisions. Design, Setting, and Participants This serial cross-sectional study of prescribing prevalences in 16 health systems included electronic health records data from pediatric inpatient and outpatient encounters from January 1, 2011, to December 31, 2017. The health systems included academic medical centers with free-standing children’s hospitals and community hospitals that were part of an adult health care system. Participants included approximately 2.9 million patients younger than 21 years observed per year. Data were analyzed from June 5, 2018, to April 14, 2020. Exposures Prescription of 38 level A medications based on electronic health records. Main Outcomes and Measures Annual prevalence of level A medication prescribing and estimated actionable exposures, calculated by combining estimated site-year prevalences across sites with each site weighted equally. Results Data from approximately 2.9 million pediatric patients (median age, 8 [interquartile range, 2-16] years; 50.7% female, 62.3% White) were analyzed for a typical calendar year. The annual prescribing prevalence of at least 1 level A drug ranged from 7987 to 10 629 per 100 000 patients with increasing trends from 2011 to 2014. The most prescribed level A drug was the antiemetic ondansetron (annual prevalence of exposure, 8107 [95% CI, 8077-8137] per 100 000 children). Among commonly prescribed opioids, annual prevalence per 100 000 patients was 295 (95% CI, 273-317) for tramadol, 571 (95% CI, 557-586) for codeine, and 2116 (95% CI, 2097-2135) for oxycodone. The antidepressants citalopram, escitalopram, and amitriptyline were also commonly prescribed (annual prevalence, approximately 250 per 100 000 patients for each). Estimated prevalences of actionable exposures were highest for oxycodone and ondansetron (>300 per 100 000 patients annually). CYP2D6 and CYP2C19 substrates were more frequently prescribed than medications influenced by other genes. Conclusions and Relevance These findings suggest that opportunities for pharmacogenetic implementation among pediatric patients in the US are abundant. As expected, the greatest opportunity exists with implementing CYP2D6 and CYP2C19 pharmacogenetic guidance for commonly prescribed antiemetics, analgesics, and antidepressants.

Background: In population-based research exome sequencing, the path from variant discovery to return of results is not well established. Variants discovered by research exome sequencing have the potential to improve population health. Methods: Population-based exome sequencing and agnostic ExWAS were performed 5521 Amish individuals. Additional phenotyping and in vitro studies enabled reclassification of a KCNQ1 variant from variant of unknown significance to pathogenic. Results were returned to participants in a community setting. Results: A missense variant was identified in KCNQ1 (c.671C>T, p.T224M), a gene associated with long QT syndrome type 1, which can cause syncope and sudden cardiac death. The p.T224M variant, present in 1/45 Amish individuals is rare in the general population (1/248 566 in gnomAD) and was highly associated with QTc on electro-cardiogram ( P =5.53E-24, β=20.2 ms/allele). Because of the potential importance of this variant to the health of the population, additional phenotyping was performed in 88 p.T224M carriers and 54 noncarriers. There was stronger clinical evidence of long QT syndrome in carriers (38.6% versus 5.5%, P =0.0006), greater history of syncope (32% versus 17%, P =0.020), and higher rate of sudden cardiac death in first degree relativesP =0.026). Expression of p.T224M KCNQ1 in Chinese hamster ovary cells showed near complete loss of protein function. Our clinical and functional data enabled reclassification of p.T224M from a variant of unknown significance to pathogenic. Of the 88 carriers, 93% met criteria for beta-blocker treatment and 5/88 (5.7%) were on medications that may further prolong QTc. Carriers were provided a Clinical Laboratory Improvement Amendments confirmed report, genetic counseling, and treatment recommendations. Follow-up care was coordinated with local physicians. Conclusions: This work provides a framework by which research exome sequencing can be rapidly translated in a culturally appropriate manner to directly benefit research participants and enable population precision health.

BACKGROUND Interindividual variability in blood pressure (BP) response to antihypertensives has been reported. Although plasma renin activity (PRA) is a potential biomarker for personalizing antihypertensive therapy in European American (EA) and African American (AA) hypertensives, clinical utility of PRA-guided prescribing is incompletely understood. METHODS Using systematic-phased approach, PRA’s clinical utility was assessed. After categorizing by baseline PRA, clinic systolic BP (SBP) responses to metoprolol and chlorthalidone were compared in 134 EAs and 102 AAs enrolled in the Pharmacogenomics Evaluation of Antihypertensive Responses-2 (PEAR-2) trial. Receiver operating characteristic (ROC) analysis was conducted in EAs. Data from PEAR-2 AAs were used to estimate an optimal PRA cut point using multivariable linear regression models. The derived cut point in AAs was tested in a meta-analysis of 2 independent AA cohorts, and its sensitivity and specificity were assessed. RESULTS EAs with PRA < 0.65 ng/ml/hour had a greater decrease in SBP to chlorthalidone than metoprolol (by –15.9 mm Hg, adjusted P < 0.0001), whereas those with PRA ≥ 0.65 ng/ml/hour had a greater decrease in SBP to metoprolol than chlorthalidone (by 3.3 mm Hg, adjusted P = 0.04). Area under ROC curve (0.69, P = 0.0001) showed that PRA can predict SBP response among EAs. However, we observed no association between PRA and SBP response in PEAR-2 AAs. Among independent AA cohorts, those with PRA ≥ 1.3 ng/ml/hour (PEAR-2-derived cut point) responded better to atenolol/candesartan than hydrochlorothiazide (meta-analysis P = 0.01). However, sensitivity of the derived cut point was 10%. CONCLUSIONS PRA at the previously established 0.60–0.65 ng/ml/hour cut point is an effective predictive biomarker of BP response in EAs. However, we were unable to identify PRA cut point that could be used to guide antihypertensive selection in AAs. TRIAL REGISTRATION NCT01203852, NCT00246519, NCT00005520.

Acute renal depletion of sorting nexin 1 (SNX1) in mice results in blunted natriuretic response and hypertension due to impaired dopamine D(5) receptor (D(5)R) activity. We elucidated the molecular mechanisms for these phenotypes in Snx1(−/−) mice. These mice had increased renal expressions of angiotensin II type 1 receptor (AT(1)R), NADPH oxidase (NOX) subunits, D(5)R, and NaCl cotransporter. Basal reactive oxygen species (ROS), NOX activity, and blood pressure (BP) were also higher in Snx1(−/−) mice, which were normalized by apocynin, a drug that prevents NOX assembly. Renal proximal tubule (RPT) cells from hypertensive (HT) Euro-American males had deficient SNX1 activity, impaired D(5)R endocytosis, and increased ROS compared with cells from normotensive (NT) Euro-American males. siRNA-mediated depletion of SNX1 in RPT cells from NT subjects led to a blunting of D(5)R agonist-induced increase in cAMP production and decrease in Na(+) transport, effects that were normalized by over-expression of SNX1. Among HT African-Americans, three of the 12 single nucleotide polymorphisms interrogated for the SNX1 gene were associated with a decrease in systolic BP in response to hydrochlorothiazide (HCTZ). The results illustrate a new paradigm for the development of hypertension and imply that the trafficking protein SNX1 may be a crucial determinant for hypertension and response to antihypertensive therapy.

Chromosome 12q15 was identified in Genetic Epidemiology of Response Assessment (GERA) and replicated in Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) for its association with blood pressure (BP) response to hydrochlorothiazide (HCTZ). However, the functional variant is unknown and we aimed to identify the likely functional variants through targeted sequencing. The chromosome 12q15 region was sequenced in 397 best and worst responders to HCTZ in PEAR (N=199) and GERA (N=198) hypertensive study participants. Logistic regression was used for the association analysis adjusting for age, sex, race, and principal components 1 and 2. For validation, the significant single nucleotide polymorphism was tested for association with the change in systolic (ΔSBP) and diastolic BP (ΔDBP) post-treatment in the entire PEAR (N=370) and GERA (N=570) cohorts. A novel missense polymorphism (G>A, Pro383Leu) in BEST3, rs61747221, was significantly associated with better HCTZ response (P=0.0021, odds ratio=2.05). It was validated in the entire cohort of PEAR (ΔSBP: P=0.021, β=-1.60, ΔDBP: P=0.023, β=-1.08) and GERA (ΔSBP: P=0.028, β=-1.95, ΔDBP: P=0.032, β=-1.28). BEST3 encodes the calcium sensitive chloride channel in the vascular smooth muscle implicated in the regulation of BP, especially in response to vasoconstrictors like angiotensin II. These results suggest that BEST3 is involved in the chronic BP lowering mechanism of thiazides and highlight its importance as a genetic predictor of the BP response to thiazide diuretics.

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans., Circulating lipoprotein(a) is an important risk factor for cardiovascular disease and shows variability between different ethnic groups. Here, Zekavat et al. perform whole-genome sequencing in individuals of European and African ancestries and find ancestry-specific genetic determinants for lipoprotein(a) levels.

Despite the availability of many antihypertensive drug classes, half of patients with hypertension have uncontrolled blood pressure (BP). The authors sought to assess the effect of age on BP response in European American and African American patients with hypertension. Clinic BP from the PEAR2 (Pharmacogenomics Evaluation of Antihypertensive Responses 2) study was used to estimate BP responses from baseline following sequential treatment with metoprolol 100 mg twice daily and chlorthalidone 25 mg daily for 8 to 9 weeks each, with a minimum 4-week washout between treatments. BP responses to both drugs were compared in 159 European Americans and 119 African Americans by age with adjustment for baseline BP and sex. European Americans younger than 50 years responded better to metoprolol than chlorthalidone (diastolic BP: -9.6 ± 8.0 vs -5.9 ± 6.8 mm Hg, adjusted P = .003), whereas patients 50 years and older responded better to chlorthalidone than metoprolol (systolic BP: -18.7 ± 13.8 vs -13.6 ± 14.8 mm Hg, adjusted P = .008). African Americans younger than 50 years responded similarly to both drugs, whereas those 50 years and older responded better to chlorthalidone than metoprolol (-17.0 ± 13.2/-9.6 ± 7.5 vs -7.0 ± 18.6/-6.7 ± 9.3 mm Hg, adjusted P

Benjamin Q Duong,1 Meghan J Arwood,2 J Kevin Hicks,3 Amber L Beitelshees,4 Francesco Franchi,5 John T Houder,2 Nita A Limdi,6 Kelsey J Cook,7,8 Aniwaa Owusu Obeng,9 Natasha Petry,10 Sony Tuteja,11 Amanda R Elsey,2 Larisa H Cavallari,2 Kristin Wiisanen2 on behalf of the IGNITE Network1Department of Precision Medicine, Nemours/Alfred I. DuPont Hospital for Children, Wilmington, DE, USA; 2Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics & Precision Medicine, University of Florida College of Pharmacy, Gainesville, FL, USA; 3Department of Individualized Cancer Management, Moffitt Cancer Center, Tampa, FL, USA; 4Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; 5Department of Cardiology, University of Florida College of Medicine, Jacksonville, FL, USA; 6University of Alabama School at Birmingham, Birmingham, AL, USA; 7Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Jacksonville, FL, USA; 8Department of Precision Medicine, Nemours Children’s Specialty Care, Jacksonville, FL, USA; 9The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 10Department of Pharmacy Practice, North Dakota State University College of Health Professions, Fargo, ND, USA; 11Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USACorrespondence: Kristin WiisanenDepartment of Pharmacotherapy and Translational Research and Center for Pharmacogenomics & Precision Medicine, University of Florida College of Pharmacy, P.O. Box 100486, Gainesville, FL 32610-0486, USATel +1 352-273-5114Email kwiisanen@cop.ufl.eduIntroduction: Clinical adoption of genomic medicine has lagged behind the pace of scientific discovery. Practice-based resources can help overcome implementation challenges.Methods: In 2015, the IGNITE (Implementing GeNomics In pracTicE) Network created an online genomic medicine implementation resource toolbox that was expanded in 2017 to incorporate the ability for users to create targeted implementation guides. This expansion was led by a multidisciplinary team that developed an evidence-based, structured framework for the guides, oversaw the technical process/build, and pilot tested the first guide, CYP2C19-Clopidogrel Testing Implementation.Results: Sixty-five resources were collected from 12 institutions and categorized according to a seven-step implementation framework for the pilot CYP2C19-Clopidogrel Testing Implementation Guide. Five months after its launch, 96 CYP2C19-Clopidogrel Testing Implementation Guides had been created. Eighty percent of the resources most frequently selected by users were created by IGNITE to fill an identified resource gap. Resources most often included in guides were from the test reimbursement (22%), Implementation support gathering (22%), EHR integration (17%), and genetic testing workflow steps (17%).Conclusion: Lessons learned from this implementation guide development process provide insight for prioritizing development of future resources and support the value of collaborative efforts to create resources for genomic medicine implementation.Keywords: pharmacogenomics, CYP2C19, clopidogrel, implementation, precision medicine, personalized medicine, clinical pharmacogenomics, CYP2D6

Lower melatonin level, melatonin receptor gene variations, and atenolol treatment are associated with glucose dysregulation. We investigated whether atenolol-related glucose and melatonin changes are correlated, and whether single nucleotide polymorphisms (SNPs) in melatonin candidate genes contribute to interindividual variation in glucose change. Hypertensive Caucasians (n = 232) from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study treated with atenolol for 9 weeks were studied. Urinary 6-sulfatoxymelatonin (aMT6s) was measured pre- and posttreatment and normalized to urinary creatinine. Pharmacogenetic effects on glucose change of 160 SNPs in 16 melatonin candidate genes were assessed with multiple linear regression. Atenolol was associated with increased glucose (1.8 ± 10.1mg/dl, P = 0.02) and decreased aMT6s (-4.5 ± 10.1 ng/mg, P < 0.0001). However, the aMT6s change was not correlated with post-atenolol glucose change. SNP rs11649514 in PRKCB was associated with glucose change (P = 1.0×10(-4)). PRKCB is involved in the melatonin-insulin regulatory pathway, and may be important in mediating clinically meaningful atenolol-related hyperglycemia.

Genotype-guided antiplatelet therapy is increasingly being incorporated into clinical care. The purpose of this study is to determine the extent to which patients initially genotyped for CYP2C19 to guide antiplatelet therapy were prescribed additional medications affected by CYP2C19. We assembled a cohort of patients from eight sites performingCYP2C19 genotyping to inform antiplatelet therapy. Medication orders were evaluated from time of genotyping through one year. The primary endpoint was the proportion of patients prescribed two or more CYP2C19 substrates. Secondary endpoints were the proportion of patients with a drug–genotype interaction and time to receiving a CYP2C19 substrate. Nine thousand one hundred ninety-one genotyped patients (17% nonwhite) with a mean age of 68 ± 3 years were evaluated; 4701 (51%) of patients received two or more CYP2C19 substrates and 3835 (42%) of patients had a drug–genotype interaction. The average time between genotyping and CYP2C19 substrate other than antiplatelet therapy was 25 ± 10 days. More than half of patients genotyped in the setting of CYP2C19-guided antiplatelet therapy received another medication impacted by CYP2C19 in the following year. Given that genotype is stable for a patient’s lifetime, this finding has implications for cost effectiveness, patient care, and treatment outcomes beyond the indication for which it was originally performed.

β-Blockers’ heart rate (HR)-lowering effect is an important determinant of the effectiveness for this class of drugs, yet it is variable among β-blocker–treated patients. To date, genetic studies have revealed several genetic signals associated with HR response to β-blockers. However, these genetic signals have not been consistently replicated across multiple independent cohorts. Here we sought to use data from 3 hypertension clinical trials to validate single-nucleotide polymorphisms (SNPs) previously associated with the HR response to β-blockers. Using linear regression analysis, we investigated the effects of 6 SNPs in 3 genes, including ADRB1, ADRB2, and GNB3, relative to the HR response following β-blocker used in the PEAR (n = 757), PEAR-2 (n = 368), and INVEST (n = 1401) trials, adjusting for baseline HR, age, sex, and ancestry. Atenolol was used in PEAR and INVEST, and metoprolol was used in PEAR-2. We found that rs1042714 and rs1042713 in ADRB2 were significantly associated with HR response to both β-blockers in whites (rs1042714 C-allele carriers, meta-analysis β = −0.95 beats per minute [bpm], meta-analysis P = 3×10(−4); rs1042713 A-allele carriers, meta-analysis β = −1.15 bpm, meta-analysis P = 2×10(−3)). In conclusion,the results of our analyses provide strong evidence to support the hypothesis that rs1042714 and rs1042713 in the ADRB2 gene are important predictors of HR response to cardioselective β-blockade in hypertensive patient cohorts.

β-blockers show variable efficacy as antihypertensives. Herein, we evaluated plasma miRNAs as biomarkers for defining antihypertensive response to β-blockers. Expression of 22 β-blocker pharmacodynamics-related miRNAs was assessed in baseline plasma samples from 30 responders and 30 non-responders to metoprolol from the PEAR-2 study (Discovery). Logistic regression was performed to identify miRNAs significantly associated with metoprolol response. Those miRNAs were profiled in baseline plasma samples from 25 responders and 25 non-responders to atenolol from the PEAR study (validation). In discovery, miR-101, miR-27a, miR-22, miR-19a, and let-7e were significantly associated with metoprolol response (P = 0.01, 0.017, 0.025, 0.025, and 0.04, respectively). In validation, miR-19a was significantly associated with atenolol response (P = 0.038). Meta-analysis between PEAR-2 and PEAR revealed significant association between miR-19a (P = 0.004), miR-101 (P = 0.006), and let-7e (P = 0.012) and β-blocker response. Hence, miR-19a, miR-101, and let-7e, which regulate β1-adrenergic receptor and other β-blocker pharmacodynamics-related genes, may be biomarkers for antihypertensive response to β-blockers.