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  • 1
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    Opportunity for Genotype‐Guided Prescribing Among Adult Patients in 11 US Health Systems
    Wiley ; 2021
    In:  Clinical Pharmacology & Therapeutics Vol. 110, No. 1 ( 2021-07), p. 179-188
    Details
    In: Clinical Pharmacology & Therapeutics, Wiley, Vol. 110, No. 1 ( 2021-07), p. 179-188
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0009-9236 , 1532-6535
    URL: Issue
    URL: Article
    DOI: 10.1002/cpt.v110.1
    DOI: 10.1002/cpt.2161
    RVK:
    XA 36900
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2040184-X
    SSG: 15,3
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  • 2
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    Prescribing Prevalence of Medications With Potential Genotype-Guided Dosing in Pediatric Patients
    American Medical Association (AMA) ; 2020
    In:  JAMA Network Open Vol. 3, No. 12 ( 2020-12-14), p. e2029411-
    Details
    In: JAMA Network Open, American Medical Association (AMA), Vol. 3, No. 12 ( 2020-12-14), p. e2029411-
    Type of Medium: Online Resource
    ISSN: 2574-3805
    URL: Article
    DOI: 10.1001/jamanetworkopen.2020.29411
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2020
    detail.hit.zdb_id: 2931249-8
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  • 3
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    Pharmacogenetic Predictors of Cannabidiol Response and Tolerability in Treatment‐Resistant Epilepsy
    Wiley ; 2021
    In:  Clinical Pharmacology & Therapeutics Vol. 110, No. 5 ( 2021-11), p. 1368-1380
    Details
    In: Clinical Pharmacology & Therapeutics, Wiley, Vol. 110, No. 5 ( 2021-11), p. 1368-1380
    Abstract: In patients with treatment‐resistant epilepsy (TRE), cannabidiol (CBD) produces variable improvement in seizure control. Patients in the University of Alabama at Birmingham CBD Expanded Access Program (EAP) were enrolled in the genomic study and genotyped using the Affymetrix Drug Metabolizing Enzymes and Transporters plus array. Associations between variants and CBD response (≥50% seizure reduction) and tolerability (diarrhea, sedation, and abnormal liver function) was evaluated under dominant and recessive models. Expression quantitative trait loci (eQTL) influencing potential CBD targets was evaluated in the UK Brain Expression Consortium data set (Braineac), and genetic co‐expression examined. Of 169 EAP patients, 112 (54.5% pediatric and 50.0% female) were included in the genetic analyses. Patients with AOX1 rs6729738 CC (aldehyde oxidase; odds ratio (OR) 6.69, 95% confidence interval (CI) 2.19–20.41, P  = 0.001) or ABP1 rs12539 (diamine oxidase; OR 3.96, 95% CI 1.62–9.73, P  = 0.002) were more likely to respond. Conversely, patients with SLC15A1 rs1339067 TT had lower odds of response (OR 0.06, 95% CI 0.01–0.56, P  = 0.001). ABCC5 rs3749442 was associated with lower likelihood of response and abnormal liver function tests, and higher likelihood of sedation. The eQTL revealed that rs1339067 decreased GPR18 expression (endocannabinoid receptor) in white matter ( P  = 5.6 × 10 −3 ), and rs3749442 decreased hippocampal HTR3E expression (serotonin 5‐HT 3E ; P  = 8.5 × 10 −5 ). Furthermore, 75% of genes associated with lower likelihood of response were co‐expressed. Pharmacogenetic variation is associated with CBD response and influences expression of CBD targets in TRE. Implicated pathways, including cholesterol metabolism and glutathione conjugation, demonstrate potential interactions between CBD and common medications (e.g., statins and acetaminophen) that may require closer monitoring. These results highlight the role of pharmacogenes in fundamental biologic processes and potential genetic underpinnings of treatment‐resistance.
    Type of Medium: Online Resource
    ISSN: 0009-9236 , 1532-6535
    URL: Issue
    URL: Article
    DOI: 10.1002/cpt.v110.5
    DOI: 10.1002/cpt.2408
    RVK:
    XA 36900
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2040184-X
    SSG: 15,3
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  • 4
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    Personalizing Direct Oral Anticoagulant Therapy for a Diverse Population: Role of Race, Kidney Function, Drug Interactions, and Pharmacogenetics
    Wiley ; 2023
    In:  Clinical Pharmacology & Therapeutics Vol. 113, No. 3 ( 2023-03), p. 585-599
    Details
    In: Clinical Pharmacology & Therapeutics, Wiley, Vol. 113, No. 3 ( 2023-03), p. 585-599
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0009-9236 , 1532-6535
    URL: Issue
    URL: Article
    DOI: 10.1002/cpt.v113.3
    DOI: 10.1002/cpt.2714
    RVK:
    XA 36900
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2040184-X
    SSG: 15,3
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  • 5
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    Evaluation of population‐level pharmacogenetic actionability in Alabama
    Wiley ; 2021
    In:  Clinical and Translational Science Vol. 14, No. 6 ( 2021-11), p. 2327-2338
    Details
    In: Clinical and Translational Science, Wiley, Vol. 14, No. 6 ( 2021-11), p. 2327-2338
    Abstract: The evolution of evidence and availability of Clinical Pharmacogenetic Implementation Consortium (CPIC) guidelines have enabled assessment of pharmacogenetic (PGx) actionability and clinical implementation. However, population‐level actionability is not well‐characterized. We leveraged the Alabama Genomic Health Initiative (AGHI) to evaluate population‐level PGx actionability. Participants ( 〉 18 years), representing all 67 Alabama counties, were genotyped using the Illumina Global Screening array. Using CPIC guidelines, actionability was evaluated using (1) genotype data and genetic ancestry, (2) prescribing data, and (3) combined genotype and medication data. Of 6,331 participants, 4230 had genotype data and 3386 had genotype and prescription data (76% women; 76% White/18% Black [self‐reported]). Genetic ancestry was concordant with self‐reported race. For CPIC level A genes, 98.6% had an actionable genotype (99.4% Blacks/African; 98.5% White/European). With the exception of DPYD and CYP2C19 , the prevalence of actionable genotypes by gene differed significantly by race. Based on prescribing, actionability was highest for CYP2D6 (70.9%), G6PD (54.1%), CYP2C19 (53.5%), and CYP2C9 (47.5%). Among participants prescribed atenolol, carvedilol, or metoprolol, ~ 50% had an actionable ADRB1 genotype, associated with decreased therapeutic response, with higher actionability among Blacks compared to Whites (62.5% vs. 47.4%; p  〈  0.0001). Based on both genotype and prescribing frequencies, no significant differences in actionability were observed between men and women. This statewide effort highlights PGx population‐level impact to help optimize pharmacotherapy. Almost all Alabamians harbor an actionable genotype, and a significant proportion are prescribed affected medications. Statewide efforts, such as AGHI, lay the foundation for translational research and evaluate “real‐world” outcomes of PGx.
    Type of Medium: Online Resource
    ISSN: 1752-8054 , 1752-8062
    URL: Issue
    URL: Article
    DOI: 10.1111/cts.v14.6
    DOI: 10.1111/cts.13097
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2433157-0
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  • 6
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    Pharmacogenetic actionability and medication prescribing in people with cystic fibrosis
    Wiley ; 2023
    In:  Clinical and Translational Science Vol. 16, No. 4 ( 2023-04), p. 662-672
    Details
    In: Clinical and Translational Science, Wiley, Vol. 16, No. 4 ( 2023-04), p. 662-672
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 1752-8054 , 1752-8062
    URL: Issue
    URL: Article
    DOI: 10.1111/cts.v16.4
    DOI: 10.1111/cts.13479
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2433157-0
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  • 7
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    Development and validation of a trans-ancestry polygenic risk score for type 2 diabetes in diverse populations
    Springer Science and Business Media LLC ; 2022
    In:  Genome Medicine Vol. 14, No. 1 ( 2022-06-29)
    Details
    In: Genome Medicine, Springer Science and Business Media LLC, Vol. 14, No. 1 ( 2022-06-29)
    Abstract: Type 2 diabetes (T2D) is a worldwide scourge caused by both genetic and environmental risk factors that disproportionately afflicts communities of color. Leveraging existing large-scale genome-wide association studies (GWAS), polygenic risk scores (PRS) have shown promise to complement established clinical risk factors and intervention paradigms, and improve early diagnosis and prevention of T2D. However, to date, T2D PRS have been most widely developed and validated in individuals of European descent. Comprehensive assessment of T2D PRS in non-European populations is critical for equitable deployment of PRS to clinical practice that benefits global populations. Methods We integrated T2D GWAS in European, African, and East Asian populations to construct a trans-ancestry T2D PRS using a newly developed Bayesian polygenic modeling method, and assessed the prediction accuracy of the PRS in the multi-ethnic Electronic Medical Records and Genomics (eMERGE) study (11,945 cases; 57,694 controls), four Black cohorts (5137 cases; 9657 controls), and the Taiwan Biobank (4570 cases; 84,996 controls). We additionally evaluated a post hoc ancestry adjustment method that can express the polygenic risk on the same scale across ancestrally diverse individuals and facilitate the clinical implementation of the PRS in prospective cohorts. Results The trans-ancestry PRS was significantly associated with T2D status across the ancestral groups examined. The top 2% of the PRS distribution can identify individuals with an approximately 2.5–4.5-fold of increase in T2D risk, which corresponds to the increased risk of T2D for first-degree relatives. The post hoc ancestry adjustment method eliminated major distributional differences in the PRS across ancestries without compromising its predictive performance. Conclusions By integrating T2D GWAS from multiple populations, we developed and validated a trans-ancestry PRS, and demonstrated its potential as a meaningful index of risk among diverse patients in clinical settings. Our efforts represent the first step towards the implementation of the T2D PRS into routine healthcare.
    Type of Medium: Online Resource
    ISSN: 1756-994X
    URL: Article
    DOI: 10.1186/s13073-022-01074-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2484394-5
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  • 8
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    Prostate cancer-derived cathelicidin-related antimicrobial peptide facilitates macrophage differentiation and polarization of immature myeloid progenitors to protumorigenic macrophages : The Role of CRAMP in Prostate Cancer
    Wiley ; 2016
    In:  The Prostate Vol. 76, No. 7 ( 2016-05), p. 624-636
    Details
    In: The Prostate, Wiley, Vol. 76, No. 7 ( 2016-05), p. 624-636
    Type of Medium: Online Resource
    ISSN: 0270-4137
    URL: Issue
    URL: Article
    DOI: 10.1002/pros.v76.7
    DOI: 10.1002/pros.23155
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 1494709-2
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  • 9
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    Improvement in Kidney Function After Ventricular Assist Device Implantation and Its Influence on Thromboembolism, Hemorrhage, and Mortality
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  ASAIO Journal Vol. 66, No. 3 ( 2020-03), p. 268-276
    Details
    In: ASAIO Journal, Ovid Technologies (Wolters Kluwer Health), Vol. 66, No. 3 ( 2020-03), p. 268-276
    Abstract: Although heart transplantation remains the gold standard for management of heart failure, ventricular assist devices (VAD) have emerged as viable alternatives. VAD implantation improves kidney function. However, whether the improvement is sustained or associated with improved outcomes is unclear. Herein we assess kidney function improvement, predictors of improvement, and associations with thromboembolism, hemorrhage, and mortality in VAD patients. Kidney function was defined using chronic kidney disease (CKD) stages: stage 1 (glomerular filtration rate [eGFR] ≥ 90 ml/min/1.73 m 2 ), stage 2 (eGFR 60–90 ml/min/1.73 m 2 ), stage 3a (eGFR 45–59 ml/min/1.73 m 2 ), stage 3b (eGFR 30–44 ml/min/1.73 m 2 ), stage 4 (eGFR 15–30 ml/min/1.73 m 2 ), and stage 5 (eGFR 〈 15 ml/min/1.73 m 2 ). Improvement in kidney function was defined as an improvement in eGFR that resulted in a CKD stage change to one of lesser severity. Kidney function improved post implant, and was maintained over 1 year for all patients, except those with baseline stage 5 CKD. Younger age at implantation (OR 0.93, 95% CI: 0.90–0.96, P 〈 0.0001) was associated with sustained improvement in kidney function. Poor kidney function was associated increased mortality but not with thromboembolism or hemorrhage. Compared to patients with baseline eGFR 〉 45 ml/min/1.73 m 2 ; patients with eGFR 〈 45 ml/min/1.73 m 2 had a higher mortality risk (HR 3.32, 95% CI: 1.10–9.98, p = 0.03 for stage 3b; HR 4.07, 95% CI: 1.27–13.1, p = 0.02 for stage 4; and HR 4.01, 95% CI: 1.17–13.7, p = 0.03 for stage 5 CKD). Kidney function was not associated with thromboembolism or hemorrhage, and sustained improvement was not associated with lower risk of death. However, poor kidney function at implantation was associated with an increased risk of mortality.
    Type of Medium: Online Resource
    ISSN: 1058-2916
    URL: Article
    DOI: 10.1097/MAT.0000000000000989
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 2083312-X
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  • 10
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    338 The Alabama Genomic Health Initiative: Integrating Genomic Medicine into Primary Care
    Cambridge University Press (CUP) ; 2023
    In:  Journal of Clinical and Translational Science Vol. 7, No. s1 ( 2023-04), p. 100-101
    Details
    In: Journal of Clinical and Translational Science, Cambridge University Press (CUP), Vol. 7, No. s1 ( 2023-04), p. 100-101
    Abstract: OBJECTIVES/GOALS: Supported by the State of Alabama, the Alabama Genomic Health Initiative (AGHI) is aimed at preventing and treating common conditions with a genetic basis. This joint UAB Medicine-HudsonAlpha Institute for Biotechnology effort provides genomic testing, interpretation, and counseling free of charge to residents in each of Alabama’s 67 counties. METHODS/STUDY POPULATION: Launched in 2017, as a state-wide population cohort, AGHI (1.0) enrolled 6,331 Alabamians and returned individual risk of disease(s) related to the ACMG SF v2.0 medically actionable genes. In 2021, the cohort was expanded to include a primary care cohort. AGHI (2.0) has enrolled 750 primary care patients, returning individual risk of disease(s) related to the ACMG SF v3.1 gene list and pre-emptive pharmacogenetics (PGx) to guide medication therapy. Genotyping is done on the Illumina Global Diversity Array with Sanger sequencing to confirm likely pathogenic / pathogenic variants in medically actionable genes and CYP2D6 copy number variants using Taqman assays, resulting in a CLIA-grade report. Disease risk results are returned by genetic counselors and Pharmacogenetics results are returned by Pharmacists. RESULTS/ANTICIPATED RESULTS: We have engaged a statewide community ( 〉 7000 participants), returning 94 disease risk genetic reports and 500 PGx reports. Disease risk reports include increased predisposition to cancers (n=38), cardiac diseases (n=33), metabolic (n=12), other (n=11). 100% of participants harbor an actionable PGx variant, 70% are on medication with PGx guidance, 48% harbor PGx variants and are taking medications affected. In 10% of participants, pharmacists sent an active alert to the provider to consider/ recommend alternative medication. Most commonly impacted medications included antidepressants, NSAIDS, proton-pump inhibitors and tramadol. To enable the EMR integration of genomic information, we have developed an automated transfer of reports into the EMR with Genetics Reports and PGx reports viewable in Cerner. DISCUSSION/SIGNIFICANCE: We share our experience on pre-emptive implementation of genetic risk and pharmacogenetic actionability at a population and clinic level. Both patients and providers are actively engaged, providing feedback to refine the return of results. Real time alerts with guidance at the time of prescription are needed to ensure future actionability and value.
    Type of Medium: Online Resource
    ISSN: 2059-8661
    URL: Article
    DOI: 10.1017/cts.2023.383
    Language: English
    Publisher: Cambridge University Press (CUP)
    Publication Date: 2023
    detail.hit.zdb_id: 2898186-8
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