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Genes Aug 2020Drug development (target identification, advancing drug leads to candidates for preclinical and clinical studies) can be facilitated by genetic and genomic knowledge.... (Review)
Review
Drug development (target identification, advancing drug leads to candidates for preclinical and clinical studies) can be facilitated by genetic and genomic knowledge. Here, we review the contribution of population genomics to target identification, the value of bulk and single cell gene expression analysis for understanding the biological relevance of a drug target, and genome-wide CRISPR editing for the prioritization of drug targets. In genomics, we discuss the different scope of genome-wide association studies using genotyping arrays, versus exome and whole genome sequencing. In transcriptomics, we discuss the information from drug perturbation and the selection of biomarkers. For CRISPR screens, we discuss target discovery, mechanism of action and the concept of gene to drug mapping. Harnessing genetic support increases the probability of drug developability and approval.
Topics: Animals; CRISPR-Cas Systems; Drug Development; Gene Editing; Gene Expression Profiling; Genome-Wide Association Study; Genomics; Genotype; Humans; Pharmacogenomic Testing; Single-Cell Analysis; Transcriptome; Whole Genome Sequencing
PubMed: 32824125
DOI: 10.3390/genes11080942 -
The Pharmacogenomics Journal Oct 2017Pharmacogenetics (PGx) has the potential to personalize pharmaceutical treatments. Many relevant gene-drug associations have been discovered, but PGx-guided treatment... (Review)
Review
Pharmacogenetics (PGx) has the potential to personalize pharmaceutical treatments. Many relevant gene-drug associations have been discovered, but PGx-guided treatment needs to be cost-effective as well as clinically beneficial to be incorporated into standard health-care. We reviewed economic evaluations for PGx associations listed in the US Food and Drug Administration (FDA) Table of Pharmacogenomic Biomarkers in Drug Labeling. We determined the proportion of evaluations that found PGx-guided treatment to be cost-effective or dominant over the alternative strategies, and estimated the impact on this proportion of removing the cost of genetic testing. Of the 137 PGx associations in the FDA table, 44 economic evaluations, relating to 10 drugs, were identified. Of these evaluations, 57% drew conclusions in favour of PGx testing, of which 30% were cost-effective and 27% were dominant (cost-saving). If genetic information was freely available, 75% of economic evaluations would support PGx-guided treatment, of which 25% would be cost-effective and 50% would be dominant. Thus, PGx-guided treatment can be a cost-effective and even a cost-saving strategy. Having genetic information readily available in the clinical health record is a realistic future prospect, and would make more genetic tests economically worthwhile.
Topics: Cost-Benefit Analysis; Economics, Pharmaceutical; Pharmacogenetics; Pharmacogenomic Testing; Precision Medicine; United States; United States Food and Drug Administration
PubMed: 28607506
DOI: 10.1038/tpj.2017.21 -
Canadian Journal of Psychiatry. Revue... Jun 2023With increasing evidence for the clinical utility of pharmacogenomic (PGx) testing for depression, there is a growing need to consider issues related to the clinical...
OBJECTIVES
With increasing evidence for the clinical utility of pharmacogenomic (PGx) testing for depression, there is a growing need to consider issues related to the clinical implementation of this testing. The perspectives of key stakeholders (both people with lived experience [PWLE] and providers) are critical, but not frequently explored. The purpose of this study was to understand how PWLE and healthcare providers/policy experts (P/HCPs) perceive PGx testing for depression, to inform the consideration of clinical implementation within the healthcare system in British Columbia (BC), Canada.
METHODS
We recruited two cohorts of participants to complete individual 1-h, semi-structured interviews: (a) PWLE, recruited from patient and research engagement networks and organizations and (b) P/HCPs, recruited via targeted invitation. Interviews were audiotaped, transcribed verbatim, de-identified, and analysed using interpretive description.
RESULTS
Seventeen interviews were completed with PWLE (7 with experience of PGx testing for depression; 10 without); 15 interviews were completed with P/HCPs (family physicians, psychiatrists, nurses, pharmacists, genetic counsellors, medical geneticists, lab technologists, program directors, and insurers). Visual models of PWLE's and P/HCP's perceptions of and attitudes towards PGx testing were developed separately, but both were heavily influenced by participants' prior professional and/or personal experiences with depression and/or PGx testing. Both groups expressed a need for evidence and numerous considerations for the implementation of PGx testing in BC, including the requirement for conclusive economic analyses, patient and provider education, technological and clinical support, local testing facilities, and measures to ensure equitable access to testing.
CONCLUSIONS
While hopeful about the potential for therapeutic benefit from PGx testing, PWLE and P/HCPs see the need for robust evidence of utility, and BC-wide infrastructure and policies to ensure equitable and effective access to PGx testing. Further research into the accessibility, effectiveness, and cost-effectiveness of various implementation strategies is needed to inform PGx testing use in BC.
Topics: Humans; Pharmacogenomic Testing; Depressive Disorder, Major; Depression; Pharmacogenetics; British Columbia
PubMed: 36437757
DOI: 10.1177/07067437221140383 -
Clinical and Translational Science Jan 2024The DPYD gene encodes dihydropyrimidine dehydrogenase, the rate-limiting enzyme for the metabolism of fluoropyrimidines 5-fluorouracil and capecitabine. Genetic variants...
The DPYD gene encodes dihydropyrimidine dehydrogenase, the rate-limiting enzyme for the metabolism of fluoropyrimidines 5-fluorouracil and capecitabine. Genetic variants in DPYD have been associated with altered enzyme activity, therefore accurate detection and interpretation is critical to predict metabolizer status for individualized fluoropyrimidine therapy. The most commonly observed deleterious variation is the causal variant linked to the previously described HapB3 haplotype, c.1129-5923C>G (rs75017182) in intron 10, which introduces a cryptic splice site. A benign synonymous variant in exon 11, c.1236G>A (rs56038477) is also linked to HapB3 and is commonly used for testing. Previously, these single-nucleotide polymorphisms (SNPs) have been reported to be in perfect linkage disequilibrium (LD); therefore, c.1236G>A is often utilized as a proxy for the function-altering intronic variant. Clinical genotyping of DPYD identified a patient who had c.1236G>A, but not c.1129-5923C>G, suggesting that these two SNPs may not be in perfect LD, as previously assumed. Additional individuals with c.1236G>A, but not c.1129-5923C>G, were identified in the Children's Mercy Data Warehouse and the All of Us Research Program version 7 cohort substantiating incomplete SNP linkage. Consequently, testing only c.1236G>A can generate false-positive results in some cases and lead to suboptimal dosing that may negatively impact patient therapy and prospect of survival. Our data show that DPYD genotyping should include the functional variant c.1129-5923C>G, and not the c.1236G>A proxy, to accurately predict DPD activity.
Topics: Child; Humans; Dihydrouracil Dehydrogenase (NADP); Haplotypes; Antimetabolites, Antineoplastic; Pharmacogenomic Testing; Population Health; Genotype
PubMed: 38129972
DOI: 10.1111/cts.13699 -
Archives of Pathology & Laboratory... May 2016-Precision medicine is the promise of individualized therapy and management of patients based on their personal biology. There are now multiple global initiatives to... (Review)
Review
CONTEXT
-Precision medicine is the promise of individualized therapy and management of patients based on their personal biology. There are now multiple global initiatives to perform whole-genome sequencing on millions of individuals. In the United States, an early program was the Million Veteran Program, and a more recent proposal in 2015 by the president of the United States is the Precision Medicine Initiative. To implement precision medicine in routine oncology care, genetic variants present in tumors need to be matched with effective clinical therapeutics. When we focus on the current state of precision medicine for gastrointestinal malignancies, it becomes apparent that there is a mixed history of success and failure.
OBJECTIVE
-To present the current state of precision medicine using gastrointestinal oncology as a model. We will present currently available targeted therapeutics, promising new findings in clinical genomic oncology, remaining quality issues in genomic testing, and emerging oncology clinical trial designs.
DATA SOURCES
-Review of the literature including clinical genomic studies on gastrointestinal malignancies, clinical oncology trials on therapeutics targeted to molecular alterations, and emerging clinical oncology study designs.
CONCLUSIONS
-Translating our ability to sequence thousands of genes into meaningful improvements in patient survival will be the challenge for the next decade.
Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Clinical Trials as Topic; Gastrointestinal Neoplasms; Gastrointestinal Tract; Health Policy; Humans; Molecular Sequence Data; Molecular Targeted Therapy; Mutation; Neoplasm Proteins; Pathology, Clinical; Pharmacogenomic Testing; Precision Medicine; Prognosis; Quality of Health Care; Research Design
PubMed: 27128302
DOI: 10.5858/arpa.2015-0317-RA -
Cancer Apr 2022In recent years, there has been increasing evidence supporting the role of germline pharmacogenomic factors predicting toxicity for anticancer therapies. Although...
BACKGROUND
In recent years, there has been increasing evidence supporting the role of germline pharmacogenomic factors predicting toxicity for anticancer therapies. Although somatic genomic data are used frequently in oncology care planning, germline pharmacogenomic testing is not. This study hypothesizes that comprehensive germline pharmacogenomic profiling could have high relevance for cancer care.
METHODS
Between January 2011 and August 2020, patients at the University of Chicago Medical Center were genotyped across custom germline pharmacogenomic panels for reasons unrelated to cancer care. Actionable anticancer pharmacogenomic gene/drug interactions identified by the FDA were defined including: CYP2C9 (erdafitinib), CYP2D6 (gefitinib), DPYD (5-fluorouracil and capecitabine), TPMT (thioguanine and mercaptopurine), and UGT1A1 (belinostat, irinotecan, nilotinib, pazopanib, and sacituzumab-govitecan hziy). The primary objective was to determine the frequency of individuals with actionable or high-risk genotypes across these 5 key pharmacogenes, thus potentially impacting prescribing for at least 1 of these 11 commonly prescribed anticancer therapies.
RESULTS
Data from a total of 1586 genotyped individuals were analyzed. The oncology pharmacogene with the highest prevalence of high-risk, actionable genotypes was UGT1A1, impacting 17% of genotyped individuals. Actionable TPMT and DPYD genotypes were found in 9% and 4% of patients, respectively. Overall, nearly one-third of patients genotyped across all 5 genes (161/525, 31%) had at least one actionable genotype.
CONCLUSIONS
These data suggest that germline pharmacogenomic testing for 5 key pharmacogenes could identify a substantial proportion of patients at risk with standard dosing, an estimated impact similar to that of somatic genomic profiling.
LAY SUMMARY
Differences in our genes may explain why some drugs work safely in certain individuals but can cause side effects in others. Pharmacogenomics is the study of how genetic variations affect an individual's response to medications. In this study, an evaluation was done for important genetic variations that can affect the tolerability of anticancer therapy. By analyzing the genetic results of >1500 patients, it was found that nearly one-third have genetic variations that could alter recommendations of what drug, or how much of, an anticancer therapy they should be given. Performing pharmacogenomic testing before prescribing could help to guide personalized oncology care.
Topics: Cytochrome P-450 CYP2D6; Drug-Related Side Effects and Adverse Reactions; Genotype; Humans; Pharmacogenetics; Pharmacogenomic Testing
PubMed: 35090043
DOI: 10.1002/cncr.34104 -
Pharmacogenomics Sep 2016We aimed to understand consent practices for pharmacogenetic (PGx) testing. (Review)
Review
AIM
We aimed to understand consent practices for pharmacogenetic (PGx) testing.
METHODS
We conducted a literature review and analysis of consent forms from clinical laboratories offering PGx testing.
RESULTS
Our review of the literature shows a lack of consensus about the need for and type of informed consent for PGx testing. We identified 35 companies offering PGx testing and were able to confirm consent practices for 22 of those. We found a range of variability in the consent practices regarding the consent approach and information disclosed.
CONCLUSION
Variability in the consent practices among laboratories offering PGx testing mirrors the ambiguous practices and recommendations reported in the literature. Establishing a minimal set of information to be disclosed to patients may help address the disparities in consent practice.
Topics: Humans; Informed Consent; Pharmacogenomic Testing
PubMed: 27533720
DOI: 10.2217/pgs-2016-0039 -
Romanian Journal of Internal Medicine =... Jun 2020Pharmacogenomics describes the link between the genetic code and variations in drug response or adverse effects. It is rapidly gaining in both interest and... (Review)
Review
Pharmacogenomics describes the link between the genetic code and variations in drug response or adverse effects. It is rapidly gaining in both interest and accessibility. The knowledge of the gene-drug pairing for a wide range of medications will allow the clinician to select drugs with the best efficacy, appropriate dose and lowest likelihood of serious side effects. In order to apply this knowledge, practitioners need to be familiar with the basic principles of pharmacodynamics and pharmacokinetics and how these relate to drug response. Once these are understood, so can be the genetic variations that lead to different phenotypes. Our review explains these concepts and uses examples of commonly prescribed medications and their gene pairings. At the present time, the Food and Drug Administration (FDA) guidelines remain sparse in regards to pharmacogenomic testing but, despite this, direct-to-consumer testing is widely available. In this context, we detail how to interpret a pharmacogenomic report, we review the indications for testing, as well as its limitations. This information is a step ahead towards invidualized medicine, in the hope that tailoring medications and doses to an individual's genetic make-up will predict a safe and effective response.
Topics: Cytochrome P-450 Enzyme System; HLA Antigens; Humans; Liver-Specific Organic Anion Transporter 1; Methyltransferases; Pharmacogenetics; Pharmacogenomic Testing; Pharmacogenomic Variants; Practice Guidelines as Topic
PubMed: 32074077
DOI: 10.2478/rjim-2020-0001 -
Transplant International : Official... Mar 2018Treatment of acute rejection (AR) following kidney transplantation has improved in recent years, but there are still limitations to successful outcomes. This review... (Review)
Review
Treatment of acute rejection (AR) following kidney transplantation has improved in recent years, but there are still limitations to successful outcomes. This review article covers literature in regard to recipient and donor genetics of AR kidney and secondarily of liver allografts. Many candidate gene and some genome-wide association studies (GWASs) have been conducted for AR in kidney transplantation. Genetic associations with AR in kidney and liver are mostly weak, and in most cases, the associations have not been reproducible. A limitation in the study of AR is the lack of sufficiently large populations that account for population stratification to study the AR phenotype which in this era occurs in <10% of transplants. Furthermore, the AR phenotype has been difficult to define and the definitions of classifications have evolved over time. Literature related to the pharmacogenomics of tacrolimus is robust and has been validated in many studies. Associations between gene expression and AR are emerging as markers of outcomes and AR classification. In the future, combinations of pretransplant genotype for AR risk prediction, genotype-based immune suppressant dosing, and pharmacogenomic markers to select AR maintenance or treatment and expression markers from biopsies may provide valuable clinical tools for guiding treatment.
Topics: Gene Expression Profiling; Graft Rejection; Humans; Kidney Transplantation; Pharmacogenomic Testing; Polymorphism, Single Nucleotide
PubMed: 29030886
DOI: 10.1111/tri.13084 -
Translational Psychiatry Mar 2022The pharmacological treatment of depression consists of stages of trial and error, with less than 40% of patients achieving remission during first medication trial.... (Randomized Controlled Trial)
Randomized Controlled Trial
The pharmacological treatment of depression consists of stages of trial and error, with less than 40% of patients achieving remission during first medication trial. However, in a large, randomized-controlled trial (RCT) in the U.S. ("GUIDED"), significant improvements in response and remission rates were observed in patients who received treatment guided by combinatorial pharmacogenomic testing, compared to treatment-as-usual (TAU). Here we present results from the Canadian "GAPP-MDD" RCT. This 52-week, 3-arm, multi-center, participant- and rater-blinded RCT evaluated clinical outcomes among patients with depression whose treatment was guided by combinatorial pharmacogenomic testing compared to TAU. The primary outcome was symptom improvement (change in 17-item Hamilton Depression Rating Scale, HAM-D17) at week 8. Secondary outcomes included response (≥50% decrease in HAM-D17) and remission (HAM-D17 ≤ 7) at week 8. Numerically, patients in the guided-care arm had greater symptom improvement (27.6% versus 22.7%), response (30.3% versus 22.7%), and remission rates (15.7% versus 8.3%) compared to TAU, although these differences were not statistically significant. Given that the GAPP-MDD trial was ultimately underpowered to detect statistically significant differences in patient outcomes, it was assessed in parallel with the larger GUIDED RCT. We observed that relative improvements in response and remission rates were consistent between the GAPP-MDD (33.0% response, 89.0% remission) and GUIDED (31.0% response, 51.0% remission) trials. Together with GUIDED, the results from the GAPP-MDD trial indicate that combinatorial pharmacogenomic testing can be an effective tool to help guide depression treatment in the context of the Canadian healthcare setting (ClinicalTrials.gov NCT02466477).
Topics: Antidepressive Agents; Canada; Depression; Depressive Disorder, Major; Humans; Pharmacogenomic Testing; Treatment Outcome
PubMed: 35288545
DOI: 10.1038/s41398-022-01847-8