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Frontiers in Endocrinology 2021Strong efforts have been placed on understanding the physiological roles and therapeutic potential of the proglucagon peptide hormones including glucagon, GLP-1 and...
Strong efforts have been placed on understanding the physiological roles and therapeutic potential of the proglucagon peptide hormones including glucagon, GLP-1 and GLP-2. However, little is known about the extent and magnitude of variability in the amino acid composition of the proglucagon precursor and its mature peptides. Here, we identified 184 unique missense variants in the human proglucagon gene obtained from exome and whole-genome sequencing of more than 450,000 individuals across diverse sub-populations. This provides an unprecedented source of population-wide genetic variation data on missense mutations and insights into the evolutionary constraint spectrum of proglucagon-derived peptides. We show that the stereotypical peptides glucagon, GLP-1 and GLP-2 display fewer evolutionary alterations and are more likely to be functionally affected by genetic variation compared to the rest of the gene products. Elucidating the spectrum of genetic variations and estimating the impact of how a peptide variant may influence human physiology and pathophysiology through changes in ligand binding and/or receptor signalling, are vital and serve as the first important step in understanding variability in glucose homeostasis, amino acid metabolism, intestinal epithelial growth, bone strength, appetite regulation, and other key physiological parameters controlled by these hormones.
Topics: Amino Acid Sequence; DNA Mutational Analysis; Datasets as Topic; Gene Frequency; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Humans; Models, Molecular; Mutation, Missense; Pharmacogenomic Testing; Proglucagon; Protein Precursors; Protein Structure, Secondary
PubMed: 34220721
DOI: 10.3389/fendo.2021.698511 -
Journal of Personalized Medicine Aug 2022Ensuring that patients have an adequate understanding of pharmacogenomic (PGx) test results is a critical component of implementing precision medicine into clinical...
Ensuring that patients have an adequate understanding of pharmacogenomic (PGx) test results is a critical component of implementing precision medicine into clinical care. However, no PGx-specific validated literacy assessment has yet been developed. To address this need, we developed and validated the Minnesota Assessment of Pharmacogenomic Literacy (MAPLTM). Foundational work included a scoping review of patient and general public attitudes and experiences with pharmacogenomic testing, three focus groups, readability assessments, and review by experts and members of the general public. This resulted in a 15-item assessment designed to assess knowledge in four domains: underlying concepts, limitations, benefits, and privacy. For validation, 646 participants completed the MAPL as a part of a larger survey about pharmacogenomic research and statewide PGx implementation. Two items were deemed to be “too easy” and dropped. The remaining 13 items were retained in the final MAPL with good internal reliability (Cronbach’s alpha = 0.75). Confirmatory factor analysis validated the four-domain construct of MAPL and suggested good model performance and high internal validity. The estimated coefficient loadings across 13 questions on the corresponding domains are all positive and statistically significant (p < 0.05). The MAPL covers multiple knowledge domains of specific relevance to PGx and is a useful tool for clinical and research settings where quantitative assessment of PGx literacy is of value.
PubMed: 36143184
DOI: 10.3390/jpm12091398 -
Frontiers in Medicine 2023It is well known that common variants in specific genes influence drug metabolism and response, but it is currently unknown what fraction of patients are given...
It is well known that common variants in specific genes influence drug metabolism and response, but it is currently unknown what fraction of patients are given prescriptions over a lifetime that could be contraindicated by their pharmacogenomic profiles. To determine the clinical utility of pharmacogenomics over a lifetime in a general patient population, we sequenced the genomes of 300 deceased Marshfield Clinic patients linked to lifelong medical records. Genetic variants in 33 pharmacogenes were evaluated for their lifetime impact on drug prescribing using extensive electronic health records. Results show that 93% of the 300 deceased patients carried clinically relevant variants. Nearly 80% were prescribed approximately three medications on average that may have been impacted by these variants. Longitudinal data suggested that the optimal age for pharmacogenomic testing was prior to age 50, but the optimal age is greatly influenced by the stability of the population in the healthcare system. This study emphasizes the broad clinical impact of pharmacogenomic testing over a lifetime and demonstrates the potential application of genomic medicine in a general patient population for the advancement of precision medicine.
PubMed: 38020121
DOI: 10.3389/fmed.2023.1006743 -
Translational and Clinical Pharmacology Dec 2020There are several hurdles to overcome before implementing pharmacogenomics (PGx) in precision medicine. One of the hurdles is unawareness of PGx by clinicians due to...
There are several hurdles to overcome before implementing pharmacogenomics (PGx) in precision medicine. One of the hurdles is unawareness of PGx by clinicians due to insufficient pharmacogenomic information on drug labels. Therefore, it might be important to implement PGx that reflects pharmacogenomic information on drug labels, standard of prescription for clinicians. This study aimed to evaluate the level at which PGx was being used in clinical practice by comparing the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group guidelines and drug labels of the US Food and Drug Administration (FDA) and the Korea Ministry of Food and Drug Safety (MFDS). Two PGx guidelines and drugs labels were scrutinized, and the concordance of the pharmacogenomic information between guidelines and drug labels was confirmed. The concordance of the label between FDA and MFDS was analyzed. In FDA labels, the number of concordant drug with guidelines was 24, while 13 drugs were concordant with MFDS labels. The number of drugs categorized as contraindication, change dose, and biomarker testing required was 7, 12 and 12 for the FDA and 8, 5 and 4 for the MFDS, respectively. The pharmacogenomic information of 9 drugs approved by both FDA and MFDS was identical. In conclusion, pharmacogenomic information on clinical implementation guidelines was limited on both FDA and MFDS labels because of various reasons including the characteristics of the guidelines and the drug labels. Therefore, more effort from pharmaceutical companies, academia and regulatory affairs needs to be made to implement pharmacogenomic information on drug labels.
PubMed: 33425802
DOI: 10.12793/tcp.2020.28.e18 -
International Journal of Bipolar... Jul 2020Treatment in bipolar disorder (BD) is commonly applied as a multimodal therapy based on decision algorithms that lack an integrative understanding of molecular... (Review)
Review
Potential pharmacogenomic targets in bipolar disorder: considerations for current testing and the development of decision support tools to individualize treatment selection.
BACKGROUND
Treatment in bipolar disorder (BD) is commonly applied as a multimodal therapy based on decision algorithms that lack an integrative understanding of molecular mechanisms or a biomarker associated clinical outcome measure. Pharmacogenetics/genomics study the individual genetic variation associated with drug response. This selective review of pharmacogenomics and pharmacogenomic testing (PGT) in BD will focus on candidate genes and genome wide association studies of pharmacokinetic drug metabolism and pharmacodynamic drug response/adverse event, and the potential role of decision support tools that incorporate multiple genotype/phenotype drug recommendations.
MAIN BODY
We searched PubMed from January 2013 to May 2019, to identify studies reporting on BD and pharmacogenetics, pharmacogenomics and PGT. Studies were selected considering their contribution to the field. We summarize our findings in: targeted candidate genes of pharmacokinetic and pharmacodynamic pathways, genome-wide association studies and, PGT platforms, related to BD treatment. This field has grown from studies of metabolizing enzymes (i.e., pharmacokinetics) and drug transporters (i.e., pharmacodynamics), to untargeted investigations across the entire genome with the potential to merge genomic data with additional biological information.
CONCLUSIONS
The complexity of BD genetics and, the heterogeneity in BD drug-related phenotypes, are important considerations for the design and interpretation of BD PGT. The clinical applicability of PGT in psychiatry is in its infancy and is far from reaching the robust impact it has in other medical disciplines. Nonetheless, promising findings are discovered with increasing frequency with remarkable relevance in neuroscience, pharmacology and biology.
PubMed: 32632502
DOI: 10.1186/s40345-020-00184-3 -
Frontiers in Pharmacology 2022Adverse drug reactions (ADR) remain the major problems in healthcare. Most severe ADR are unpredictable, dose-independent and termed as type B idiosyncratic reactions.... (Review)
Review
Adverse drug reactions (ADR) remain the major problems in healthcare. Most severe ADR are unpredictable, dose-independent and termed as type B idiosyncratic reactions. Recent pharmacogenomic studies have demonstrated the strong associations between severe ADR and genetic markers, including specific HLA alleles (e.g., for carbamazepine-induced severe cutaneous adverse drug reactions [SCAR], for allopurinol-SCAR, for abacavir-hypersensitivity, for dapsone/co-trimoxazole-induced SCAR, and for terbinafine-induced liver injury), drug metabolism enzymes (such as for phenytoin-induced SCAR and missense variant of / for thiopurine-induced leukopenia), drug transporters (e.g., SLCO1B1 polymorphism for statin-induced myopathy), and T cell receptors (Sulfanilamide binding into the CDR3/Vα of the TCR 1.3). This mini review article aims to summarize the current knowledge of pharmacogenomics of severe ADR, and the potentially clinical use of these genetic markers for avoidance of ADR.
PubMed: 35548363
DOI: 10.3389/fphar.2022.886377 -
Revista Brasileira de Psiquiatria (Sao... Apr 2020
Topics: Antidepressive Agents; Decision Support Techniques; Depressive Disorder; Humans; Pharmacogenomic Testing; Practice Guidelines as Topic; Treatment Outcome; United States; United States Food and Drug Administration
PubMed: 32187320
DOI: 10.1590/1516-4446-2019-0799 -
Clinical and Translational Science Sep 2020Asians as a group comprise > 60% the world's population. There is an incredible amount of diversity in Asian and admixed populations that has not been addressed in a... (Review)
Review
Asians as a group comprise > 60% the world's population. There is an incredible amount of diversity in Asian and admixed populations that has not been addressed in a pharmacogenetic context. The known pharmacogenetic differences in Asian subgroups generally represent previously known variants that are present at much lower or higher frequencies in Asians compared with other populations. In this review we summarize the main drugs and known genes that appear to have differences in their pharmacogenetic properties in certain Asian populations. Evidence-based guidelines and summary statistics from the US Food and Drug Administration and the Clinical Pharmacogenetics Implementation Consortium were analyzed for ethnic differences in outcomes. Implicated drugs included commonly prescribed drugs such as warfarin, clopidogrel, carbamazepine, and allopurinol. The majority of these associations are due to Asians more commonly being poor metabolizers of cytochrome P450 (CYP) 2C19 and carriers of the human leukocyte antigen (HLA)-B*15:02 allele. The relative risk increase was shown to vary between genes and drugs, but could be > 100-fold higher in Asians. Specifically, there was a 172-fold increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis with carbamazepine use among HLA-B*15:02 carriers. The effects ranged from relatively benign reactions such as reduced drug efficacy to severe cutaneous skin reactions. These reactions are severe and prevalent enough to warrant pharmacogenetic testing and appropriate changes in dose and medication choice for at-risk populations. Further studies should be done on Asian cohorts to more fully understand pharmacogenetic variants in these populations and to clarify how such differences may influence drug response.
Topics: Anticoagulants; Anticonvulsants; Antidepressive Agents; Antifungal Agents; Antineoplastic Agents; Antiviral Agents; Asian People; Cytochrome P-450 CYP2C19; Global Burden of Disease; HLA-B15 Antigen; Heterozygote; Humans; Incidence; Pharmacogenomic Testing; Pharmacogenomic Variants; Platelet Aggregation Inhibitors; Stevens-Johnson Syndrome
PubMed: 32100936
DOI: 10.1111/cts.12771 -
Frontiers in Pharmacology 2021Pharmacogenomics (PGx) studies the use of genetic data to optimize drug therapy. Numerous clinical centers have commenced implementing pharmacogenetic tests in clinical... (Review)
Review
Pharmacogenomics (PGx) studies the use of genetic data to optimize drug therapy. Numerous clinical centers have commenced implementing pharmacogenetic tests in clinical routines. Next-generation sequencing (NGS) technologies are emerging as a more comprehensive and time- and cost-effective approach in PGx. This review presents the main considerations for applying NGS in guiding drug treatment in clinical practice. It discusses both the advantages and the challenges of implementing NGS-based tests in PGx. Moreover, the limitations of each NGS platform are revealed, and the solutions for setting up and management of these technologies in clinical practice are addressed.
PubMed: 34512329
DOI: 10.3389/fphar.2021.693453 -
Medecine Sciences : M/S Dec 2019Therapeutic antibodies have been increasingly used for the treatment of various diseases, including cancers and chronic inflammatory diseases. The pharmacokinetic... (Review)
Review
Therapeutic antibodies have been increasingly used for the treatment of various diseases, including cancers and chronic inflammatory diseases. The pharmacokinetic interindividual variability of mAbs is large and influences, at least in part, the clinical response to antibody treatment. This variability is explained by a number of individual sources of variability, which are reviewed here. Some of them are major because they are frequently reported to greatly influence the interindividual variability; notably, increased body size, the presence of anti-drug antibodies, and high antigen mass are associated with decreased antibody concentrations. Other individual sources of variability are of less critical importance. They include sex, age, co-treatments, or genetic polymorphisms of IgG Fc receptors (FcgRs). The interindividual variability of antibody pharmacokinetics should be soundly described in order to design optimal dosing strategy.
Topics: Age Factors; Antibodies, Monoclonal; Biomarkers, Pharmacological; Comorbidity; Dose-Response Relationship, Immunologic; Female; Humans; Individuality; Male; Pharmacogenomic Testing; Polymorphism, Genetic; Precision Medicine; Sex Factors
PubMed: 31903927
DOI: 10.1051/medsci/2019210