Nature. 2022 Oct 12. doi: 10.1038/s41586-022-05275-y. Online ahead of print.

ABSTRACT

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

PMID:36224396 | DOI:10.1038/s41586-022-05275-y

Front Biosci (Landmark Ed). 2022 Sep 28;27(9):266. doi: 10.31083/j.fbl2709266.

ABSTRACT

BACKGROUND: Psoriasis vulgaris is an immune-mediated inflammatory skin disease. Although the pathogenesis of psoriasis is unclear, genetic susceptibility, such as HLA-C*06:02, is believed to be a major risk factor. However, there is a paucity of knowledge regarding the relationship between genetics and the response to systemic treatment of psoriasis. We hypothesized that genetic variations in human leukocyte antigen (HLA) genes may act as predictors of acitretin treatment in psoriasis. The aim of our study was to explore the presence of HLA gene variants in patients with moderate-to-severe psoriasis receiving acitretin treatment.

METHODS: A total of 100 Han Chinese patients with psoriasis completed the study. 24 patients including 16 responders and 8 non-responders underwent deep sequencing by MHC targeted region capture and 76 samples were genotyped by Sanger sequencing (SBT) based HLA typing for validation.

RESULTS: Regressions with adjustment for age, sex, body mass index (BMI), and baseline psoriasis area and severity index (PASI) revealed that two HLA alleles (HLA-DQA1*:02:01, DQB*:02:02) were associated with the response to acitretin. The DQA1*0201-positive patients showed a better response to acitretin compared to the DQA1*0201-negative patients (relative risk (RR) = 10.34, 95% confidence interval (CI): 2.62-40.77, p = 0.001), and the DQB1*0202-positive patients manifested a better response to acitretin when compared to the DQB1*0202-negative patients (RR = 21.01, 95% CI: 2.53-174.27, p = 0.005).

CONCLUSIONS: Our observations support the potential role of HLA-DQA1*:02:01 and DQB*:02:02 as pharmacogenetic markers of the acitretin response in patients with psoriasis.

PMID:36224009 | DOI:10.31083/j.fbl2709266

Bioinformatics. 2022 Oct 12:btac646. doi: 10.1093/bioinformatics/btac646. Online ahead of print.

ABSTRACT

MOTIVATION: Despite the increasing evidence of utility of genomic medicine in clinical practice, systematically integrating genomic medicine information and knowledge into clinical systems with a high-level of consistency, scalability, and computability remains challenging. A comprehensive terminology is required for relevant concepts and the associated knowledge model for representing relationships.

METHODS: In this study, we leveraged PharmGKB, a comprehensive pharmacogenomics (PGx) knowledgebase, to formulate a terminology for drug response phenotypes that can represent relationships between genetic variants and treatments. We evaluated coverage of the terminology through manual review of a randomly selected subset of 200 sentences extracted from genetic reports that contained concepts for "Genes and Gene Products" and "Treatments".

RESULTS: Results showed that our proposed drug response phenotype terminology could cover 96% of the drug response phenotypes in genetic reports. Among 18,653 sentences that contained both "Genes and Gene Products" and "Treatments", 3,011 sentences were able to be mapped to a drug response phenotype in our proposed terminology, among which the most discussed drug response phenotypes were response (994), sensitivity (829), and survival (332). In addition, we were able to re-analyze genetic report context incorporating the proposed terminology and enrich our previously proposed PGx knowledge model to reveal relationships between genetic variants and treatments.

CONCLUSION: In conclusion, we proposed a drug response phenotype terminology that enhanced structured knowledge representation of genomic medicine.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:36222570 | DOI:10.1093/bioinformatics/btac646

Pharmacogenomics. 2022 Oct 12. doi: 10.2217/pgs-2022-0106. Online ahead of print.

ABSTRACT

Background: Various genetic factors influence warfarin maintenance dose. Methods: A literature search was performed on PubMed, Embase and the Cochrane Library, and a meta-analysis to analyze the impact of CYP2C19 polymorphisms on warfarin maintenance dose was conducted. Results: From nine studies encompassing 1393 patients, three CYP2C19 SNPs were identified: rs4244285, rs4986893 and rs3814637. Warfarin maintenance dose was significantly reduced by 10% in individuals with the rs4986893 A allele compared with the GG carriers and was 34%, 16% and 18% lower in patients with rs3814637 TT and CT genotypes and T allele, respectively, than that in CC carriers. No significant dose difference was observed among the rs4244285 genotypes. Conclusion: CYP2C19 rs4986893 and rs3814637 are associated with significantly reduced warfarin dose requirements.

PMID:36222113 | DOI:10.2217/pgs-2022-0106

Expert Opin Drug Metab Toxicol. 2022 Oct 12:1-4. doi: 10.1080/17425255.2022.2134775. Online ahead of print.

NO ABSTRACT

PMID:36222027 | DOI:10.1080/17425255.2022.2134775

Transl Psychiatry. 2022 Oct 11;12(1):442. doi: 10.1038/s41398-022-02203-6.

ABSTRACT

Genetic testing has evolved rapidly over recent years and new developments have the potential to provide insights that could improve the ability to diagnose, treat, and prevent diseases. Information obtained through genetic testing has proven useful in other specialties, such as cardiology and oncology. Nonetheless, a range of barriers impedes techniques, such as whole-exome or whole-genome sequencing, pharmacogenomics, and polygenic risk scoring, from being implemented in psychiatric practice. These barriers may be procedural (e.g., limitations in extrapolating results to the individual level), economic (e.g., perceived relatively elevated costs precluding insurance coverage), or related to clinicians' knowledge, attitudes, and practices (e.g., perceived unfavorable cost-effectiveness, insufficient understanding of probability statistics, and concerns regarding genetic counseling). Additionally, several ethical concerns may arise (e.g., increased stigma and discrimination through exclusion from health insurance). Here, we provide an overview of potential barriers for the implementation of genetic testing in psychiatry, as well as an in-depth discussion of strategies to address these challenges.

PMID:36220808 | DOI:10.1038/s41398-022-02203-6

Gene. 2022 Oct 8:146960. doi: 10.1016/j.gene.2022.146960. Online ahead of print.

ABSTRACT

PURPOSE: Our study genotyped pharmacogenes in 200 individuals from Inner Mongolia Autonomous Region, China. Aim to find distinct pharmacogenomic variations among the Mongolian population and to investigate the potential clinically operable gene-drug connection and genotype-phenotype correlation of differential variation in the Mongolian population.

METHODS: We sampled 61 variations of 28 genes in PharmGKB and genotyped them using Agena MassARRAY Assay. We also obtained the allele frequency and genotype distribution data of 26 populations from the 1000 Genomes Project (1000G),and then conducted comparison and statistical analysis.

RESULTS: After Bonferroni correction, there were significant genotype frequency distribution differences between the Mongolian and 26 populations: PTGS2 (rs20417), NAT2 (rs1801280, rs1799929, and rs1208), ALOX5(rs2115819), and CYP2D6 (rs1065852). It was also found that the KHV showed the smallest differences from the Mongolian and the GWD showed the largest differences. Furthermor, the differences in variants might be related to the risk of non-steroidal anti-inflammatory drug use, the slow acetylation phenotype, and other pharmacological effectiveness and toxicity in the Mongolian population.

CONCLUSION: Our study demonstrates different pharmacogenomic variants in the Mongolian and fills the gaps in pharmacogenomic information of the Mongolian. Our analysis of VIPs variants in the Mongolian population may contribute to the development of safer treatment regimens and the use of personalized treatment approaches.

PMID:36220448 | DOI:10.1016/j.gene.2022.146960

Int J Clin Pharm. 2022 Oct 10. doi: 10.1007/s11096-022-01483-8. Online ahead of print.

ABSTRACT

BACKGROUND: Pharmacogenomics is a novel arena of medicine that uses patients' Deoxyribonucleic Acid to support pharmacists and prescribers selecting the most appropriate medicine for patients.

AIM: To review and validate a service specification for a pharmacogenomics testing service.

METHOD: Consensus methods (Delphi method and the Nominal Group Technique) were deployed. A consensus panel comprising of pharmacists, prescribers and patients was convened to participate in the co-design process. Panel members were first surveyed to obtain their views on Behaviour Change Techniques identified as necessary for the service in a previous study. Following this, a workshop was convened to discuss, agree and confirm details for the service specification and recommend strategies for operationalisation. Outputs from the workshop were used to inform a final version of the service specification.

RESULTS: From the consensus panel (pharmacists (n = 6), general practitioners (n = 3) and patients (n = 3)), strategies for operationalisation of nine Behaviour Change Techniques were agreed as being required. In addition, several unique and innovative strategies for implementation of the community pharmacy service were identified and included in the service specification.

CONCLUSION: The research shows that to encourage community pharmacist engagement in providing a pharmacogenomic testing service and prescriber acceptance of recommendations for any changes to patients' prescriptions, a multi-professional launch event is required. To agree communication strategies and professional boundaries, training in clinical decision making and patient support materials are required as is guidance on how to deliver the service in a standardised manner. Finally, healthcare professionals would be reassured by the provision of an expert help-line for any complex patients.

PMID:36216993 | DOI:10.1007/s11096-022-01483-8

Nat Chem. 2022 Oct 10. doi: 10.1038/s41557-022-01057-1. Online ahead of print.

ABSTRACT

State-of-the-art photoactivation strategies in chemical biology provide spatiotemporal control and visualization of biological processes. However, using high-energy light (λ < 500 nm) for substrate or photocatalyst sensitization can lead to background activation of photoactive small-molecule probes and reduce its efficacy in complex biological environments. Here we describe the development of targeted aryl azide activation via deep red-light (λ = 660 nm) photoredox catalysis and its use in photocatalysed proximity labelling. We demonstrate that aryl azides are converted to triplet nitrenes via a redox-centric mechanism and show that its spatially localized formation requires both red light and a photocatalyst-targeting modality. This technology was applied in different colon cancer cell systems for targeted protein environment labelling of epithelial cell adhesion molecule (EpCAM). We identified a small subset of proteins with previously known and unknown association to EpCAM, including CDH3, a clinically relevant protein that shares high tumour-selective expression with EpCAM.

PMID:36216892 | DOI:10.1038/s41557-022-01057-1

Pediatr Ann. 2022 Oct;51(10):e381-e386. doi: 10.3928/19382359-20220803-03. Epub 2022 Oct 1.

ABSTRACT

Exciting new developments in biomedical and computational sciences provide an extraordinary and unparalleled opportunity to compile, connect, and analyze multiple types of "big data," driving the development of personalized medicine. These insights must begin in early life (ie, pregnancy, neonatal, and infancy) and focus on early prevention, diagnosis, and intervention-areas of medicine where pediatricians are poised to lead the way to a personalized medicine future. The rapid growth of genomics (including pharmacogenomics), transcriptomics, and related "omics" has revolutionized the diagnosis of rare monogenic disorders. It is now clarifying the pathogenesis of complex conditions ranging from autism spectrum disorder to asthma. Collaborations between clinicians and basic scientists integrating multiomics approaches in evaluating children with severe illness are transforming the fields of perinatal, neonatal, and pediatric critical care medicine. Improvements in rapid diagnostic and prognostic information suggest that pediatric personalized medicine is under way and has an exciting future. [Pediatr Ann. 2022;51(10):e381-e386.].

PMID:36215089 | DOI:10.3928/19382359-20220803-03

Pediatr Ann. 2022 Oct;51(10):e390-e395. doi: 10.3928/19382359-20220803-05. Epub 2022 Oct 1.

ABSTRACT

Precision medicine is a developing strategy for individualized treatment of a wide range of diseases. Congenital heart disease is the most common of all congenital defects and carries a high degree of variability in outcomes because of unidentified causes. Advances have identified individual genetic and environmental factors that have helped understand variations in morbidity and mortality in pediatric cardiology. A focus on genomics and pharmacogenetics has also been key to risk prediction and improvement in drug safety and efficacy in the pediatric population. With the rapidly evolving understanding of these individual factors, there also come challenges in implementation of personalized medicine into our health care model. This review outlines the key features of precision medicine in pediatric cardiology and highlights the clinical effects of these findings in patients with congenital heart disease. [Pediatr Ann. 2022;51(10):e390-e395.].

PMID:36215086 | DOI:10.3928/19382359-20220803-05

Res Ethics. 2022 Jul;18(3):193-209. doi: 10.1177/17470161221076974. Epub 2022 Feb 7.

ABSTRACT

This study aimed to explore experiences and practices of key research team members in obtaining informed consent for pharmacogenetics research and to identify the approaches used for enhancing understanding during the consenting process. Data collection involved 15 qualitative, in-depth interviews with key researchers who were involved in obtaining informed consent from HIV infected individuals in Uganda for participation in pharmacogenetic clinical trials. The study explored two prominent themes: approaches used to convey information and enhance research participants' understanding and challenges faced during the consenting process. Several barriers and facilitators for obtaining consent were identified. Innovative and potentially effective consenting strategies were identified in this study that should be studied and independently verified.

PMID:36213304 | PMC:PMC9536131 | DOI:10.1177/17470161221076974

Front Oncol. 2022 Sep 21;12:979519. doi: 10.3389/fonc.2022.979519. eCollection 2022.

ABSTRACT

INTRODUCTION: The combination of lenvatinib plus pembrolizumab demonstrated a relevant clinical benefit in patients with endometrial carcinoma. The safety profile was consistent with the established profiles of each drug in monotherapy, with the most frequent adverse events being hypertension, an on-target effect, hypothyroidism, diarrhea, nausea, vomiting, loss of appetite, fatigue, and weight loss.

AREAS COVERED: We first review the rationale based on the combination of a VEGFR inhibitor and an immune checkpoint inhibitor, highlighting the main pharmacokinetic and pharmacodynamic features of lenvatinib. Next, we focus on the common adverse events associated with lenvatinib and guide how to optimally prevent, detect, and manage them, while minimizing interruptions during lenvatinib treatment.

DISCUSSION: The side effects profile of lenvatinib is very well known, being similar across different tumor types. Most toxicities can be preventable. An appropriate, proactive, and thorough management of lenvatinib toxicities during treatment is required to maximize potential lenvatinib efficacy. Adverse events should be detected as early as possible, by both carefully monitoring the patient from lenvatinib initiation and preventing their occurrence. Patients should be followed also during treatment as some adverse events, e.g., cardiac dysfunction might appear later. Increased awareness on risk to benefit ratio among clinicians would be helpful to avoid dose interruptions or discontinuation of lenvatinib, with preferring other medical interventions and supportive care.

PMID:36212444 | PMC:PMC9535356 | DOI:10.3389/fonc.2022.979519

Front Pharmacol. 2022 Sep 23;13:837164. doi: 10.3389/fphar.2022.837164. eCollection 2022.

ABSTRACT

Variants in thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) are associated with an accumulation of cytotoxic metabolites leading to increased risk of drug-related toxicity with standard doses of thiopurine drugs. We established TPMT and NUDT15 genetic testing for clinical use and evaluated the utilization, service outcomes and potential value of multi-gene PGx testing for 210 patients that underwent pharmacogenetics (PGx) testing for thiopurine therapy with the aim to optimize service delivery for future prescribing. The test was most commonly ordered for Gastroenterology (40.0%) and Neurology (31.4%), with an average turnaround time of 2 days. Following testing, 24.3% patients were identified as intermediate or poor metabolizers, resulting in 51 recommendations for a drug or dose change in thiopurine therapy, which were implemented in 28 (54.9%) patients. In the remaining patients, 14 were not adjusted and 9 had no data available. Focusing on drug gene interactions available for testing in our laboratory, multi-gene PGx results would present opportunities for treatment optimization for at least 33.8% of these patients who were on 2 or more concurrent medications with actionable PGx guidance. However, the use of PGx panel testing in clinical practice will require the development of guidelines and education as revealed by a survey with the test providers. The evaluation demonstrated successful implementation of single gene PGx testing and this experience guides the transition to a pre-emptive multi-gene testing approach that provides the opportunity to improve clinical care.

PMID:36210828 | PMC:PMC9537458 | DOI:10.3389/fphar.2022.837164

Front Pharmacol. 2022 Sep 23;13:967082. doi: 10.3389/fphar.2022.967082. eCollection 2022.

ABSTRACT

Diversity in pharmacogenomic studies is poor, especially in relation to the inclusion of black African patients. Lack of funding and difficulties in recruitment, together with the requirement for large sample sizes because of the extensive genetic diversity in Africa, are amongst the factors which have hampered pharmacogenomic studies in Africa. Warfarin is widely used in sub-Saharan Africa, but as in other populations, dosing is highly variable due to genetic and non-genetic factors. In order to identify genetic factors determining warfarin response variability, we have conducted a genome-wide association study (GWAS) of plasma concentrations of warfarin enantiomers/metabolites in sub-Saharan black-Africans. This overcomes the issue of non-adherence and may have greater sensitivity at genome-wide level, to identify pharmacokinetic gene variants than focusing on mean weekly dose, the usual end-point used in previous studies. Participants recruited at 12 outpatient sites in Uganda and South Africa on stable warfarin dose were genotyped using the Illumina Infinium H3Africa Consortium Array v2. Imputation was conducted using the 1,000 Genomes Project phase III reference panel. Warfarin/metabolite plasma concentrations were determined by high-performance liquid chromatography with tandem mass spectrometry. Multivariable linear regression was undertaken, with adjustment made for five non-genetic covariates and ten principal components of genetic ancestry. After quality control procedures, 548 participants and 17,268,054 SNPs were retained. CYP2C9*8, CYP2C9*9, CYP2C9*11, and the CYP2C cluster SNP rs12777823 passed the Bonferroni-adjusted replication significance threshold (p < 3.21E-04) for warfarin/metabolite ratios. In an exploratory GWAS analysis, 373 unique SNPs in 13 genes, including CYP2C9*8, passed the Bonferroni-adjusted genome-wide significance threshold (p < 3.846E-9), with 325 (87%, all located on chromosome 10) SNPs being associated with the S-warfarin/R-warfarin outcome (top SNP rs11188082, CYP2C19 intron variant, p = 1.55E-17). Approximately 69% of these SNPs were in linkage disequilibrium (r 2 > 0.8) with CYP2C9*8 (n = 216) and rs12777823 (n = 8). Using a pharmacokinetic approach, we have shown that variants other than CYP2C9*2 and CYP2C9*3 are more important in sub-Saharan black-Africans, mainly due to the allele frequencies. In exploratory work, we conducted the first warfarin pharmacokinetics-related GWAS in sub-Saharan Africans and identified novel SNPs that will require external replication and functional characterization before they can be considered for inclusion in warfarin dosing algorithms.

PMID:36210801 | PMC:PMC9537548 | DOI:10.3389/fphar.2022.967082

Orthop Clin North Am. 2022 Oct;53(4):361-375. doi: 10.1016/j.ocl.2022.06.001. Epub 2022 Sep 14.

ABSTRACT

Pharmacogenomic testing, together with the early detection of drug-drug-gene interactions (DDGI) before initiating opioids, can improve the selection of dosage and reduce the risk of adverse drug interactions and therapeutic failures following Total Joint Arthroplasty. The variants of CYP genes can mediate DDGI. Orthopedic surgeons should become familiar with the genetic aspect of opioid use and abuse, as well as the influence of the patient genetic makeup in opioid selection and response, and polymorphic variants in pain modulation.

PMID:36208880 | DOI:10.1016/j.ocl.2022.06.001

Toxicol Appl Pharmacol. 2022 Oct 5:116256. doi: 10.1016/j.taap.2022.116256. Online ahead of print.

ABSTRACT

Colorectal cancer (CRC) is estimated as the third most incident cancer and second in mortality worldwide. Moreover, CRC metastasis reduces patients' survival rates. Thus, the study and identification of new compounds with anticancer activity selectively to tumor cells are encouraged in the CRC treatment. Naphtoquinones are compounds with several pharmacologic activities, including antitumoral properties. Therefore, this study aimed to investigate the anticancer mechanism of synthetic 8-Hydroxy-2-(P-Nitrothiophenol)-1,4-Naphthoquinone (CNN16) in colon cancer cell line HCT-116. CNN16 showed an IC50 of 5.32 μM in HCT-116, and 9.36, 10.77, and 24.57 μM in the non-cancerous cells MRC-5, MNP-01, and PMBC, respectively, evaluated by the MTT assay. CNN16 showed an anticlonogenic effect in HCT-116 and induced cell fragmentation identified by flow cytometry analysis. Furthermore, we observed that CNN16 presented genotoxicity and induces reactive oxygen species (ROS) after 3 h of treatment visualized by alkaline comet assay and DCFH-DA dye fluorescence, respectively. Furthermore, CNN16 caused cellular membrane disruption, reduction in the mitochondrial membrane polarization, and the presence of apoptotic bodies and chromatin condensation was visualized by differential stained (HO/FD/PI) in fluorescent microscopy along with PARP1, TP53, BCL-2, and BAX analyzed by RT-qPCR. Results also evidenced inhibition in the migratory process analyzed by wound healing assay. Therefore, CNN16 can be considered as a potential new leader molecule for CRC treatment, although further studies are still necessary to comprehend the effects of CNN16 in in vivo models to evaluate the anti-migratory effect, and toxicology and assure compound safety and selectively.

PMID:36208702 | DOI:10.1016/j.taap.2022.116256

Sci Rep. 2022 Oct 7;12(1):16873. doi: 10.1038/s41598-022-21003-y.

ABSTRACT

Opioid addiction (OA) is moderately heritable, yet only rs1799971, the A118G variant in OPRM1, has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data together with published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (rg > 0.9). We observed the strongest evidence to date for OPRM1: lead SNP rs9478500 (p = 2.56 × 10-9). Gene-based analyses identified novel genome-wide significant associations with PPP6C and FURIN. Variants within these loci appear to be pleiotropic for addiction and related traits.

PMID:36207451 | DOI:10.1038/s41598-022-21003-y

Curr Protoc. 2022 Oct;2(10):e534. doi: 10.1002/cpz1.534.

ABSTRACT

Genome sequencing holds the promise for great public health benefits. It is currently being used in the context of rare disease diagnosis and novel gene identification, but also has the potential to identify genetic disease risk factors in healthy individuals. Genome sequencing technologies are currently being used to identify genetic factors that may influence variability in symptom severity and immune response among patients infected by SARS-CoV-2. The GENCOV study aims to look at the relationship between genetic, serological, and biochemical factors and variability of SARS-CoV-2 symptom severity, and to evaluate the utility of returning genome screening results to study participants. Study participants select which results they wish to receive with a decision aid. Medically actionable information for diagnosis, disease risk estimation, disease prevention, and patient management are provided in a comprehensive genome report. Using a combination of bioinformatics software and custom tools, this article describes a pipeline for the analysis and reporting of genetic results to individuals with COVID-19, including HLA genotyping, large-scale continental ancestry estimation, and pharmacogenomic analysis to determine metabolizer status and drug response. In addition, this pipeline includes reporting of medically actionable conditions from comprehensive gene panels for Cardiology, Neurology, Metabolism, Hereditary Cancer, and Hereditary Kidney, and carrier screening for reproductive planning. Incorporated into the genome report are polygenic risk scores for six diseases-coronary artery disease; atrial fibrillation; type-2 diabetes; and breast, prostate, and colon cancer-as well as blood group genotyping analysis for ABO and Rh blood types and genotyping for other antigens of clinical relevance. The genome report summarizes the findings of these analyses in a way that extensively communicates clinically relevant results to patients and their physicians. © 2022 Wiley Periodicals LLC. Basic Protocol 1: HLA genotyping and disease association Basic Protocol 2: Large-scale continental ancestry estimation Basic Protocol 3: Dosage recommendations for pharmacogenomic gene variants associated with drug response Support Protocol: System setup.

PMID:36205462 | DOI:10.1002/cpz1.534

Transplant Direct. 2022 Sep 15;8(10):e1379. doi: 10.1097/TXD.0000000000001379. eCollection 2022 Oct.

ABSTRACT

Pharmacogenetic profiling of transplant recipients demonstrates that the marked variation in the metabolism of immunosuppressive medications, particularly tacrolimus, is related to genetic variants. Patients of African ancestry are less likely to carry loss-of-function (LoF) variants in the CYP3A5 gene and therefore retain a rapid metabolism phenotype and higher clearance of tacrolimus. Patients with this rapid metabolism typically require higher dosing to achieve therapeutic trough concentrations. This study aims to further characterize the impact of CYP3A5 genotype on clinical outcomes and financial expenditure.

METHODS: The CYP3A5 phenotype status was identified in 438 adult kidney transplant (KTx) recipients (96% were African American) using 3 LoF alleles (CYP3A5*3, *6 or *7). Individuals were categorized as rapid metabolism phenotype without LoF alleles' intermediate phenotype for 1 LoF allele' and slow phenotype for 2 LoF alleles. KTx outcomes (patient/kidney survival and Medicare spending) were determined using linked transplant registry and claims data.

RESULTS: Among the cohort, 23% had a rapid, 47% intermediate, and 30% a slow metabolism phenotype based on genotype. At 3 y, the rate of death censored graft failure and all cause graft failure was highest in the rapid metabolism phenotype and lowest in the intermediate metabolism phenotype group. First-year Medicare reimbursement differed significantly by genotype (rapid: $79 535, intermediate: $72 796, slow: $79 346, P = 0.03). After adjustment for donor and recipient characteristics, care for patients with intermediate metabolism was $4790 less expensive (P = 0.003).

CONCLUSIONS: Pharmacogenomic assessment of African American KTx recipients may be useful to guide therapy when as CYP3A5 functional variants appear to be associated with differential outcome and spending after transplant.

PMID:36204191 | PMC:PMC9529042 | DOI:10.1097/TXD.0000000000001379