Clin Pharmacol Ther. 2021 Jun 24. doi: 10.1002/cpt.2345. Online ahead of print.

ABSTRACT

Smoking continues to be the leading preventable contributor to death worldwide. Twin studies have suggested a significant genetic contribution underlying most smoking behaviours (40-70% heritability estimates). Candidate gene studies of smoking phenotypes have identified several pharmacogenes implicated in nicotine's pharmacokinetics (CYP2A6, CYP2B6, CYP2A13, FMOs, UGTs, and OCT2), and nicotine's pharmacodynamic response in the central nervous system (nicotinic acetylcholine receptors, as well as through the dopaminergic and serotonergic systems). Subsequent genome-wide association studies have confirmed the role of certain pharmacogenes through hypothesis-free approaches. Furthermore, pharmacogenes that alter the efficacy of smoking cessation pharmacotherapies including nicotine replacement therapies, bupropion, and varenicline, may also impact quitting success. In this brief review we highlight the role of pharmacogenes in smoking behaviours such as smoking status, consumption, nicotine dependence, spontaneous quitting, and altered abstinence to pharmacotherapies; We provide examples from initial candidate gene associations and subsequent genome-wide association studies. The genes CYP2A6 and the CHRNA5-A3-B4 confer the most replicated sources of genetic variation in smoking behaviours, likely due to their importance in nicotine's pharmacology. We will also provide examples of genetic scoring approaches, and the role of rare variants in explaining a portion of the missing heritability in smoking behaviours.

PMID:34165800 | DOI:10.1002/cpt.2345

Microbiol Resour Announc. 2021 Jun 24;10(25):e0035221. doi: 10.1128/MRA.00352-21. Epub 2021 Jun 24.

ABSTRACT

In the battle against tuberculosis (TB), plasticity of the Mycobacterium tuberculosis genome is believed to contribute to the pathogen's virulence and drug resistance. Here, we report 10 draft genome sequences of clinical M. tuberculosis isolated in Malaysia as the basis for understanding the genome plasticity of the M. tuberculosis isolates.

PMID:34165334 | DOI:10.1128/MRA.00352-21

NPJ Precis Oncol. 2021 Jun 23;5(1):59. doi: 10.1038/s41698-021-00191-2.

ABSTRACT

Precision oncology is currently based on pairing molecularly targeted agents (MTA) to predefined single driver genes or biomarkers. Each tumor harbors a combination of a large number of potential genetic alterations of multiple driver genes in a complex system that limits the potential of this approach. We have developed an artificial intelligence (AI)-assisted computational method, the digital drug-assignment (DDA) system, to prioritize potential MTAs for each cancer patient based on the complex individual molecular profile of their tumor. We analyzed the clinical benefit of the DDA system on the molecular and clinical outcome data of patients treated in the SHIVA01 precision oncology clinical trial with MTAs matched to individual genetic alterations or biomarkers of their tumor. We found that the DDA score assigned to MTAs was significantly higher in patients experiencing disease control than in patients with progressive disease (1523 versus 580, P = 0.037). The median PFS was also significantly longer in patients receiving MTAs with high (1000+ <) than with low (<0) DDA scores (3.95 versus 1.95 months, P = 0.044). Our results indicate that AI-based systems, like DDA, are promising new tools for oncologists to improve the clinical benefit of precision oncology.

PMID:34162980 | DOI:10.1038/s41698-021-00191-2

Haematologica. 2021 Jun 24. doi: 10.3324/haematol.2021.278743. Online ahead of print.

ABSTRACT

Despite significant progress in the treatment of patients with diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), prognosis of patients with relapsed disease remains poor due to the emergence of drug resistance and subsequent disease progression. Identification of novel targets and therapeutic strategies for these diseases represents an urgent need. Here, we report that both MCL and DLBCL are exquisitely sensitive to transcription-targeting drugs, particular to THZ531, a covalent inhibitor of cyclin-dependent kinase 12 (CDK12). By implementing pharmacogenomics and a cell-based drug screen, we found that THZ531 leads to inhibition of oncogenic transcriptional programs, especially the DNA damage response (DDR) pathway, MYC target genes and the mTOR-4EBP1-MCL-1 axis, contributing to dramatic lymphoma suppression in vitro. We also identified de novo and established acquired THZ531 resistant lymphoma cells conferred by over-activation of the MEKERK and PI3K-AKT-mTOR pathways and upregulation of multidrug resistance-1 (MDR1) protein. Of note, EZH2 inhibitors reversed THZ531 resistance by competitive inhibition of MDR1 and, in combination with THZ531, synergistically inhibited MCL and DLBCL growth in vitro. Our study indicates that CDK12 inhibitor, alone or together with EZH2 inhibitors, offer promise as novel effective approaches for difficult to treat DLBCL and MCL.

PMID:34162179 | DOI:10.3324/haematol.2021.278743

J Cell Biochem. 2021 Jun 23. doi: 10.1002/jcb.30069. Online ahead of print.

ABSTRACT

Past several decades, therapeutic investigations lead to the discovery of numerous antihypertensive drugs. Although it has been proved for their potency, altered efficacy is common norms in several conditions due to genetic variations. Cytochrome P450 plays a crucial role in drug metabolism and responsible for the pharmacokinetic and pharmacodynamic properties of the drug molecules. Here, we report the deleterious point mutations in the genes associated with the altered response of antihypertensive drug molecules and their metabolizers. Missense variants were filtered as potential nonsynonymous single nucleotide polymorphisms among the available data for the target genes (REN, CYP2D6, CYP3A4). The key objective of the work is to identify the deleterious single nucleotide polymorphisms (SNPs) responsible for the drug response and metabolism for the application of personalized medication. The molecular docking studies revealed that Aliskiren and other clinically approved drug molecules have a high binding affinity with both wild and mutant structures of renin, CYP2D6, and CYP3A4 proteins. The docking (Glide XP) score was observed to have in the range of -8.896 to -11.693 kcal/mol. The molecular dynamics simulation studies were employed to perceive the structural changes and conformational deviation through various analyses. Each studied SNPs was observed to have disparate scoring in the binding affinity to the specific drug molecules. As a prospective plan, we assume this study might be applied to identify the risky SNPs associated with hypertension from the patients to recommend the suitable drug for personalized hypertensive treatment. Further, extensive clinical pharmacogenomics studies are required to support the findings.

PMID:34161641 | DOI:10.1002/jcb.30069

J Bone Miner Res. 2021 Jun 22. doi: 10.1002/jbmr.4324. Online ahead of print.

ABSTRACT

Adolescent idiopathic scoliosis (AIS) is a common disease causing three-dimensional spinal deformity in as many as 3% of adolescents. Development of a method that can accurately predict the onset and progression of AIS is an immediate need for clinical practice. Because the heritability of AIS is estimated as high as 87.5% in twin studies, prediction of its onset and progression based on genetic data is a promising option. We show the usefulness of polygenic risk score (PRS) for the prediction of onset and progression of AIS. We used AIS genomewide association study (GWAS) data comprising 79,211 subjects in three cohorts and constructed a PRS based on association statistics in a discovery set including 31,999 female subjects. After calibration using a validation data set, we applied the PRS to a test data set. By integrating functional annotations showing heritability enrichment in the selection of variants, the PRS demonstrated an association with AIS susceptibility (p = 3.5 × 10-40 with area under the receiver-operating characteristic [AUROC] = 0.674, sensitivity = 0.644, and specificity = 0.622). The decile with the highest PRS showed an odds ratio of as high as 3.36 (p = 1.4 × 10-10 ) to develop AIS compared with the fifth in decile. The addition of a predictive model with only a single clinical parameter (body mass index) improved predictive ability for development of AIS (AUROC = 0.722, net reclassification improvement [NRI] 0.505 ± 0.054, p = 1.6 × 10-8 ), potentiating clinical use of the prediction model. Furthermore, we found the Cobb angle (CA), the severity measurement of AIS, to be a polygenic trait that showed a significant genetic correlation with AIS susceptibility (rg = 0.6, p = 3.0 × 10-4 ). The AIS PRS demonstrated a significant association with CA. These results indicate a shared polygenic architecture between onset and progression of AIS and the potential usefulness of PRS in clinical settings as a predictor to promote early intervention of AIS and avoid invasive surgery. © 2021 American Society for Bone and Mineral Research (ASBMR).

PMID:34159637 | DOI:10.1002/jbmr.4324

Pharmacogenomics J. 2021 Jun 22. doi: 10.1038/s41397-021-00245-5. Online ahead of print.

ABSTRACT

Although a few studies have reported the effects of several polymorphisms on major adverse cardiovascular events (MACE) in patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI), these genotypes account for only a small fraction of the variation and evidence is insufficient. This study aims to identify new genetic variants associated with MACE end point during the 18-month follow-up period by a two-stage large-scale sequencing data, including high-depth whole exome sequencing of 168 patients in the discovery cohort and high-depth targeted sequencing of 1793 patients in the replication cohort. We discovered eight new genotypes and their genes associated with MACE in patients with ACS, including MYOM2 (rs17064642), WDR24 (rs11640115), NECAB1 (rs74569896), EFR3A (rs4736529), AGAP3 (rs75750968), ZDHHC3 (rs3749187), ECHS1 (rs140410716), and KRTAP10-4 (rs201441480). Notably, the expressions of MYOM2 and ECHS1 are downregulated in both animal models and patients with phenotypes related to MACE. Importantly, we developed the first superior classifier for predicting 18-month MACE and achieved high predictive performance (AUC ranged between 0.92 and 0.94 for three machine-learning methods). Our findings shed light on the pathogenesis of cardiovascular outcomes and may help the clinician to make a decision on the therapeutic intervention for ACS patients.

PMID:34158603 | DOI:10.1038/s41397-021-00245-5

Singapore Med J. 2021 Jun 22. doi: 10.11622/smedj.2021080. Online ahead of print.

NO ABSTRACT

PMID:34157805 | DOI:10.11622/smedj.2021080

Biochem Pharmacol. 2021 Jun 19:114662. doi: 10.1016/j.bcp.2021.114662. Online ahead of print.

ABSTRACT

Circulating estrogens levels significantly decrease in menopause and levels off in postmenopausal women. Accordingly, the liver represses levels of enzymes and membrane transporters, thereby decreasing capability of inactivating and excreting estrogens. Women increasingly develop type 2 diabetes during or after menopause. Estrogens are known to promote liver diseases in these women. Here, we have found that the estrogen inactivating sulfotransferase (SULT1E1) and an efflux transporter ATP-binding cassette subfamily G member 2 (ABCG2) that exports sulfated estrogens increased their expression levels in diabetic women but not men. For the sulfotransferase gene, phosphorylated nuclear receptors ERα and RORα, at Ser212 and Ser100, respectively, bind their response elements to activate the SULT1E1 promoter in women. This coordinated increase in estrogen inactivation and excretion, and the phosphorylated nuclear receptor-mediated gene activation could be a defense mechanism against toxicities of estrogens through inactivation and excretion in the livers of women.

PMID:34157297 | DOI:10.1016/j.bcp.2021.114662

J Clin Pharmacol. 2021 Jun 22. doi: 10.1002/jcph.1931. Online ahead of print.

ABSTRACT

The wide variability of isoniazid (INH) pharmacokinetics is mainly attributed to the trimodal N-acetyltransferase 2 (NAT2) acetylator phenotype, i.e., rapid, intermediate, and slow. Consequently, a uniform INH dose in the current clinical practice may lead to treatment failure and drug resistance emergence. There is a lack of studies on specific doses of INH for different NAT2 acetylator phenotypes among tuberculosis patients. Therefore, we aimed to provide insight into the optimal dosing of INH for each NAT2 acetylator phenotype with respect to the probability of achieving a pharmacokinetic (PK)/pharmacodynamic target. PK, NAT2 genotype, and clinical data were collected in a multicenter prospective cohort study conducted at 13 clinical centers in Korea. Population PK modeling and simulation were carried out. Data from 454 TB patients were divided into a training dataset and a test dataset with a ratio of 4 to 1. The PK of the training data were best described by a two-compartment model with allometric scaling for the body size effect. Importantly, NAT2 acetylator phenotypes significantly affected the apparent clearance. Our model provided better predictive performance compared to previously published models, which was evaluated by external validation using the test set. The simulation for assessing the target efficacy and toxicity indicated that the best INH dosing regimens for Korean tuberculosis patients were once-daily doses of 400, 300, and 200 mg for rapid, intermediate, and slow acetylators, respectively. In conclusion, our study provides a step forward in precision dosing for anti-tuberculosis management. This article is protected by copyright. All rights reserved.

PMID:34157153 | DOI:10.1002/jcph.1931

Nucleic Acids Res. 2021 Jun 22:gkab516. doi: 10.1093/nar/gkab516. Online ahead of print.

ABSTRACT

Epigenetic changes, such as aberrant DNA methylation, contribute to cancer clonal expansion and disease progression. However, identifying subpopulation-level changes in a heterogeneous sample remains challenging. Thus, we have developed a computational approach, DXM, to deconvolve the methylation profiles of major allelic subpopulations from the bisulfite sequencing data of a heterogeneous sample. DXM does not require prior knowledge of the number of subpopulations or types of cells to expect. We benchmark DXM's performance and demonstrate improvement over existing methods. We further experimentally validate DXM predicted allelic subpopulation-methylation profiles in four Diffuse Large B-Cell Lymphomas (DLBCLs). Lastly, as proof-of-concept, we apply DXM to a cohort of 31 DLBCLs and relate allelic subpopulation methylation profiles to relapse. We thus demonstrate that DXM can robustly find allelic subpopulation methylation profiles that may contribute to disease progression using bisulfite sequencing data of any heterogeneous sample.

PMID:34157105 | DOI:10.1093/nar/gkab516

J Genet Eng Biotechnol. 2021 Jun 22;19(1):95. doi: 10.1186/s43141-021-00193-4.

ABSTRACT

BACKGROUND: Drug response is below genetic influence, proven by the genetic variants. Pharmacogenetics trials are performed in many diseases, including coronary artery disease. This study was designed to determine the genetic polymorphism (rs676210) Pro2739leu G > A in the lipid metabolism-related gene (ApoB gene) and its pharmacogenetic role in the response to atorvastatin drug in a sample of Iraqi population with coronary artery disease (CAD).

RESULTS: Significant differences of genotype distribution in CAD patients and controls were observed in ApoB+ 8216 in Iraqi population from Hardy Weinberg Analysis. It also found that dramatic difference of low-density lipoprotein (LDL-C) level in response to 40 mg/day of atorvastatin therapy, the minor allele (A) observed a greater LDL-C lowering than the wild type allele (G). In ANOVA analysis, the result showed that the rs676210, Pro2739Leu, in ApoB gene increased non significantly, but gradually in plasma level of total cholesterol (TC), triglyceride (TG), very low-density lipoprotein (VLDL), and oxidize low-density lipoprotein (oxLDL) in the order of genotype AA, GA, and GG in response to 40 mg atorvastatin.

CONCLUSION: We found the results highlighted the function of the rs676210, Pro2739Leu, in the ApoB gene in CAD etiology, and the findings support this variant's impact in predicting the response of (LDL-C) to 40 mg of atorvastatin therapy. ApoB gene polymorphism (rs676210, Pro2739Leu), specifically the AA genotype, may help to identify individuals who will profit from atorvastatin's lowering effects.

PMID:34156559 | DOI:10.1186/s43141-021-00193-4

Cancer Med. 2021 Jun 22. doi: 10.1002/cam4.4026. Online ahead of print.

ABSTRACT

BACKGROUND: Pharmacokinetics (PK) of docetaxel is characterized by high inter-individual variability (IIV). While covariate models that explain the PK variability of docetaxel exist, not much is known about the effects of genetic variations on docetaxel disposition.

METHODS: Fifty patients with head and neck or prostate cancer were enrolled of whom two patients withdrew consent before the start of the study. Docetaxel was administered at either 50 or 75 mg/m2 as intravenous infusion over 1 h. One pharmacogenetic sample and a series of PK samples, either intensive (N = 5; 13 samples each) or sparse (N = 43; 6 samples each), were collected from each patient. Docetaxel levels were estimated using a validated HPLC method. Polymorphic loci on the Absorption, Distribution, Metabolism, and Elimination (ADME) genes were identified using the PharmacoScan array platform. Population pharmacokinetic analysis was carried out using NONMEM v7.2.

RESULTS: Docetaxel PK was well characterized by a three-compartment model. Clearance (Cl) was found to be 18 L/h with an IIV of 45.3%. None of the genetic variants showed significant covariate effect on the Cl of docetaxel. Patients with abnormal alanine aminotransferase (ALT) were found to have 25% lower Cl as compared to patients with normal ALT values. However, the covariate effect could not be established in the final model possibly due to lack of adequate number of patients with abnormal ALT.

CONCLUSION: Genetic polymorphisms in the ADME gene do not explain the IIV in PK of docetaxel. However, patients with abnormal liver function might require dose reduction.

CLINICAL TRIAL REGISTRATION: Not applicable since participants in this study received treatment that was standard of care.

PMID:34156160 | DOI:10.1002/cam4.4026

Pharmacogenomics J. 2021 Jun 21. doi: 10.1038/s41397-021-00246-4. Online ahead of print.

ABSTRACT

One in every ten drug candidates fail in clinical trials mainly due to efficacy and safety related issues, despite in-depth preclinical testing. Even some of the approved drugs such as chemotherapeutics are notorious for their side effects that are burdensome on patients. In order to pave the way for new therapeutics with more tolerable side effects, the mechanisms underlying side effects need to be fully elucidated. In this work, we addressed the common side effects of chemotherapeutics, namely alopecia, diarrhea and edema. A strategy based on Random Forest algorithm unveiled an expression signature involving 40 genes that predicted these side effects with an accuracy of 89%. We further characterized the resulting signature and its association with the side effects using functional enrichment analysis and protein-protein interaction networks. This work contributes to the ongoing efforts in drug development for early identification of side effects to use the resources more effectively.

PMID:34155353 | DOI:10.1038/s41397-021-00246-4

Curr Probl Cardiol. 2021 Jun 18:100899. doi: 10.1016/j.cpcardiol.2021.100899. Online ahead of print.

NO ABSTRACT

PMID:34154818 | DOI:10.1016/j.cpcardiol.2021.100899

Genome Med. 2021 Jun 21;13(1):103. doi: 10.1186/s13073-021-00920-z.

ABSTRACT

BACKGROUND: Medulloblastoma (MB) is the most common malignant paediatric brain tumour and a leading cause of cancer-related mortality and morbidity. Existing treatment protocols are aggressive in nature resulting in significant neurological, intellectual and physical disabilities for the children undergoing treatment. Thus, there is an urgent need for improved, targeted therapies that minimize these harmful side effects.

METHODS: We identified candidate drugs for MB using a network-based systems-pharmacogenomics approach: based on results from a functional genomics screen, we identified a network of interactions implicated in human MB growth regulation. We then integrated drugs and their known mechanisms of action, along with gene expression data from a large collection of medulloblastoma patients to identify drugs with potential to treat MB.

RESULTS: Our analyses identified drugs targeting CDK4, CDK6 and AURKA as strong candidates for MB; all of these genes are well validated as drug targets in other tumour types. We also identified non-WNT MB as a novel indication for drugs targeting TUBB, CAD, SNRPA, SLC1A5, PTPRS, P4HB and CHEK2. Based upon these analyses, we subsequently demonstrated that one of these drugs, the new microtubule stabilizing agent, ixabepilone, blocked tumour growth in vivo in mice bearing patient-derived xenograft tumours of the Sonic Hedgehog and Group 3 subtype, providing the first demonstration of its efficacy in MB.

CONCLUSIONS: Our findings confirm that this data-driven systems pharmacogenomics strategy is a powerful approach for the discovery and validation of novel therapeutic candidates relevant to MB treatment, and along with data validating ixabepilone in PDX models of the two most aggressive subtypes of medulloblastoma, we present the network analysis framework as a resource for the field.

PMID:34154646 | DOI:10.1186/s13073-021-00920-z

Am J Psychiatry. 2021 Jun 22:appiajp202020121686. doi: 10.1176/appi.ajp.2020.20121686. Online ahead of print.

ABSTRACT

OBJECTIVE: Stimulant medications are effective for treating attention deficit hyperactivity disorder (ADHD), yet discontinuation and switch to nonstimulant ADHD medications are common. This study aimed to identify genetic, clinical, and sociodemographic factors influencing stimulant treatment initiation, discontinuation, and switch to nonstimulants in individuals with ADHD.

METHODS: The authors obtained genetic and national register data for 9,133 individuals with ADHD from the Danish iPSYCH2012 sample and defined stimulant treatment initiation, discontinuation, and switch from prescriptions. For each stimulant treatment outcome, they examined associations with polygenic risk scores (PRSs) for psychiatric disorders and clinical and sociodemographic factors using survival analyses, and conducted genome-wide association studies (GWASs) and estimated single-nucleotide polymorphism heritability (h2SNP).

RESULTS: Eighty-one percent of the sample initiated stimulant treatment. Within 2 years, 45% discontinued stimulants and 15% switched to nonstimulants. Bipolar disorder PRS (hazard ratio=1.05, 95% CI=1.02, 1.09) and schizophrenia PRS (hazard ratio=1.07, 95% CI=1.03, 1.11) were associated with discontinuation. Depression, bipolar disorder, and schizophrenia PRSs were marginally but not significantly associated with switch (hazard ratio range, 1.05-1.07). No associations were observed for ADHD and autism PRSs. Individuals diagnosed with ADHD at age 13 or older had higher rates of stimulant initiation, discontinuation, and switch (hazard ratio range, 1.27-2.01). Psychiatric comorbidities generally reduced rates of initiation (hazard ratio range, 0.84-0.88) and increased rates of discontinuation (hazard ratio range, 1.19-1.45) and switch (hazard ratio range, 1.40-2.08). h2SNP estimates were not significantly different from zero. No GWAS hits were identified for stimulant initiation or discontinuation. A locus on chromosome 16q23.3 reached genome-wide significance for switch.

CONCLUSIONS: The study findings suggest that individuals with ADHD with higher polygenic liability for mood and/or psychotic disorders, delayed ADHD diagnosis, and psychiatric comorbidities have a higher risk for stimulant treatment discontinuation and switch to nonstimulants. Despite the study's limited sample size, one putative GWAS hit for switch was identified, illustrating the potential of utilizing genomics linked to prescription databases to advance ADHD pharmacogenomics.

PMID:34154395 | DOI:10.1176/appi.ajp.2020.20121686

Hum Mutat. 2021 Jun 21. doi: 10.1002/humu.24243. Online ahead of print.

ABSTRACT

Next generation sequencing technology has afforded discovery of many novel variants that are of significance to inheritable pharmacogenomics (PGx) traits but a large proportion of them have unknown consequences. These include missense variants resulting in single amino acid substitutions in cytochrome P450 (CYP) proteins that can impair enzyme function leading to altered drug efficacy and toxicity. While most unknown variants are rare, an overlooked minority are variants that are collectively rare but enriched in specific populations. Here, we analyzed sequence variation data in 141,456 individuals from across eight study populations in gnomAD for 38 CYP genes to identify such variants in addition to common variants. By further comparison with data from two PGx-specific databases (PharmVar and PharmGKB) and ClinVar, we identified 234 missense variants in 35 CYP genes, of which 107 were unknown to these databases. Most unknown variants (n = 83) were population-specific common variants and several (n = 7) were found in important CYP pharmacogenes (CYP2D6, CYP4F2, CYP2C19). Overall, 29% (n = 31) of 107 unknown variants were predicted to affect CYP enzyme function although further biochemical characterization is necessary. These variants may elucidate part of the unexplained inter-population differences observed in drug response. This article is protected by copyright. All rights reserved.

PMID:34153149 | DOI:10.1002/humu.24243

Clin Pharmacol Ther. 2021 Jun 20. doi: 10.1002/cpt.2323. Online ahead of print.

ABSTRACT

Pharmacogenomic studies have successfully identified variants - typically with large effect sizes in drug target and metabolism enzymes - that predict drug outcome phenotypes. However, these variants may account for a limited proportion of phenotype variability attributable to the genome. Using genome-wide common variation, we measured the narrow-sense heritability [ h SNP 2 ] of 7 pharmacodynamic and 5 pharmacokinetic phenotypes across 3 cardiovascular drugs, 2 antibiotics, and 3 immunosuppressants. We used a Bayesian Hierarchical Mixed Model, BayesR, to model the distribution of genome-wide variant effect sizes for each drug phenotype as a mixture of 4 normal distributions of fixed variance (0, 0.01%, 0.1% and 1% of the total additive genetic variance). This model allowed us to parse h SNP 2 into bins representing contributions of no-, small-, moderate- and large-effect size variants respectively. For the 12 phenotypes, a median of 969 (range 235-6,304) unique individuals of European ancestry and a median of 1,201,626 (range 777,427-1,514,275) variants were included in our analyses. The number of variants contributing to h SNP 2 ranged from 2,791 to 5,356 (median 3,347). Estimates for h SNP 2 ranged from 0.05 (ACE-inhibitor induced cough) to 0.59 (gentamicin concentration). Small- and moderate-effect variants contributed a majority to h SNP 2 for every phenotype (range 61-95%). We conclude that drug outcome phenotypes are highly polygenic. Thus, larger genome-wide association studies of drug phenotypes are needed both to discover novel variants and to determine how genome-wide approaches may improve clinical prediction of drug outcomes.

PMID:34151428 | DOI:10.1002/cpt.2323

Front Cardiovasc Med. 2021 Jun 4;8:651269. doi: 10.3389/fcvm.2021.651269. eCollection 2021.

ABSTRACT

Chemotherapy is widely used in the treatment of cancer patients, but the cardiotoxicity induced by chemotherapy is still a major concern to most clinicians. Currently, genetic methods have been used to detect patients with high risk of chemotherapy-induced cardiotoxicity (CIC), and our study evaluated the correlation between genomic variants and CIC. The systematic literature search was performed in the PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), China Biology Medicine disc (CBMdisc), the Embase database, China National Knowledge Internet (CNKI) and Wanfang database from inception until June 2020. Forty-one studies were identified that examined the relationship between genetic variations and CIC. And these studies examined 88 different genes and 154 single nucleotide polymorphisms (SNPs). Our study indicated 6 variants obviously associated with the increased risk for CIC, including CYBA rs4673 (pooled odds ratio, 1.93; 95% CI, 1.13-3.30), RAC2 rs13058338 (2.05; 1.11-3.78), CYP3A5 rs776746 (2.15; 1.00-4.62) ABCC1 rs45511401 (1.46; 1.05-2.01), ABCC2 rs8187710 (2.19; 1.38-3.48), and HER2-Ile655Val rs1136201 (2.48; 1.53-4.02). Although further studies are required to validate the diagnostic and prognostic roles of these 6 variants in predicting CIC, our study emphasizes the promising benefits of pharmacogenomic screening before chemotherapy to minimize the CIC.

PMID:34150864 | PMC:PMC8213036 | DOI:10.3389/fcvm.2021.651269