The HLA-DRB1*09:01-DQB1*03:03 haplotype is associated with the risk for late-onset Alzheimer's disease in APOE [Formula: see text]4-negative Japanese adults.

Late-onset Alzheimer's disease (LOAD) is the most common cause of dementia among those older than 65 years. The onset of LOAD is influenced by neuroinflammation. The human leukocyte antigen (HLA) system is involved in regulating inflammatory responses. Numerous HLA alleles and their haplotypes have shown varying associations with LOAD in diverse populations, yet their impact on the Japanese population remains to be elucidated. Here, we conducted a comprehensive investigation into the associations between LOAD and HLA alleles within the Japanese population. Using whole-genome sequencing (WGS) data from 303 LOAD patients and 1717 cognitively normal (CN) controls, we identified four-digit HLA class I alleles (A, B, and C) and class II alleles (DRB1, DQB1, and DPB1). We found a significant association between the HLA-DRB1*09:01-DQB1*03:03 haplotype and LOAD risk in APOE [Formula: see text]4-negative samples (odds ratio = 1.81, 95% confidence interval = 1.38-2.38, P = 2.03[Formula: see text]). These alleles not only showed distinctive frequencies specific to East Asians but demonstrated a high degree of linkage disequilibrium in APOE [Formula: see text]4-negative samples (r2 = 0.88). Because HLA class II molecules interact with T-cell receptors (TCRs), we explored potential disparities in the diversities of TCR α chain (TRA) and ß chain (TRB) repertoires between APOE [Formula: see text]4-negative LOAD and CN samples. Lower diversity of TRA repertoires was associated with LOAD in APOE [Formula: see text]4-negative samples, irrespective of the HLA DRB1*09:01-DQB1*03:03 haplotype. Our study enhances the understanding of the etiology of LOAD in the Japanese population and provides new insights into the underlying mechanisms of its pathogenesis.

Genotyping, characterization, and imputation of known and novel CYP2A6 structural variants using SNP array data.

CYP2A6 metabolically inactivates nicotine. Faster CYP2A6 activity is associated with heavier smoking and higher lung cancer risk. The CYP2A6 gene is polymorphic, including functional structural variants (SV) such as gene deletions (CYP2A6*4), duplications (CYP2A6*1 × 2), and hybrids with the CYP2A7 pseudogene (CYP2A6*12, CYP2A6*34). SVs are challenging to genotype due to their complex genetic architecture. Our aims were to develop a reliable protocol for SV genotyping, functionally phenotype known and novel SVs, and investigate the feasibility of CYP2A6 SV imputation from SNP array data in two ancestry populations. European- (EUR; n = 935) and African- (AFR; n = 964) ancestry individuals from smoking cessation trials were genotyped for SNPs using an Illumina array and for CYP2A6 SVs using Taqman copy number (CN) assays. SV-specific PCR amplification and Sanger sequencing was used to characterize a novel SV. Individuals with SVs were phenotyped using the nicotine metabolite ratio, a biomarker of CYP2A6 activity. SV diplotype and SNP array data were integrated and phased to generate ancestry-specific SV reference panels. Leave-one-out cross-validation was used to investigate the feasibility of CYP2A6 SV imputation. A minimal protocol requiring three Taqman CN assays for CYP2A6 SV genotyping was developed and known SV associations with activity were replicated. The first domain swap CYP2A6-CYP2A7 hybrid SV, CYP2A6*53, was identified, sequenced, and associated with lower CYP2A6 activity. In both EURs and AFRs, most SV alleles were identified using imputation (>70% and >60%, respectively); importantly, false positive rates were <1%. These results confirm that CYP2A6 SV imputation can identify most SV alleles, including a novel SV.

Augmenting Granzyme B-Expressing NK Cells by Invariant NKT Ligand-Loaded APCs in Patients with Postoperative Early Stage Non-Small Cell Lung Cancer: Results of a Randomized Phase II Study.

NK cells are major effector cells involved in the elimination of early tumors and prevent metastasis. They often have an impaired function in patients with cancer. Preclinical studies have demonstrated NK cell activation as the adjunctive effect of invariant NKT (iNKT) cells. Activation of iNKT cells after administration of the glycolipid ligand α-galactosylceramide, loaded with CD1d-expressing human PBMC-derived APCs (APC/Gal), is an attractive cancer therapy to optimize the use of NK cells. However, the subsets of NK cells that are activated following iNKT cell activation as well as the period of NK cell activation remain unclear. In this study, we report that the granzyme B-expressing NK cell response in postoperative lung cancer patients was enhanced 49 d after administration of APC/Gal in a phase II study. We found maximum IFN-γ production on day 49 in 13 out of 27 APC/Gal-treated patients. On day 49, 14 out of 27 patients (51.9%) had higher IFN-γ production by iNKT cells (>6-fold higher than the baseline level). This increment significantly correlated with granzyme B-expressing NK cells. Although IFN-γ production was lower in patients in the nontreated group, we detected maximum IFN-γ production 12 mo after the resection of lung cancer (9 out of 29 patients [31%]). These findings suggest that elimination of cancer cells leads to increased NK cell function, which can be further enhanced by APC/Gal therapy.

Genome-Wide Meta-Analysis Identifies Variants in DSCAM and PDLIM3 That Correlate with Efficacy Outcomes in Metastatic Renal Cell Carcinoma Patients Treated with Sunitinib.

Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in CYP3A5 and ABCB1. Our aim is to provide novel insights into biological mechanisms underlying sunitinib action. We included mRCC patients from the European EuroTARGET consortium (n = 550) and the RIKEN cohort in Japan (n = 204) which were analysed separately and in a meta-analysis of genome-wide association studies (GWAS). SNPs were tested for association with progression-free survival (PFS) and overall survival (OS) using Cox regression. Summary statistics were combined using a fixed effect meta-analysis. SNP rs28520013 in PDLIM3 and the correlated SNPs rs2205096 and rs111356738 both in DSCAM, showed genome-wide significance (p < 5 × 10−8) with PFS and OS in the meta-analysis. The variant T-allele of rs28520013 associated with an inferior PFS of 5.1 months compared to 12.5 months in non-carriers (p = 4.02 × 10−10, HR = 7.26). T-allele carriers of rs28520013 showed an inferior OS of 6.9 months versus 30.2 months in non-carriers (p = 1.62 × 10−8, HR = 5.96). In this GWAS we identified novel genetic variants in PDLIM3 and DSCAM that impact PFS and OS in mRCC patients receiving sunitinib. The underlying link between the identified genes and the molecular mechanisms of sunitinib action needs to be elucidated.

Accuracy and applications of sequencing and genotyping approaches for CYP2A6 and homologous genes.

OBJECTIVES: We evaluated multiple genotyping/sequencing approaches in a homologous region of chromosome 19, and investigated associations of two common 3'-UTR CYP2A6 variants with activity in vivo. METHODS: Individuals (n = 1704) of European and African ancestry were phenotyped for the nicotine metabolite ratio (NMR), an index of CYP2A6 activity, and genotyped/sequenced using deep amplicon exon sequencing, SNP array, genotype imputation and targeted capture sequencing. Amplicon exon sequencing was the gold standard to which other methods were compared within-individual for CYP2A6, CYP2A7, CYP2A13, and CYP2B6 exons to identify highly discordant positions. Linear regression models evaluated the association of CYP2A6*1B and rs8192733 genotypes (coded additively) with logNMR. RESULTS: All approaches were ≤2.6% discordant with the gold standard; discordant calls were concentrated at few positions. Fifteen positions were discordant in >10% of individuals, with 12 appearing in regions of high identity between homologous genes (e.g. CYP2A6 and CYP2A7). For six, allele frequencies in our study and online databases were discrepant, suggesting errors in online sources. In the European-ancestry group (n = 935), CYP2A6*1B and rs8192733 were associated with logNMR (P < 0.001). A combined model found main effects of both variants on increasing logNMR. Similar trends were found in those of African ancestry (n = 506). CONCLUSION: Multiple genotyping/sequencing approaches used in this chromosome 19 region contain genotyping/sequencing errors, as do online databases. Gene-specific primers and SNP array probes must consider gene homology; short-read sequencing of related genes in a single reaction should be avoided. Using improved sequencing approaches, we characterized two gain-of-function 3'-UTR variants, including the relatively understudied rs8192733.

Identification and functional validation of novel pharmacogenomic variants using a next-generation sequencing-based approach for clinical pharmacogenomics.

Inter-individual variability in pharmacokinetics and drug response is heavily influenced by single-nucleotide variants (SNVs) and copy-number variations (CNVs) in genes with importance for drug disposition. Nowadays, a plethora of studies implement next generation sequencing to capture rare and novel pharmacogenomic (PGx) variants that influence drug response. To address these issues, we present a comprehensive end-to-end analysis workflow, beginning from targeted PGx panel re-sequencing to in silico analysis pipelines and in vitro validation assays. Specifically, we show that novel pharmacogenetic missense variants that are predicted or putatively predicted to be functionally deleterious, significantly alter protein activity levels of CYP2D6 and CYP2C19 proteins. We further demonstrate that variant priorization pipelines tailored with functional in vitro validation assays provide supporting evidence for the deleterious effect of novel PGx variants. The proposed workflow could provide the basis for integrating next-generation sequencing for PGx testing into routine clinical practice.

Functional characterization of novel rare CYP2A6 variants and potential implications for clinical outcomes.

CYP2A6 activity, phenotyped by the nicotine metabolite ratio (NMR), is a predictor of several smoking behaviors, including cessation and smoking-related disease risk. The heritability of the NMR is 60-80%, yet weighted genetic risk scores (wGRSs) based on common variants explain only 30-35%. Rare variants (minor allele frequency <1%) are hypothesized to explain some of this missing heritability. We present two targeted sequencing studies where rare protein-coding variants are functionally characterized in vivo, in silico, and in vitro to examine this hypothesis. In a smoking cessation trial, 1687 individuals were sequenced; characterization measures included the in vivo NMR, in vitro protein expression, and metabolic activity measured from recombinant proteins. In a human liver bank, 312 human liver samples were sequenced; measures included RNA expression, protein expression, and metabolic activity from extracted liver tissue. In total, 38 of 47 rare coding variants identified were novel; characterizations ranged from gain-of-function to loss-of-function. On a population level, the portion of NMR variation explained by the rare coding variants was small (~1%). However, upon incorporation, the accuracy of the wGRS was improved for individuals with rare protein-coding variants (i.e., the residuals were reduced), and approximately one-third of these individuals (12/39) were re-assigned from normal to slow metabolizer status. Rare coding variants can alter an individual's CYP2A6 activity; their integration into wGRSs through precise functional characterization is necessary to accurately assess clinical outcomes and achieve precision medicine for all. Investigation into noncoding variants is warranted to further explain the missing heritability in the NMR.

Pharmacogenomics variants are associated with BMI differences between individuals with bipolar and other psychiatric disorders.

Aim: Regardless of the plethora of next-generation sequencing studies in the field of pharmacogenomics (PGx), the potential effect of covariate variables on PGx response within deeply phenotyped cohorts remains unexplored. Materials & methods: We explored with advanced statistical methods the potential influence of BMI, as a covariate variable, on PGx response in a Greek cohort with psychiatric disorders. Results: Nine PGx variants within UGT1A6, SLC22A4, GSTP1, CYP4B1, CES1, SLC29A3 and DPYD were associated with altered BMI in different psychiatric disorder groups. Carriers of rs2070959 (UGT1A6), rs199861210 (SLC29A3) and rs2297595 (DPYD) were also characterized by significant changes in the mean BMI, depending on the presence of psychiatric disorders. Conclusion: Specific PGx variants are significantly associated with BMI in a Greek cohort with psychiatric disorders.

Effect of 5-fluorouracil on mRNA expression of drug metabolizing enzyme and transporter genes in human hepatoma cell lines.

Fluoropyrimidines such as 5-fluorouracil (5-FU) are well known to have drug-drug interactions with anticoagulant medications such as warfarin. This study investigated the mRNA expression of pharmacokinetic (PK)-related genes in response to 5-FU using the hepatocarcinoma cell lines after examining relevant gene expression via RNA sequencing. We used HepaRG cells for 5-FU treatment analysis because these cells displayed PK-related gene expression. 5-FU exposure significantly reduced cytochrome P450 3A4 (CYP3A4) mRNA expression. Additionally, the mRNA expression of nuclear receptor subfamily 1 group I member 2 (also known as pregnane X receptor), a nuclear receptor transcription factor that promotes the expression of many CYP genes, was also decreased in HepaRG cells following 5-FU treatment. The mRNA expressions of the CYP2B6 and ATP-binding cassette transporter genes were decreased after 5-FU treatment. This study revealed that 5-FU treatment reduced PK-related gene expression in HepaRG cells. These findings should be useful for further drug-drug interaction research.

Genome-wide association study reveals an association between the HLA-DPB1∗02:01:02 allele and wheat-dependent exercise-induced anaphylaxis.

Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a life-threatening food allergy triggered by wheat in combination with the second factor such as exercise. The identification of potential genetic risk factors for this allergy might help high-risk individuals before consuming wheat-containing food. We aimed to identify genetic variants associated with WDEIA. A genome-wide association study was conducted in a discovery set of 77 individuals with WDEIA and 924 control subjects via three genetic models. The associations were confirmed in a replication set of 91 affected individuals and 435 control individuals. Summary statistics from the combined set were analyzed by meta-analysis with a random-effect model. In the discovery set, a locus on chromosome 6, rs9277630, was associated with WDEIA in the dominant model (OR = 3.95 [95% CI, 2.31-6.73], p = 7.87 × 10-8). The HLA-DPB1∗02:01:02 allele displayed the most significant association with WDEIA (OR = 4.51 [95% CI, 2.66-7.63], p = 2.28 × 10-9), as determined via HLA imputation following targeted sequencing. The association of the allele with WDEIA was confirmed in replication samples (OR = 3.82 [95% CI, 2.33-6.26], p = 3.03 × 10-8). A meta-analysis performed in the combined set revealed that the HLA-DPB1∗02:01:02 allele was significantly associated with an increased risk of WDEIA (OR = 4.13 [95% CI, 2.89-5.93], p = 1.06 × 10-14). Individuals carrying the HLA-DPB1∗02:01:02 allele have a significantly increased risk of WDEIA. Further validation of these findings in independent multiethnic cohorts is needed.

Displacement of center of mass in dogs in response to foot sensory stimulation.

OBJECTIVE: Evaluate center of mass (CoM) displacement values during four-limb and three-limb standing with limb suspension in dogs before and after applying sensory stimulation to a forelimb or hindlimb. STUDY DESIGN: Experimental study. ANIMALS: Six clinically normal beagles. METHODS: A four force-plate apparatus was built to assess static weight distribution. Dogs stood on the device with one limb in contact with each force plate. We created a plastic device to induce sensory stimulation so that lameness could not be detected visually when stimulating the paw. Experimenters confirmed the degree of lameness by walking before and after measurement. Body-weight shifts were induced via suspension of each limb and transient sensory stimulation to the right forelimb or left hindlimb. CoMs of five postures were compared, with and without transient sensory stimulation. RESULTS: The four-limb CoM was located cranial to the center of the X- and Y-axis coordinates (X: -0.82 ± 9.12, Y: 61.00 ± 5.82). During three-limb standing with suspension of either forelimb, CoM shifted backward toward the contralateral side compared to four-limb standing. During hindlimb suspension, CoM shifted to the contralateral side. With right forelimb sensory stimulation, there were large CoM changes for both four-limb and three-limb standing (X: -34.53 ± 9.09, Y: 52.21 ± 6.88). CoM changes were small with left hindlimb sensory stimulation (X: 6.47 ± 13.86, Y: 69.41 ± 5.55). CONCLUSION: CoMs during four-limb and three-limb standing were influenced by sensory stimulation of a forelimb and, to a lesser extent, of a hindlimb. CLINICAL SIGNIFICANCE: Static evaluation of CoM may aid clinicians in the diagnosis and recovery of forelimb lameness.

Functional Characterization of the Effects of N-acetyltransferase 2 Alleles on N-acetylation of Eight Drugs and Worldwide Distribution of Substrate-Specific Diversity.

Variability in the enzymatic activity of N-acetyltransferase 2 (NAT2) is an important contributor to interindividual differences in drug responses. However, there is little information on functional differences in N-acetylation activities according to NAT2 phenotypes, i.e., rapid, intermediate, slow, and ultra-slow acetylators, between different substrate drugs. Here, we estimated NAT2 genotypes in 990 Japanese individuals and compared the frequencies of different genotypes with those of different populations. We then calculated in vitro kinetic parameters of four NAT2 alleles (NAT2∗4, ∗5, ∗6, and ∗7) for N-acetylation of aminoglutethimide, diaminodiphenyl sulfone, hydralazine, isoniazid, phenelzine, procaineamide, sulfamethazine (SMZ), and sulfapyrizine. NAT2∗5, ∗6, and ∗7 exhibited significantly reduced N-acetylation activities with lower Vmax and CLint values of all drugs when compared with NAT2∗4. Hierarchical clustering analysis revealed that 10 NAT2 genotypes were categorized into three or four clusters. According to the results of in vitro metabolic experiments using SMZ as a substrate, the frequencies of ultra-slow acetylators were calculated to be 29.05-54.27% in Europeans, Africans, and South East Asians, whereas Japanese and East Asian populations showed lower frequencies (4.75 and 11.11%, respectively). Our findings will be helpful for prediction of responses to drugs primarily metabolized by NAT2.

Discrepancies and similarities in the genome-informed guidance for psychiatric disorders amongst different regulatory bodies and research consortia using next generation sequencing-based clinical pharmacogenomics data.

Undoubtedly, pharmacogenomics (PGx) aims in optimizing drug treatment responses whilst also improving the patients' quality of life, either via a reduction of adverse drug reactions and/or an enhancement of drug treatment efficacy. To achieve this, PGx guidance is provided by the two major regulatory bodies in a worldwide level, specifically the U.S. Food and Drug Administration (FDA) and the European Medicine Agency (EMA), and occasionally some research consortia, such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) or the Dutch Pharmacogenomics Working Group (DPWG). However, so far, there is a limited number of studies focusing on the delineation of the similarities and more importantly, the discrepancies in the PGx guidance by the different regulatory bodies and consortia. Herein, we use real-life clinical PGx data to highlight such discrepancies and similarities for genome-guided interventions in psychiatric disorders, thus demonstrating the need for harmonization of the guidelines and recommendations. More precisely, we used the PharmCAT genome-informed drug treatment reports from 304 Greek individuals with psychiatric disorders in order to emphasize on the discrepancies in the PGx guidance/guidelines between FDA vs EMA and CPIC vs DPWG, respectively. For example, CYP2D6-pimozide pair is characterized as 'Testing Required' according to FDA and is accompanied by a DPWG PGx guideline, whilst no EMA or CPIC PGx guidance is found for this drug-gene pair. Moreover, discrepancies are observed regarding the type of PGx guidance for CYP2C19-doxepin pair, with 89 individuals from our study cohort requiring a dose prescribing change based on FDA, whilst only 5 individuals have to receive genome-guided treatment adjustment according to CPIC. To our knowledge, this is the first study, in which discrepancies regarding the type of PGx guidance and the number of actionable drug-gene pairs amongst FDA and EMA, as well as CPIC and DPWG, are brought to light with an emphasis on psychiatric disorders.

Prevalence of pharmacogenomic variants in 100 pharmacogenes among Southeast Asian populations under the collaboration of the Southeast Asian Pharmacogenomics Research Network (SEAPharm).

Pharmacogenomics can enhance the outcome of treatment by adopting pharmacogenomic testing to maximize drug efficacy and lower the risk of serious adverse events. Next-generation sequencing (NGS) is a cost-effective technology for genotyping several pharmacogenomic loci at once, thereby increasing publicly available data. A panel of 100 pharmacogenes among Southeast Asian (SEA) populations was resequenced using the NGS platform under the collaboration of the Southeast Asian Pharmacogenomics Research Network (SEAPharm). Here, we present the frequencies of pharmacogenomic variants and the comparison of these pharmacogenomic variants among different SEA populations and other populations used as controls. We investigated the different types of pharmacogenomic variants, especially those that may have a functional impact. Our results provide substantial genetic variations at 100 pharmacogenomic loci among SEA populations that may contribute to interpopulation variability in drug response phenotypes. Correspondingly, this study provides basic information for further pharmacogenomic investigations in SEA populations.

Update on next generation sequencing of pharmacokinetics-related genes: Development of the PKseq panel, a platform for amplicon sequencing of drug-metabolizing enzyme and drug transporter genes.

Genetic variation in pharmacokinetics (PK)-related genes encoding drug metabolizing enzymes or drug transporters is one of the most practical pharmacogenetic biomarkers for the prediction or explanation of an individual's response to drugs. Many pharmacogenomic variations are identified using targeted, whole-exome, and whole-genome sequencing, and the number of known novel variations and alleles in PK-related genes is increasing. The high homology of sequences among PK-related genes is suspected to lead to potential read misalignment and genotyping errors when short-read sequencing was performed. Therefore, highly efficient and accurate next generation sequencing (NGS) platforms for the sequencing of PK-related genes are needed. We have developed PKseq, a targeted sequencing panel based on multiplex PCR, which targets the coding regions of 37 drug transporters, 30 cytochrome P450 isoforms, 10 UDP-glucuronosyltransferases, 5 flavin-containing monooxygenases, 4 glutathione S-transferases, 4 sulfotransferases, and 10 other genes. In this review, we describe the current NGS platforms for the sequencing of PK-related genes. The NGS platforms, including the PKseq panel, will be useful not only for the identification of all the variants of PK-related genes associated with adverse drug reactions and drug efficacy, but also for clinical sequencing to achieve pharmacogenomics-based stratified medicine.

Determination of novel CYP2D6 haplotype using the targeted sequencing followed by the long-read sequencing and the functional characterization in the Japanese population.

Next-generation sequencing (NGS) has identified variations in cytochrome P450 (CYP) 2D6 associated with drug responses. However, determination of novel haplotypes is difficult because of the short reads generated by NGS. We aimed to identify novel CYP2D6 variants in the Japanese population and predict the CYP2D6 phenotype based on in vitro metabolic studies. Using a targeted NGS panel (PKSeq), 990 Japanese genomes were sequenced, and then novel CYP2D6 haplotypes were determined. Km, Vmax, and intrinsic clearance (Vmax/Km) of N-desmethyl-tamoxifen 4-hydroxylation were calculated by in vitro metabolic studies using cDNA-expressed CYP2D6 proteins. After determination of the CYP2D6 diplotypes, phenotypes of the individuals were predicted based on the in vitro metabolic activities. Targeted NGS identified 14 CYP2D6 variants not registered in the Pharmacogene Variation Consortium (PharmVar) database. Ten novel haplotypes were registered as CYP2D6*128 to *137 alleles in the PharmVar database. Based on the Vmax/Km value of each allele, *128, *129, *130, *131, *132, and *133 were predicted to be nonfunctional alleles. According to the results of the present study, six normal metabolizers (NM) and one intermediate (IM) metabolizers were designated as IM and poor metabolizers (PM), respectively. Our findings provide important insights into novel haplotypes and haplotypes of CYP2D6 and the effects on in vitro metabolic activities.

Transferability of Ancestry-Specific and Cross-Ancestry CYP2A6 Activity Genetic Risk Scores in African and European Populations.

The Nicotine Metabolite Ratio (NMR; 3-hydroxycotinine/cotinine), a highly heritable index of nicotine metabolic inactivation by the CYP2A6 enzyme, is associated with numerous smoking behaviors and diseases, as well as unique cessation outcomes. However, the NMR cannot be measured in nonsmokers, former smokers, or intermittent smokers, for example, in evaluating tobacco-related disease risk. Traditional pharmacogenetic groupings based on CYP2A6 * alleles capture a modest portion of NMR variation. We previously created a CYP2A6 weighted genetic risk score (wGRS) for European (EUR)-ancestry populations by incorporating independent signals from genome-wide association studies to capture a larger proportion of NMR variation. However, CYP2A6 genetic architecture is unique to ancestral populations. In this study, we developed and replicated an African-ancestry (AFR) wGRS, which captured 30-35% of the variation in NMR. We demonstrated model robustness against known environmental sources of NMR variation. Furthermore, despite the vast diversity within AFR populations, we showed that the AFR wGRS was consistent between different US geographical regions and unaltered by fine AFR population substructure. The AFR and EUR wGRSs can distinguish slow from normal metabolizers in their respective populations, and were able to reflect unique smoking cessation pharmacotherapy outcomes previously observed for the NMR. Additionally, we evaluated the utility of a cross-ancestry wGRS, and the capacity of EUR, AFR, and cross-ancestry wGRSs to predict the NMR within stratified or admixed AFR-EUR populations. Overall, our findings establish the clinical benefit of applying ancestry-specific wGRSs, demonstrating superiority of the AFR wGRS in AFRs.

Variation in 100 relevant pharmacogenes among emiratis with insights from understudied populations.

Genetic variations have an established impact on the pharmacological response. Investigating this variation resulted in a compilation of variants in "pharmacogenes". The emergence of next-generation sequencing facilitated large-scale pharmacogenomic studies and exhibited the extensive variability of pharmacogenes. Some rare and population-specific variants proved to be actionable, suggesting the significance of population pharmacogenomic research. A profound gap exists in the knowledge of pharmacogenomic variants enriched in some populations, including the United Arab Emirates (UAE). The current study aims to explore the landscape of variations in relevant pharmacogenes among healthy Emiratis. Through the resequencing of 100 pharmacogenes for 100 healthy Emiratis, we identified 1243 variants, of which 63% are rare (minor allele frequency ≤ 0.01), and 30% were unique. Filtering the variants according to Pharmacogenomics Knowledge Base (PharmGKB) annotations identified 27 diplotypes and 26 variants with an evident clinical relevance. Comparison with global data illustrated a significant deviation of allele frequencies in the UAE population. Understudied populations display a distinct allelic architecture and various rare and unique variants. We underscored pharmacogenes with the highest variation frequencies and provided investigators with a list of candidate genes for future studies. Population pharmacogenomic studies are imperative during the pursuit of global pharmacogenomics implementation.