Methods Mol Biol. 2022;2547:47-61. doi: 10.1007/978-1-0716-2573-6_3.

ABSTRACT

Targeted therapies have significantly altered the landscape of available cancer therapies across all diagnoses and patient populations, and supportive care therapies have steadily improved throughout the years to make therapy more tolerable for patients. Even so, these therapies have varied efficacy and toxicity among patients with cancer, and pharmacogenomics presents an opportunity to identify which patients are most at risk of toxicities and most likely to benefit from them. While the field of pharmacogenomics in targeted cancer therapy is still growing, we review current knowledge, hypotheses, and clinical practices in this chapter, along with a brief review of pharmacogenomics in supportive therapies in cancer treatment.

PMID:36068460 | DOI:10.1007/978-1-0716-2573-6_3

Methods Mol Biol. 2022;2547:21-45. doi: 10.1007/978-1-0716-2573-6_2.

ABSTRACT

The genetic region on the short arm of chromosome 6 where the human leukocyte antigen (HLA) genes are located is the major histocompatibility complex. The genes in this region are highly polymorphic, and some loci have a high degree of homology with other genes and pseudogenes. Histocompatibility testing has traditionally been performed in the setting of transplantation and involves determining which specific alleles are present. Several HLA alleles have been associated with disease risk or increased risk of adverse drug reaction (ADR) when treated with certain medications. Testing for these applications differs from traditional histocompatibility in that the desired result is simply presence or absence of the allele of interest, rather than determining which allele is present. At present, the majority of HLA typing is done by molecular methods using commercially available kits. A subset of pharmacogenomics laboratories has developed their own methods, and in some cases, query single nucleotide variants associated with certain HLA alleles rather than directly testing for the allele. In this chapter, a brief introduction to the HLA system is provided, followed by an overview of a variety of testing technologies including those specifically used in pharmacogenomics, and the chapter concludes with details regarding specific HLA alleles associated with ADR.

PMID:36068459 | DOI:10.1007/978-1-0716-2573-6_2

Pharmacogenomics J. 2022 Sep 6. doi: 10.1038/s41397-022-00288-2. Online ahead of print.

ABSTRACT

Genes encoding cytochrome P450 enzymes (CYPs) are extremely polymorphic and multiple CYP variants constitute clinically relevant biomarkers for the guidance of drug selection and dosing. We previously reported the distribution of the most relevant CYP alleles using population-scale sequencing data. Here, we update these findings by making use of the increasing wealth of data, incorporating whole exome and whole genome sequencing data from 141,614 unrelated individuals across 12 human populations. We furthermore extend our previous studies by systematically considering also uncharacterized rare alleles and reveal that they contribute between 1.5% and 17.5% to the overall genetically encoded functional variability. By using established guidelines, we aggregate and translate the available sequencing data into population-specific patterns of metabolizer phenotypes. Combined, the presented data refine the worldwide landscape of ethnogeographic variability in CYP genes and aspire to provide a relevant resource for the optimization of population-specific genotyping strategies and precision public health.

PMID:36068297 | DOI:10.1038/s41397-022-00288-2

Metabolism. 2022 Sep 3:155309. doi: 10.1016/j.metabol.2022.155309. Online ahead of print.

NO ABSTRACT

PMID:36067806 | DOI:10.1016/j.metabol.2022.155309

Ugeskr Laeger. 2022 Aug 22;184(34):V05220300.

ABSTRACT

Use of predictive biomarkers plays a promising role in stratifying patients to a more effective medical treatment with less side effects. This review provides a brief overview in a Danish context of the potential of applying pharmacogenomics (PGx) including companion diagnostics (CDx) in daily clinical practice based on the current knowledge and regulation from the FDA and EMA, Summary of Product Characteristics (SPC), PharmGKB (pharmacogenomics knowledge resource providing clinical dosing guidelines) and partly promedicin.dk. Also, the barriers to more widespread use are being addressed.

PMID:36065863

Expert Rev Clin Pharmacol. 2022 Sep 5:1-11. doi: 10.1080/17512433.2022.2118714. Online ahead of print.

ABSTRACT

INTRODUCTION: Metformin has been recognized as the first-choice drug for type 2 diabetes mellitus (T2DM). The potency of metformin in the treatment of type 2 diabetes has always been in the spotlight and shown significant individual differences. Based on previous studies, the efficacy of metformin is related to the single-nucleotide polymorphisms of transporter genes carried by patients, amongst which a variety of gene polymorphisms of transporter and target protein genes affect the effectiveness and adverse repercussion of metformin.

AREAS COVERED: Here, we reviewed the current knowledge about gene polymorphisms impacting metformin efficacy based on transporter and drug target proteins.

EXPERT OPINION: The reason for the difference in clinical drug potency of metformin can be attributed to the gene polymorphism of drug transporters and drug target proteins in the human body. Substantial evidence shows that genetic polymorphisms in transporters such as organic cation transporter 1 (OCT1) and organic cation transporter 2 (OCT2) affect the glucose-lowering effectiveness of metformin. However, optimization of individualized dosing regimens of metformin is necessary to clarify the role of several polymorphisms.

PMID:36065506 | DOI:10.1080/17512433.2022.2118714

Life Sci. 2022 Sep 2:120929. doi: 10.1016/j.lfs.2022.120929. Online ahead of print.

ABSTRACT

AIMS: Although impaired insulin signaling at a post-receptor level was a well-established key driver of insulin resistance, the role of surface abnormal insulin receptor (INSR) location in insulin resistance pathogenesis tended to be ignored and its molecular mechanisms remained obscure. Herein, this study aimed to investigate hepatic apolipoprotein E (APOE) impaired cellular insulin action via reducing cell surface INSR, especially in caveolae.

KEY FINDINGS: Downregulation of APOE enhanced the caveolae translocation of INSR and glucose transporter 2 (GLUT2), and improved hepatic cells' sensitivity to insulin. Consistently, mice with selective suppression of liver tissue APOE showed lower fasting insulin and fasting glucose levels, better homeostatic model assessment (HOMA) index (HOMA-IS, HOMA-IR, HOMA-β) and quantitative insulin sensitivity check index (QUICKI). Furthermore, the co-localization of INSR and CAV1 in the liver of these mice were more substantial than controls.

SIGNIFICANCE: APOE might adversely set the basal gain of INSR signaling implied that APOE could be a new endogenous INSR regulator.

PMID:36063979 | DOI:10.1016/j.lfs.2022.120929

Eur J Haematol. 2022 Sep 5. doi: 10.1111/ejh.13862. Online ahead of print.

ABSTRACT

Acute myeloid leukemia (AML) is a complex disease, and its treatment needs to be adjusted to the risk, which is conferred by cytogenetics and molecular markers. Cytarabine is the main drug to treat AML, and it has been suggested that the genotype of cytarabine metabolizing enzymes may have a prognostic relevance in AML. Here we report the association between the 5'-nucleotidase, cytosolic II (NT5C2) rs10883841, cytidine deaminase (CDA) rs2072671 and rs532545 genotypes and the clinical outcome of 477 intermediate-risk cytogenetic AML patients receiving cytarabine-based chemotherapy. Patients younger than 50 years old with the NT5C2 rs10883841 AA genotype had lower overall survival (OS) (p: 0.003; HR 2.16, 95%CI 1.29 - 3.61) and lower disease-free survival (DFS) (p: 0.002; HR 2.45, 95%CI 1.41 - 4.27), associated to a higher relapse incidence (p: 0.010; HR 2.23, 95%CI 1.21 - 4.12). Interestingly, subgroup analysis showed that the negative effect of the NT5C2 rs10883841 AA genotype was detected in all subgroups except in patients with nucleophosmin mutation without high ratio FLT-3 internal tandem duplication. CDA polymorphisms were associated with the complete remission rate after induction chemotherapy, without influencing OS. Further studies are warranted to determine whether this pharmacogenomic approach may be helpful to individualize AML treatment.

PMID:36063368 | DOI:10.1111/ejh.13862

Cardiovasc Res. 2022 Sep 5:cvac150. doi: 10.1093/cvr/cvac150. Online ahead of print.

NO ABSTRACT

PMID:36063101 | DOI:10.1093/cvr/cvac150

Front Pharmacol. 2022 Aug 17;13:943538. doi: 10.3389/fphar.2022.943538. eCollection 2022.

ABSTRACT

Cytochrome P450 (CYP) drug metabolizing enzymes are responsible for the metabolism of over 70% of currently used medications with the CYP3A family being the most important CYP enzymes in the liver. Large inter-person variability in expression/activity of the CYP3As greatly affects drug exposure and treatment outcomes, yet the cause of such variability remains elusive. Micro-RNAs (miRNAs) are small noncoding RNAs that negatively regulate gene expression and are involved in diverse cellular processes including metabolism of xenobiotics and therapeutic outcomes. Target prediction and in vitro functional assays have linked several miRNAs to the control of CYP3A4 expression. Yet, their co-expression with CYP3As in the liver remain unclear. In this study, we used genome-wide miRNA profiling in liver samples to identify miRNAs associated with the expression of the CYP3As. We identified and validated both miR-107 and miR-1260 as strongly associated with the expression of CYP3A4, CYP3A5, and CYP3A43. Moreover, we found associations between miR-107 and nine transcription factors (TFs) that regulate CYP3A expression, with estrogen receptor alpha (ESR1) having the largest effect size. Including ESR1 and the other TFs in the regression model either diminished or abolished the associations between miR-107 and the CYP3As, indicating that the role of miR-107 in CYP3A expression may be indirect and occur through these key TFs. Indeed, testing the other nine CYPs previously shown to be regulated by ESR1 identified similar miR-107 associations that were dependent on the exclusion of ESR1 and other key TFs in the regression model. In addition, we found significant differences in miRNA expression profiles in liver samples between race and sex. Together, our results identify miR-107 as a potential epigenetic regulator that is strongly associated with the expression of many CYPs, likely via impacting the CYP regulatory network controlled by ESR1 and other key TFs. Therefore, both genetic and epigenetic factors that alter the expression of miR-107 may have a broad influence on drug metabolism.

PMID:36059981 | PMC:PMC9428441 | DOI:10.3389/fphar.2022.943538

Front Med (Lausanne). 2022 Aug 18;9:945352. doi: 10.3389/fmed.2022.945352. eCollection 2022.

ABSTRACT

Several healthcare organizations have developed pre-emptive pharmacogenetic testing programs, where testing is undertaken prior to the prescription of a medicine. This review characterizes the barriers and facilitators which influenced the development of these programs. A bidirectional citation searching strategy identified relevant publications before a standardized data extraction approach was applied. Publications were grouped by program and data synthesis was undertaken using the Consolidated Framework for Implementation Research (CFIR). 104 publications were identified from 40 programs and 4 multi-center initiatives. 26 (66%) of the programs were based in the United States and 95% in high-income countries. The programs were heterogeneous in their design and scale. The Characteristics of the Intervention, Inner Setting, and Process domains were referenced by 92.5, 80, and 77.5% of programs, respectively. A positive institutional culture, leadership engagement, engaging stakeholders, and the use of clinical champions were frequently described as facilitators to implementation. Clinician self-efficacy, lack of stakeholder knowledge, and the cost of the intervention were commonly cited barriers. Despite variation between the programs, there were several similarities in approach which could be categorized via the CFIR. These form a resource for organizations planning the development of pharmacogenetic programs, highlighting key facilitators which can be leveraged to promote successful implementation.

PMID:36059837 | PMC:PMC9433561 | DOI:10.3389/fmed.2022.945352

Hum Mutat. 2022 Sep 4. doi: 10.1002/humu.24457. Online ahead of print.

ABSTRACT

To determine the phase of NUDT15 sequence variants for more comprehensive star (*) allele diplotyping, we developed a novel long-read single molecule real-time HiFi amplicon sequencing method. A 10.5 kb NUDT15 amplicon assay was validated using reference material positive controls and additional samples for specimen type and blinded accuracy assessment. Triplicate NUDT15 HiFi sequencing of two reference material samples had non-reference genotype concordances of >99.9%, indicating that the assay is robust. Notably, short-read genome sequencing of a subset of samples was unable to determine the phase of star (*) allele-defining NUDT15 variants, resulting in ambiguous diplotype results. In contrast, long-read HiFi sequencing phased all variants across the NUDT15 amplicons, including a *2/*9 diplotype that previously was characterized as *1/*2 in the 1000 Genomes Project v3 dataset. Assay throughput was also tested using 8.5 kb amplicons from 100 Ashkenazi Jewish individuals, which identified a novel NUDT15 *1 sub-allele (c.-121G>A) and a rare likely-deleterious coding variant (p.Pro129Arg). Both novel alleles were Sanger confirmed and assigned as *1.007 and *20, respectively, by the PharmVar Consortium. Taken together, NUDT15 HiFi amplicon sequencing is an innovative method for phased full-gene characterization and novel allele discovery, which could improve NUDT15 pharmacogenomic testing and subsequent phenotype prediction. This article is protected by copyright. All rights reserved.

PMID:36057977 | DOI:10.1002/humu.24457

Eur J Hum Genet. 2022 Sep 2. doi: 10.1038/s41431-022-01180-0. Online ahead of print.

ABSTRACT

The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the gene-drug interaction of ABCG2 with allopurinol, HLA-B with allopurinol, MTHFR with folic acid, and MTHFR with methotrexate, relevant for the treatment of gout, cancer, and rheumatoid arthritis. A systematic review was performed based on which pharmacotherapeutic recommendations were developed. Allopurinol is less effective in patients with the ABCG2 p.(Gln141Lys) variant. In HLA-B*58:01 carriers, the risk of severe cutaneous adverse events associated with allopurinol is strongly increased. The DPWG recommends using a higher allopurinol dose in patients with the ABCG2 p.(Gln141Lys) variant. For HLA-B*58:01 positive patients the DPWG recommends choosing an alternative (for instance febuxostat). The DPWG indicates that another option would be to precede treatment with allopurinol tolerance induction. Genotyping of ABCG2 in patients starting on allopurinol was judged to be 'potentially beneficial' for drug effectiveness, meaning genotyping can be considered on an individual patient basis. Genotyping for HLA-B*58:01 in patients starting on allopurinol was judged to be 'beneficial' for drug safety, meaning it is advised to consider genotyping the patient before (or directly after) drug therapy has been initiated. For MTHFR-folic acid there is evidence for a gene-drug interaction, but there is insufficient evidence for a clinical effect that makes therapy adjustment useful. Finally, for MTHFR-methotrexate there is insufficient evidence for a gene-drug interaction.

PMID:36056234 | DOI:10.1038/s41431-022-01180-0

Alcohol Clin Exp Res. 2022 Sep 2. doi: 10.1111/acer.14932. Online ahead of print.

ABSTRACT

BACKGROUND: In a previous study, ondansetron, a serotonin 5-HT3 receptor antagonist, reduced drinking intensity (drinks/drinking day [DPDD]) among European-ancestry (EA) participants with moderate-to-severe alcohol use disorder (AUD) and variants in genes encoding the serotonin transporter (SLC6A4), and 5-HT3A (HTR3A) and 5-HT3B (HTR3B) receptors. We tested whether 1) ondansetron reduces DPDD among individuals of either European or African ancestry (AA) and 2) that reductions in DPDD are greatest among ondansetron-treated individuals with population-specific combinations of genotypes at SLC6A4, HTR3A, and HTR3B.

METHODS: In this 16-week, double-blind, placebo-controlled, parallel-group clinical trial, adults with AUD were randomized to receive low-dose oral ondansetron (0.33 mg twice daily) or placebo stratified by "responsive" vs. "non-responsive" genotype defined using population-specific genotypes at the three genetic loci. Generalized estimating equation regression models and a modified intent-to-treat analysis were used to compare the treatment groups on the primary outcome-DPDD-and two secondary outcomes-heavy drinking days per week [HDD] and drinks per day [DPD] across 16 weeks of treatment.

RESULTS: Of 296 prospective participants screened, 95 (58 EA and 37 AA) were randomized and received at least one dose of study medication. In the modified intent-to-treat analysis, the ondansetron group averaged 0.40 more DPDD (p=0.51), 1.35 times as many HDD (p=0.16), and 1.06 times as many DPD (p=0.59) as the placebo group. There were no significant interactions with genotype. There were no study-related serious adverse events (AEs) and similar proportions of participants in the two treatment groups experienced AEs across organ systems.

CONCLUSIONS: We found no evidence that low-dose oral ondansetron is beneficial in the treatment of AUD, thus failing to confirm prior study findings. However, the study was underpowered to identify medication by genotype interactions.

PMID:36055978 | DOI:10.1111/acer.14932

Mol Metab. 2022 Aug 30:101588. doi: 10.1016/j.molmet.2022.101588. Online ahead of print.

ABSTRACT

Thermogenic fat differentiation and function can be promoted through multiple pathways, resulting in a common cell phenotype characterized by the expression of Uncoupling Protein-1 and the ability to dissipate energy, but local and systemic stimuli are necessary to promote adequate thermogenic fat vascularization, which is a precondition for the transport of substrate and the dissipation of heat. Angiopoietin-2 is an important driver of vascularization, and its transcription is in part promoted by estrogen signaling. In this study we demonstrate that adipose tissue-specific knock out of Angiopoietin-2 causes a female-specific reduced thermogenic fat differentiation and function, resulting in obesity and impaired glucose tolerance with end-organ features consistent with metabolic syndrome. In humans, angiopoietin-2 levels are higher in females than in males, and are inversely correlated with adiposity and age more strongly in pre-menopause when compared to post-menopause. Collectively, these data indicate a novel and important role for estrogen-mediated Angiopoietin-2 adipose tissue production in the protection against calorie overload in females, and potentially in the development of postmenopausal weight gain.

PMID:36055577 | DOI:10.1016/j.molmet.2022.101588

Am J Hum Genet. 2022 Sep 1;109(9):1638-1652. doi: 10.1016/j.ajhg.2022.08.004.

ABSTRACT

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are currently under clinical development for treating anemia in chronic kidney disease (CKD), but it is important to monitor their cardiovascular safety. Genetic variants can be used as predictors to help inform the potential risk of adverse effects associated with drug treatments. We therefore aimed to use human genetics to help assess the risk of adverse cardiovascular events associated with therapeutically altered EPO levels to help inform clinical trials studying the safety of HIF-PHIs. By performing a genome-wide association meta-analysis of EPO (n = 6,127), we identified a cis-EPO variant (rs1617640) lying in the EPO promoter region. We validated this variant as most likely causal in controlling EPO levels by using genetic and functional approaches, including single-base gene editing. Using this variant as a partial predictor for therapeutic modulation of EPO and large genome-wide association data in Mendelian randomization tests, we found no evidence (at p < 0.05) that genetically predicted long-term rises in endogenous EPO, equivalent to a 2.2-unit increase, increased risk of coronary artery disease (CAD, OR [95% CI] = 1.01 [0.93, 1.07]), myocardial infarction (MI, OR [95% CI] = 0.99 [0.87, 1.15]), or stroke (OR [95% CI] = 0.97 [0.87, 1.07]). We could exclude increased odds of 1.15 for cardiovascular disease for a 2.2-unit EPO increase. A combination of genetic and functional studies provides a powerful approach to investigate the potential therapeutic profile of EPO-increasing therapies for treating anemia in CKD.

PMID:36055212 | DOI:10.1016/j.ajhg.2022.08.004

Tuberculosis (Edinb). 2022 Aug 25;136:102248. doi: 10.1016/j.tube.2022.102248. Online ahead of print.

ABSTRACT

Rifampicin is one of the most important drugs for the treatment of tuberculosis (TB). Polymorphisms in SLCO1B1 and SLC10A1 genes are associated with impaired transporter function of drug compounds such as rifampicin. The relationship between genetic variation, clinical comorbidities, and rifampicin exposures in TB patients has not been completely elucidated. The aim of this study was to investigate the prevalence of SLCO1A1 and SLCO1B1 polymorphisms in TB and TB-DM patients and to determine their relationship with rifampicin pharmacokinetics on patients from México. Blood samples were collected in two hospitals in Baja California, Mexico from February through December 2017. Sampling included 19 patients with TB, 11 with T2DM and 17 healthy individuals. Polymorphisms genotype rs2306283, rs11045818, rs11045819, rs4149056, rs4149057, rs72559746,rs2291075 and rs4603354 of SLCO1B1 and rs4646285 and rs138880008 of SLC10A1 were analyzed by Sanger's sequencing. None of the SLCO1B1 and SLC10A1 variants were significantly associated with rifampicin Cmax. TB and T2DM patients with suboptimal Cmax rifampicin levels showed wild alleles in rs11045819 and rs2291075 in SLCO1B1 SLC10A1 and SLC10A1. This is the first study to analyze SLC10A1 and SLCO1B1 polymorphisms in TB and TB-T2DM patients and healthy individuals in Mexico. Further research to confirm and extend these findings is necessary.

PMID:36055153 | DOI:10.1016/j.tube.2022.102248

Ther Adv Psychopharmacol. 2022 Aug 23;12:20451253221112587. doi: 10.1177/20451253221112587. eCollection 2022.

ABSTRACT

BACKGROUND: Antipsychotic polypharmacy (APP) prescribing and clozapine underuse are considered inappropriate prescribing in schizophrenia. Psychiatric hospitalisations may be suitable occasions to re-evaluate patient pharmacotherapy and to switch to monotherapy.

OBJECTIVES: To explore the evolution of APP and other psychotropic prescribing patterns during psychiatric hospitalisations, to detect characteristics associated with APP on admission and at discharge, and to examine clozapine prescribing patterns.

DESIGN: We performed a retrospective observational study based on electronic health records.

METHODS: Data on adult inpatients diagnosed with schizophrenia spectrum disorders were collected retrospectively from 6 Belgian hospitals in 2020-2021.

RESULTS: Of the 516 patients included, APP prescribing increased significantly from 47.9% on hospital admission to 59.1% at discharge. On admission and at discharge, APP was associated with prior clozapine use (ORadmission = 2.53, CI = 1.1-5.84, ORdischarge = 11.01, CI = 4.45-27.28), treatment with a first-generation antipsychotic (ORadmission = 26.79, CI = 13.08-54.86, ORdischarge = 25.2, CI = 12.2-52.04), increased antipsychotic exposure (ORadmission = 8.93, CI = 5.13-15.56, ORdischarge = 19.89, CI = 10-39.54), and a greater number of hypno-sedatives (ORadmission = 1.88, CI = 1.23-2.88, ORdischarge = 4.18, CI = 2.53-6.91). APP was negatively associated with involuntary admission (ORadmission = 0.31, CI = 0.14-0.7, ORdischarge = 0.3, CI = 0.13-0.68). When using an alternative definition of monotherapy (i.e. including patients with an add-on low-dose antipsychotic for sleep disorders), alcohol use disorder (ORadmission = 0.26, CI = 0.13-0.54) and higher age (ORdischarge = 0.53, CI = 0.29-0.95) were negatively associated with APP, and living in a residential facility (ORdischarge = 2.39 CI = 1.21-4.71) and a higher daily dosage of benzodiazepines during the stay (ORdischarge = 1.32 CI = 1.03-1.69) increased the odds of being discharged on APP. On admission, 9.3% of patients were being treated with clozapine. Although 28.1% of patients were eligible for clozapine treatment, only 11% of patients were discharged with a clozapine prescription. For 7 of the 10 patients with a new clozapine prescription, it was directly prescribed in combination with another antipsychotic, without a prior trial of clozapine monotherapy.

CONCLUSION: Suboptimal prescriptions of antipsychotics in patients with schizophrenia persist after psychiatric hospitalisations and are associated with identifiable characteristics.

PMID:36051501 | PMC:PMC9425880 | DOI:10.1177/20451253221112587

Sci Rep. 2022 Sep 1;12(1):14858. doi: 10.1038/s41598-022-19318-x.

ABSTRACT

Organic anion transporting polypeptides (OATP), which are encoded by SLCO genes, participate in the hepatic elimination of drugs and xenobiotics. SLCO1B1 is an important pharmacogenomic gene (encoding OATP1B1) associated with response to the uptake of endogenous compounds, such as statin and bilirubin. Ethnicity of the patient modulates the response to these drugs; the frequency and haplotype data for SLCO1B1 genetic variants in the Arab population is lacking. Therefore, we determined the frequencies of two well-characterized SLCO1B1 single nucleotide polymorphisms (SNP) and haplotypes that affect the OATP1B1 drugs transportation activity in Qatari population. Genotyping data for two SLCO1B1 SNPs (c.388A > G, c.521 T > C) were extracted from whole exome data of 1050 Qatari individuals, who were divided into three ancestry groups, namely Bedouins, Persians/South Asians, and Africans. By way of using Fisher's exact and Chi-square tests, we evaluated the differences in minor allele frequency (MAF) of the two functional SNPs and haplotype frequencies (HF) among the three ancestry groups. The OATP1B1 phenotypes were assigned according to their function by following the guidelines from the Clinical Pharmacogenetics Implementation Consortium for SLCO1B1 and Simvastatin-Induced Myopathy.The MAF of SLCO1B1:c.388A > G was higher compared to that of SLCO1B1:c.521 T > C in the study cohort. It was significantly high in the African ancestry group compared with the other two groups, whereas SLCO1B1:c.521 T > C was significantly low in the African ancestry group compared with the other two groups. The SLCO1B1 *15 haplotype had the highest HF, followed by *1b, *1a, and *5. Only the SLCO1B1 *5 haplotype showed no significant difference in frequency across the three ancestry groups. Furthermore, we observed that the OATP1B1 normal function phenotype accounted for 58% of the Qatari individuals, the intermediate function phenotype accounted for 35% with significant differences across the ancestry groups, and the low function phenotype accounted for 6% of the total Qatari individuals with a higher trend observed in the Bedouin group.The results indicate that the phenotype frequencies of the OATP1B1 intermediate and low function in the Qatari population appear at the higher end of the frequency range seen worldwide. Thus, a pharmacogenetic screening program for SLCO1B1 variants may be necessary for the Qatari population.

PMID:36050458 | DOI:10.1038/s41598-022-19318-x

Clin Pharmacol Ther. 2022 Sep 1. doi: 10.1002/cpt.2735. Online ahead of print.

ABSTRACT

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with development of acute hemolytic anemia in the setting of oxidative stress, which can be caused by medication exposure. Regulatory agencies worldwide warn against the use of certain medications in G6PD deficient persons, but in many cases, this information is conflicting, and the clinical evidence is sparse. This guideline provides information on using G6PD genotype as part of the diagnosis of G6PD deficiency and classifies medications that have been previously implicated as unsafe in G6PD deficient individuals by one or more sources. We classify these medications as high, medium, or low-to-no risk based on a systematic review of the published evidence of the gene-drug associations and regulatory warnings. In patients with G6PD deficiency, high risk medications should be avoided, medium risk medications should be used with caution, and low-to-no risk medications can be used with standard precautions, without regard to G6PD phenotype. This new document replaces the prior Clinical Pharmacogenetics Implementation Consortium guideline for rasburicase therapy in the context of G6PD genotype (updates at www.cpicpgx.org).

PMID:36049896 | DOI:10.1002/cpt.2735