Pharmacogenetics and genomics最新文献

{"title":"Genome-wide DNA methylation profile of peripheral blood lymphocytes from subjects with nonsteroidal anti-inflammatory drug-induced respiratory diseases.","authors":"Jong-Uk Lee,&nbsp;Hun Soo Chang,&nbsp;Min Kyung Kim,&nbsp;Seung-Lee Park,&nbsp;Jung Hyun Kim,&nbsp;Jong-Sook Park,&nbsp;Choon-Sik Park","doi":"10.1097/FPC.0000000000000475","DOIUrl":"https://doi.org/10.1097/FPC.0000000000000475","url":null,"abstract":"<p><strong>Background: </strong>Significant changes in CpG methylation have been identified in nasal polyps, which are the main targets of nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (NERD); however, these polyps are composed of various cellular components. In the present study, whole-genome CpG methylation in peripheral blood lymphocytes (PBLs) was analyzed to define the epigenetic changes in lymphocytes, which are the primary immune cells involved in NERD.</p><p><strong>Materials and methods: </strong>Genomic DNA from peripheral blood mononuclear cells from 27 NERD and 24 aspirin-tolerant asthma (ATA) was subjected to bisulfate conversion and a methylation array. Quantitative CpG methylation, the β-values as a quantitative measure of DNA methylation, in lymphocytes were calculated after adjustments for cellular composition.</p><p><strong>Results: </strong>Fifty-six hypermethylated and three hypomethylated differentially methylated CpGs (DMCs) in PBLs in the NERD compared with ATA. The top 10 CpG loci predicted the methylation risk score, with a positive predictive value of 91.3%, a negative predictive value of 81.5% and an accuracy of 84.3%. As demonstrated in the nasal polyps, 30 DMCs were predicted to bind to the following 10 transcription factors, ranked in descending order: AP-2alphaA, TFII-1, STAT4, FOXP3, GR, c-Est-1, E2F-1, XBP1, ENKTF-1 and NF-1. Gene ontology analysis identified 13 categories such as regulation of T-helper 17 cell differentiation, including SMAD7 and NFKBIZ. PBLs in NERD contained no DMCs in genes associated with the prostaglandin and leukotriene pathways, which were found in ATA.</p><p><strong>Conclusion: </strong>PBLs in NERD form a unique pattern of DNA CpG methylation, and the combined analysis may provide predictive values for NERD.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":"32 6","pages":"226-234"},"PeriodicalIF":2.6,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10543653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proposals for a standardized procedure of validation of DNA extraction and allelic discrimination assays in pharmacogenomics according to ISO15189 requirements.","authors":"Laurent Imbert,&nbsp;Jennifer Lagoutte-Renosi,&nbsp;Julien Wils,&nbsp;Fabien Lamoureux","doi":"10.1097/FPC.0000000000000473","DOIUrl":"https://doi.org/10.1097/FPC.0000000000000473","url":null,"abstract":"<p><strong>Objectives: </strong>In the era of quality management in clinical laboratories, method validation can be a challenge without appropriate guidelines, such as in the field of pharmacogenetics. The present work describes a method validation for DNA extraction and CYP3A5*3 genotyping, which would meet ISO15189:2012 requirements.</p><p><strong>Methods: </strong>DNA extraction was performed using a QIAamp DSP DNA Blood kit, DNA purity and concentration were determined using a Nanodrop, and the genotyping assay was a real-rime PCR using TaqMan reagents. Validation criteria were similar to those usually verified when validating methods in the analytical field: specificity, sensitivity, cross-over contamination, stability of reagents, robustness, lower and upper limits of detection, and between-run and within-run precisions. A comparison to alternate or reference methods was also performed (i.e. QiAamp kit versus DNA extractor and TaqMan genotyping versus Sanger sequencing). Each validation step is described from the pharmacogenetic point of view, as well as acceptance criteria for both DNA extraction [i.e. concentration relative SD (RSD) below 25%, verified purity, and no DNA in blank samples] and genotyping assay (i.e. specificity and diagnostic sensitivity, RSD of mean threshold cycle below 15%, no amplification in blank samples).</p><p><strong>Results: </strong>Concerning CYP3A5 genotyping following a DNA extraction described as an example, validation criteria were met, allowing routine use of this analytical process. Cost estimation of the overall validation procedure was approximately 290 euros, concerning reagents and consumables.</p><p><strong>Conclusion: </strong>This work aims to provide a reference for method validation for pharmacogenetic analysis using real-time PCR to detect single nucleotide polymorphisms, in accordance with ISO15189:2012.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":"32 5","pages":"192-200"},"PeriodicalIF":2.6,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10247759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Composite CYP3A phenotypes influence tacrolimus dose-adjusted concentration in lung transplant recipients.","authors":"Michelle Liu,&nbsp;Ciara M Shaver,&nbsp;Kelly A Birdwell,&nbsp;Stephanie A Heeney,&nbsp;Christian M Shaffer,&nbsp;Sara L Van Driest","doi":"10.1097/FPC.0000000000000472","DOIUrl":"https://doi.org/10.1097/FPC.0000000000000472","url":null,"abstract":"<p><strong>Objectives: </strong>Interpatient variability in tacrolimus pharmacokinetics is attributed to metabolism by cytochrome P-450 3A4/5 isoenzymes (encoded by CYP3A4 and CYP3A5). Guidelines for adjusting tacrolimus based on CYP3A5 test results are published; however, CYP3A4 variants also contribute to the variability in tacrolimus pharmacokinetics. The effects of composite phenotypes incorporating CYP3A5 and CYP3A4 increased (*1G, *1B) and decreased (*22) function variants have not been evaluated. The objective of this study is to investigate the impact of both increased and decreased function CYP3A variants on weight and dose-adjusted tacrolimus concentration (C0/D).</p><p><strong>Methods: </strong>We performed a single-center retrospective cohort study of lung transplant recipients to evaluate the median tacrolimus C0/D by composite CYP3A phenotype groups during the index transplant hospitalization. CYP3A4 and CYP3A5 alleles were used to classify patients into four CYP3A groups from least to most CYP3A activity. Exploratory analyses of ABCB1 and additional candidate genes were also assessed.</p><p><strong>Results: </strong>Of the 92 included individuals, most (58) were CYP3A Group 2. The median tacrolimus C0/D differed significantly between CYP3A groups (P = 0.0001). CYP3A Group 2 median tacrolimus C0/D was 190.5 (interquartile range: 147.6-267.5) (ng/ml)/(mg/kg/d) and significantly higher than Group 4 [107.9 (90.4-116.1), P = 0.0001)]. Group 2 median tacrolimus C0/D did not significantly differ from Group 1 and Group 3 [373.5 (149.2-490.3) and 81.4 (62.6-184.1), respectively]. No significant differences in tacrolimus C0/D were found for the ABCB1 diplotypes.</p><p><strong>Conclusion: </strong>These data indicate that a composite CYP3A phenotype incorporating both increase and decrease variant information from CYP3A4 in addition to CYP3A5 may significantly influence tacrolimus C0/D during the early postoperative period.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":"32 5","pages":"209-217"},"PeriodicalIF":2.6,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9177686/pdf/nihms-1788678.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10191316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population genetic polymorphisms of pharmacogenes in Zimbabwe, a potential guide for the safe and efficacious use of medicines in people of African ancestry.","authors":"Bianza T Mbavha,&nbsp;Comfort R Kanji,&nbsp;Nadina Stadler,&nbsp;Julia Stingl,&nbsp;Andrea Stanglmair,&nbsp;Catharina Scholl,&nbsp;William Wekwete,&nbsp;Collen Masimirembwa","doi":"10.1097/FPC.0000000000000467","DOIUrl":"https://doi.org/10.1097/FPC.0000000000000467","url":null,"abstract":"<p><strong>Objective: </strong>Pharmacogenomics (PGx) is a clinically significant factor in the safe and efficacious use of medicines. While PGx knowledge is abundant for other populations, there are scarce PGx data on African populations and is little knowledge on drug-gene interactions for medicines used to treat diseases common in Africa. The aim of this study was to use a custom-designed open array to genotype clinically actionable variants in a Zimbabwean population. This study also identified some of the commonly used drugs in Zimbabwe and the associated genes involved in their metabolism.</p><p><strong>Methods: </strong>A custom-designed open array that covers 120 genetic variants was used to genotype 522 black Zimbabwean healthy volunteers using TaqMan-based single nucleotide polymorphism genotyping. Data were also accessed from Essential Drugs' List in Zimbabwe (EDLIZ), and the medicines were grouped into the associated biomarker groups based on their metabolism. We also estimated the national drug procurement levels for medicines that could benefit from PGx-guided use based on the data obtained from the national authorities in Zimbabwe.</p><p><strong>Results: </strong>The results demonstrate the applicability of an open-array chip in simultaneously determining multiple genetic variants in an individual, thus significantly reducing cost and time to generate PGx data. There were significantly high frequencies of African-specific variants, such as the CYP2D6*17 and *29 variants and the CYP2B6*18 variant. The data obtained showed that the Zimbabwean population exhibits PGx variations in genes important for the safe and efficacious use of drugs approved by the EDLIZ and are procured at significantly large amounts annually. The study has established a cohort of genotyped healthy volunteers that can be accessed and used in the conduct of clinical pharmacogenetic studies for drugs entering a market of people of predominantly African ancestry.</p><p><strong>Conclusion: </strong>Our study demonstrated the potential benefit of integrating PGx in Zimbabwe for the safe and efficacious use of drugs that are commonly used.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":"32 5","pages":"173-182"},"PeriodicalIF":2.6,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10194579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PharmGKB summary: acyclovir/ganciclovir pathway.","authors":"Maud Maillard,&nbsp;Li Gong,&nbsp;Rina Nishii,&nbsp;Jun J Yang,&nbsp;Michelle Whirl-Carrillo,&nbsp;Teri E Klein","doi":"10.1097/FPC.0000000000000474","DOIUrl":"https://doi.org/10.1097/FPC.0000000000000474","url":null,"abstract":"Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee and Departments of Biomedical Data Science and Medicine (BMIR), Stanford University, Stanford, California, USA Correspondence to Teri E. Klein, PhD, Department of Biomedical Data Science, Stanford University, 443 Via Ortega, Room 213, Stanford, CA 94305, USA Tel: +1 650 725 0659; e-mail: feedback@pharmgkb.org","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":"32 5","pages":"201-208"},"PeriodicalIF":2.6,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9179945/pdf/nihms-1799124.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10183158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of CYP2C19 genetic variants on bleeding and major adverse cardiovascular events in a cohort of Arab patients undergoing percutaneous coronary intervention and stent implantation.","authors":"Zainab Omer Ali,&nbsp;Loulia Bader,&nbsp;Shaaban Mohammed,&nbsp;Salaheddin Arafa,&nbsp;Abdulrahman Arabi,&nbsp;Larisa Cavallari,&nbsp;Taimour Langaee,&nbsp;Fatima Mraiche,&nbsp;Nasser Rizk,&nbsp;Ahmed Awaisu,&nbsp;Mohamed H Shahin,&nbsp;Hazem Elewa","doi":"10.1097/FPC.0000000000000469","DOIUrl":"https://doi.org/10.1097/FPC.0000000000000469","url":null,"abstract":"<p><strong>Introduction: </strong>One-third of patients have clopidogrel resistance that may lead to major adverse cardiac events (MACEs). By contrast, it was found that some clopidogrel-treated patients have hyperresponsive platelets that are associated with higher bleeding risk. Several studies have shown that polymorphisms in the gene encoding the CYP2C19 contribute to the variability in response to clopidogrel. Data on genetic and nongenetic factors affecting clopidogrel response in the Arab population are scarce. In this prospective cohort study, we sought to assess the association between the increased function allele (CYP2C19*17) and bleeding events, and validate the effect of the CYP2C19 genetic variants and nongenetic factors on the incidence of MACEs.</p><p><strong>Methods: </strong>Blood samples were collected from patients that were undergoing percutaneous coronary intervention and receiving clopidogrel at the Heart Hospital, a specialist tertiary hospital in Doha, Qatar. Patients were followed for 12 months. Genotyping was performed for CYP2C19*2, *3, and *17 using TaqMan assays.</p><p><strong>Results: </strong>In 254 patients, the minor allele frequencies were 0.13, 0.004, and 0.21 for *2, *3, and *17, respectively. Over a 12-month follow-up period, there were 21 bleeding events (8.5 events/100 patient-year). CYP2C19*17 carriers were found to be associated with increased risk of bleeding (OR, 21.6; 95% CI, 4.8-96.8; P < 0.0001). CYP2C19*2 or *3 carriers were found to be associated with increased risk of baseline and incident MACE combined (OR, 8.4; 95% CI, 3.2-23.9; P < 0.0001).</p><p><strong>Conclusion: </strong>This study showed a significant association between CYP2C19*17 allele and the increased risk of bleeding, and CYP2C19*2 or *3 with MACE outcomes.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":"32 5","pages":"183-191"},"PeriodicalIF":2.6,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10191322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of potential druggable targets of cell cycle with small-molecule inhibitors in oral squamous cell carcinoma.","authors":"Xiaoyi Zhou,&nbsp;Wenke Jin,&nbsp;Yanmei Chen,&nbsp;Lingjuan Zhu,&nbsp;Anchun Mo,&nbsp;Qiang Xie","doi":"10.1097/FPC.0000000000000461","DOIUrl":"https://doi.org/10.1097/FPC.0000000000000461","url":null,"abstract":"<p><p>Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors worldwide and there are few crucial regulators and druggable targets for early diagnosis. Therefore, the identification of biomarkers for the early diagnosis and druggable targets of OSCC is imminent. In this study, we integrated gene set enrichment analysis, differential gene expression analysis based on the negative binomial distribution, weighted correlation network analysis, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes into analyzing the OSCC cohort downloaded from The Cancer Genome Atlas, and found that cell cycle and related biologic processes are significantly enriched. Then, we constructed the core gene network of OSCC, which showed the connection of encode human Cyclin-A2 protein, encode RAD51-associated protein 1, encode human centromere-associated protein E (CENPE), encode humans centromere protein I (CENPI) and encode polo-like kinase 1 (PLK1) to several cell cycle-related genes. Survival analysis further showed that low expression of these genes was associated with a better prognosis. Furthermore, we utilized a high-throughput virtual screening to find new CENPE and PLK1 inhibitors, and one of the CENPE inhibitor DB04517 suppressed the proliferation of OSCC cells by cell cycle arrest of cell cycle. Taken together, these candidate regulators could serve as the candidate diagnostic and prognostic biomarkers for OSCC, and specific suppression of these genes may be a potential approach to prevent and treat OSCC with the candidate inhibitors.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":"32 4","pages":"125-137"},"PeriodicalIF":2.6,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10191302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of CYP2C19, CYP2C9 and CYP3A4 gene polymorphisms on plasma voriconazole levels in Chinese pediatric patients.","authors":"Xinghua Fan,&nbsp;Hong Zhang,&nbsp;Zhipeng Wen,&nbsp;Xiaoli Zheng,&nbsp;Yi Yang,&nbsp;Jihong Yang","doi":"10.1097/FPC.0000000000000464","DOIUrl":"https://doi.org/10.1097/FPC.0000000000000464","url":null,"abstract":"<p><strong>Objectives: </strong>Voriconazole is the most commonly used antifungal agent in clinical application. Previous studies suggested that voriconazole was extensively metabolized by CYP450 enzyme system, including CYP2C19, CYP2C9 and CYP3A4, which contributed to the individual variability of the pharmacokinetic process of voriconazole. This study aimed to investigate the effects of CYP2C19, CYP2C9 and CYP3A4 gene polymorphisms on plasma voriconazole concentrations in Chinese pediatric patients.</p><p><strong>Methods: </strong>This study prospectively evaluated pediatric patients administrating voriconazole for the treatment or prophylaxis of invasive fungal infections from October 2018 to July 2020. Seven single-nucleotide polymorphisms in CYP2C19 (CYP2C19*2, CYP2C19*3, and CYP2C19*17), CYP2C9 (CYP2C9*3, CYP2C9*13) and CYP3A4 (CYP3A4*22, rs4646437) were detected by real-time fluorescent PCR with TaqMan probes. The voriconazole trough plasma concentration was determined by UPLC-MS/MS.</p><p><strong>Results: </strong>A total of 68 pediatric patients were enrolled in this study. Our results showed that voriconazole plasma concentrations of patients with CYP2C19*2 or CYP2C19*3 allele were significantly higher than that with wild-type carriers (P < 0.0001, P = 0.004, respectively). However, CYP2C9*3 and CYP3A4 rs4646437 were not significantly associated with voriconazole plasma levels. The CYP2C19*17, CYP2C9*13 and CYP3A4*22 alleles were not observed in our study. Additionally, multiple linear regression analysis indicated that CYP2C19*2 and CYP2C19*3 alleles remained predictors of voriconazole plasma concentration (r2 = 0.428; P < 0.0001). For CYP2C19 metabolizer phenotype, trough concentration of voriconazole was significantly lower in NM group compared with IM (P < 0.0001) and PM (P = 0.004) groups.</p><p><strong>Conclusion: </strong>Voriconazole plasma levels in pediatric patients are mainly affected by CYP2C19 gene polymorphisms.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":"32 4","pages":"152-158"},"PeriodicalIF":2.6,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10189802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two polymorphic gene loci associated with treprostinil dose in pulmonary arterial hypertension.","authors":"Vasiliki Thomeas-McEwing,&nbsp;Mitchell A Psotka,&nbsp;Eric R Gamazon,&nbsp;Paula Friedman,&nbsp;Anuar Konkashbaev,&nbsp;Michiaki Kubo,&nbsp;Yusuke Nakamura,&nbsp;Mark J Ratain,&nbsp;Raymond L Benza,&nbsp;Nancy J Cox,&nbsp;Mardi I Gomberg-Maitland,&nbsp;Michael L Maitland","doi":"10.1097/FPC.0000000000000463","DOIUrl":"https://doi.org/10.1097/FPC.0000000000000463","url":null,"abstract":"<p><strong>Objective: </strong>Prostacyclin infusion for pulmonary arterial hypertension (PAH) is an effective therapy with varied dosing requirements and clinical response. The major aim of this study was to determine new biologically-based predictors of prostacyclin treatment response heterogeneity.</p><p><strong>Methods: </strong>Ninety-eight patients with hemodynamically defined PAH at two academic medical centers volunteered for registry studies. A stable dose of treprostinil was the quantitative phenotype for the genome-wide association study (GWAS). Candidate genes with the largest effect sizes and strongest statistical associations were further characterized with in silico and in-vitro assays to confirm mechanistic hypotheses. The clinical significance of these candidate predictors was assessed for mechanistically consistent physiologic effects in an independent cohort of patients.</p><p><strong>Results: </strong>GWAS identified three loci for association with P < 10-6. All three loci had clinically significant effect sizes. Specific single-nucleotide polymorphisms (SNPs) at two of the loci: rs11078738 in phosphoribosylformylglycinamidine synthase and rs10023113 in CAMK2D encoded sequence changes with clear predicted consequences. Production of the primary mediator of prostacyclin-induced vasodilation, cyclic AMP, was reduced in human cell lines by the missense variant rs11078738 (p.L621P). Located in the promoter of CAMK2D, the allele of rs10023113 associated with a higher treprostinil dose has higher ventricular transcription of CAMK2δ. At initial diagnostic catheterization in a separate cohort of patients, the same allele of rs10023113 was associated with elevated right mean atrial and ventricular diastolic pressures.</p><p><strong>Conclusions: </strong>The quantitative phenotype of stable treprostinil dose identified two gene loci associated with pharmacodynamic response and right ventricular function in PAH worth further investigation.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":"32 4","pages":"144-151"},"PeriodicalIF":2.6,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10183151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accuracy and applications of sequencing and genotyping approaches for CYP2A6 and homologous genes.","authors":"Alec W R Langlois,&nbsp;Ahmed El-Boraie,&nbsp;Koya Fukunaga,&nbsp;Taisei Mushiroda,&nbsp;Michiaki Kubo,&nbsp;Caryn Lerman,&nbsp;Jo Knight,&nbsp;Steven E Scherer,&nbsp;Meghan J Chenoweth,&nbsp;Rachel F Tyndale","doi":"10.1097/FPC.0000000000000466","DOIUrl":"https://doi.org/10.1097/FPC.0000000000000466","url":null,"abstract":"<p><strong>Objectives: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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).</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":19763,"journal":{"name":"Pharmacogenetics and genomics","volume":"32 4","pages":"159-172"},"PeriodicalIF":2.6,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9081136/pdf/nihms-1772760.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10193067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}