Genome-wide analysis of clopidogrel active metabolite levels identifies novel variants that influence antiplatelet response

Backman, Joshua; O’Connell, Jeffrey R.; Tanner, Kandice; Peer, Cody J.; Figg, William D.; Spencer, Shawn D.; Mitchell, Braxton D.; Shuldiner, Alan R.; Yerges‐Armstrong, Laura M.; Horenstein, Richard B.; Lewis, Joshua P.

doi:10.1097/fpc.0000000000000272

Cited by 25 publications

(30 citation statements)

References 22 publications

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“…Confirming the results of two previous studies [3,4], the CES1 c.428G>A SNV significantly impaired the hydrolysis of clopidogrel, increasing the exposure to the active metabolite and enhancing its antiplatelet effects. In addition to the CES1 c.428G>A SNV, CYP2C19 variants have a recognized effect on clopidogrel pharmacokinetics and pharmacodynamics [19,20]. In the present study, the CYP2C19 c.681G>A loss-offunction allele was associated with reduced antiplatelet effects, but only a non-significant trend existed towards reduced exposure to the active metabolite.…”

Section: Discussioncontrasting

confidence: 45%

Effects of Genetic Variants on Carboxylesterase 1 Gene Expression, and Clopidogrel Pharmacokinetics and Antiplatelet Effects

Neuvonen

Tarkiainen

Tornio

et al. 2017

Basic Clin Pharma Tox

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Several single nucleotide variations (SNVs) affect carboxylesterase 1 (CES1) activity, but the effects of genetic variants on CES1 gene expression have not been systematically investigated. Therefore, our aim was to investigate effects of genetic variants on CES1 gene expression in two independent whole blood sample cohorts of 192 (discovery) and 88 (replication) healthy volunteers and in a liver sample cohort of 177 patients. Furthermore, we investigated possible effects of the found variants on clopidogrel pharmacokinetics (n = 106) and pharmacodynamics (n = 46) in healthy volunteers, who had ingested a single 300 mg or 600 mg dose of clopidogrel. Using massively parallel sequencing, we discovered two CES1 SNVs, rs12443580 and rs8192935, to be strongly and independently associated with a 39% (p = 4.0 × 10 ) and 31% (p = 2.5 × 10 ) reduction in CES1 whole blood expression per copy of the minor allele. These findings were replicated in the replication cohort. However, these SNVs did not affect CES1 liver expression, or clopidogrel pharmacokinetics or pharmacodynamics. Conversely, the CES1 c.428G>A missense SNV (rs71647871) impaired the hydrolysis of clopidogrel, increased exposure to clopidogrel active metabolite and enhanced its antiplatelet effects. In conclusion, the rs12443580 and rs8192935 variants reduce CES1 expression in whole blood but not in the liver. These tissue-specific effects may result in substrate-dependent effects of the two SNVs on CES1-mediated drug metabolism.

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Section: Discussioncontrasting

confidence: 45%

Effects of Genetic Variants on Carboxylesterase 1 Gene Expression, and Clopidogrel Pharmacokinetics and Antiplatelet Effects

Neuvonen

Tarkiainen

Tornio

et al. 2017

Basic Clin Pharma Tox

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“…The variance components for the polygenic effect and random residuals were estimated using the restricted maximum likelihood (REML) approach. MMAP has been widely used in human and cattle GWAS studies [45][46][47]. The model can be generally presented as:…”

Section: Genome-wide Association Study (Gwas)mentioning

confidence: 99%

GWAS and fine-mapping of livability and six disease traits in Holstein cattle

et al. 2020

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Background: Health traits are of significant economic importance to the dairy industry due to their effects on milk production and associated treatment costs. Genome-wide association studies (GWAS) provide a means to identify associated genomic variants and thus reveal insights into the genetic architecture of complex traits and diseases. The objective of this study is to investigate the genetic basis of seven health traits in dairy cattle and to identify potential candidate genes associated with cattle health using GWAS, fine mapping, and analyses of multi-tissue transcriptome data. Results: We studied cow livability and six direct disease traits, mastitis, ketosis, hypocalcemia, displaced abomasum, metritis, and retained placenta, using de-regressed breeding values and more than three million imputed DNA sequence variants. After data edits and filtering on reliability, the number of bulls included in the analyses ranged from 11,880 (hypocalcemia) to 24,699 (livability). GWAS was performed using a mixed-model association test, and a Bayesian fine-mapping procedure was conducted to calculate a posterior probability of causality to each variant and gene in the candidate regions. The GWAS detected a total of eight genome-wide significant associations for three traits, cow livability, ketosis, and hypocalcemia, including the bovine Major Histocompatibility Complex (MHC) region associated with livability. Our fine-mapping of associated regions reported 20 candidate genes with the highest posterior probabilities of causality for cattle health. Combined with transcriptome data across multiple tissues in cattle, we further exploited these candidate genes to identify specific expression patterns in diseaserelated tissues and relevant biological explanations such as the expression of Group-specific Component (GC) in the liver and association with mastitis as well as the Coiled-Coil Domain Containing 88C (CCDC88C) expression in CD8 cells and association with cow livability. Conclusions: Collectively, our analyses report six significant associations and 20 candidate genes of cattle health. With the integration of multi-tissue transcriptome data, our results provide useful information for future functional studies and better understanding of the biological relationship between genetics and disease susceptibility in cattle.

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“…In humans, evidence suggests that variable CAM generation is the primary explanation for clopidogrel response variability. Many mechanisms are thought to cause clopidogrel response variability in people including body weight, sex, and variable metabolism of clopidogrel primarily due to gene polymorphisms affecting the CYP2C subfamily of CYP450 (Backman et al., ; Li et al., ; Shuldiner et al., ; Simon et al., ). Clopidogrel response variability also exists in cats (Hogan et al., ; Li, Stern, Ho, Tablin, & Harris, ; Teuber & Mischke, ).…”

Section: Introductionmentioning

confidence: 99%

High interindividual variability in plasma clopidogrel active metabolite concentrations in healthy cats is associated with sex and cytochrome P450 2C genetic polymorphism

Lee

Faus

Court

2018

Vet Pharm & Therapeutics

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Clopidogrel response variability has been identified in cats. In humans, evidence suggests that variable clopidogrel active metabolite (CAM) generation is the primary explanation for clopidogrel response variability with differences in body weight, sex, and variable metabolism of clopidogrel primarily due to polymorphisms of the gene encoding cytochrome P450 (CYP) 2C19 as some proposed mechanisms. The aim of this study was to evaluate whether variation in CAM concentrations exists in healthy cats and what the cause of such variation might be. Nineteen healthy cats were given 18.75 mg clopidogrel by mouth. Blood was collected 2 hr later. Plasma CAM concentrations were measured using high performance liquid chromatography and tandem mass spectrometry. Clopidogrel metabolism was estimated by calculating CAM metabolic ratio. DNA was collected, and feline CYP2C genotyping was performed. The cats demonstrated high interindividual variation of plasma CAM concentrations.Approximately 69% of this interindividual variation was primarily explained by differences in clopidogrel metabolism as measured by CAM metabolic ratio with some influence by sex but not by weight. A single nucleotide polymorphism was identified in the feline CYP2C gene that explained in part individual differences in CAM metabolic ratio and CAM plasma concentrations. K E Y W O R D S antiplatelet, antithrombotic, Plavix, thienopyridine, thromboprophylaxis | 17 LEE Et aL. response in cats is currently unknown. The aim of this study was to evaluate whether variations in CAM concentrations exist in healthy cats given the clinically used dose of 18.75 mg clopidogrel per os andwhat the cause of such variation might be. We hypothesized that interindividual variability in CAM plasma concentrations would be present and that this variability would be influenced by variability in cat weight, sex, metabolism, and/or CYP2C genetic polymorphisms. | MATERIAL S AND ME THODS | Animal inclusion criteriaEligible client-owned cats were required to be apparently healthy, between 2 and 8 years of age, and >3.4 kg in weight. Written informed owner consent was obtained prior to participation in the study. Apparent health was determined based on history, a normal physical examination, and normal laboratory values including complete blood count, serum biochemistry panel, urinalysis, negative feline leukemia virus and feline immunodeficiency virus testing, and a normal echocardiogram. All blood work and urinalyses were performed by the Washington State University Clinical Pathology Laboratory.All echocardiograms were performed by a single investigator (PML).Conventional 2D, M-mode, and Doppler examinations were performed using an echocardiographic system and transducers ranging from 4 to 10 MHz. This study was approved by the Washington State University Institutional Animal Care and Use Committee.

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Genome-wide analysis of clopidogrel active metabolite levels identifies novel variants that influence antiplatelet response

Cited by 25 publications

References 22 publications

Effects of Genetic Variants on Carboxylesterase 1 Gene Expression, and Clopidogrel Pharmacokinetics and Antiplatelet Effects

Effects of Genetic Variants on Carboxylesterase 1 Gene Expression, and Clopidogrel Pharmacokinetics and Antiplatelet Effects

GWAS and fine-mapping of livability and six disease traits in Holstein cattle

High interindividual variability in plasma clopidogrel active metabolite concentrations in healthy cats is associated with sex and cytochrome P450 2C genetic polymorphism

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