Journal of Stroke and Cerebrovascular Diseases

2021

DOI: 10.1016/j.jstrokecerebrovasdis.2020.105464

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CYP2C19 Loss-of-Function is Associated with Increased Risk of Ischemic Stroke after Transient Ischemic Attack in Intracranial Atherosclerotic Disease

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Praveen Vimalathas

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et al.

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The Evidence For Cyp2c19 Genotyping After Stroke or Tia2

Discussion1

The Genetic Technology1

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Cited by 15 publications

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“…Moreover, CYP2C19 gene polymorphism is also associated with some other cardiovascular and cerebrovascular diseases. CYP2C19 loss-of-function was associated with increased risk of first-time ischemic stroke for intracranial atherosclerotic disease patients treated with clopidogrel after transient ischemic attack [32]. CYP2C19 PM may be a candidate risk factor for coronary microvascular disorder in the female population [33].…”

Section: Discussionmentioning

confidence: 96%

CYP2C19 loss-of-function is associated with increased risk of hypertension in a Hakka population: a case-control study

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et al. 2023

BMC Cardiovasc Disord

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Background Genetic factors have a certain proportion in the risk factors of hypertension. The purpose was to investigate the relationship of cytochrome P450 2C19 (CYP2C19) polymorphisms with hypertension in Hakka population. Methods The study included 1,872 hypertensive patients and 1,110 controls. The genotypes of CYP2C19 rs4244285 and rs4986893 of all individuals were detected and analyzed. Results The genotype and allele distributions of CYP2C19 rs4244285 were significantly different between hypertension group and control group. The CYP2C19 *1/*1 genotype was the most predominant among the subjects (40.8%), followed by the CYP2C19 *1/*2 genotype (40.5%). The percentage of CYP2C19*1, *2, and *3 allele was 64.2%, 30.8%, and 5.0%, respectively. The proportion of intermediate metabolizers (IM) (49.3% vs. 42.9%), poor metabolizers (PM) (14.3% vs. 8.9%) (P < 0.001), and CYP2C19*2 allele (33.8% vs. 25.7%, P < 0.001) in hypertension group was significantly higher than that in control group. Multivariate logistic regression (adjusted for gender, age, smoking, and drinking) indicated that CYP2C19 *1/*2, *1/*3, and *2/*2 genotypes may increase susceptibility to hypertension. And the CYP2C19 IM genotype (IM vs. EM: OR 1.514, 95% CI: 1.291–1.775, P < 0.001), PM genotype (PM vs. EM: OR 2.120, 95% CI: 1.638–2.743, P < 0.001), IM + PM genotypes (IM + PM vs. EM: OR 1.617, 95% CI: 1.390–1.882, P < 0.001) may increase risk of hypertension. Conclusions CYP2C19 loss-of-function (IM, PM genotypes) is independent risk factor for hypertension susceptibility. Specifically, the risk genotypes include CYP2C19 *1/*2, *1/*3, and *2/*2.

“…Moreover, CYP2C19 gene polymorphism is also associated with some other cardiovascular and cerebrovascular diseases. CYP2C19 loss-of-function was associated with increased risk of first-time ischemic stroke for intracranial atherosclerotic disease patients treated with clopidogrel after transient ischemic attack [32]. CYP2C19 PM may be a candidate risk factor for coronary microvascular disorder in the female population [33].…”

Section: Discussionmentioning

confidence: 96%

CYP2C19 loss-of-function is associated with increased risk of hypertension in a Hakka population: a case-control study

¹

,

²

,

³

et al. 2023

BMC Cardiovasc Disord

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Background Genetic factors have a certain proportion in the risk factors of hypertension. The purpose was to investigate the relationship of cytochrome P450 2C19 (CYP2C19) polymorphisms with hypertension in Hakka population. Methods The study included 1,872 hypertensive patients and 1,110 controls. The genotypes of CYP2C19 rs4244285 and rs4986893 of all individuals were detected and analyzed. Results The genotype and allele distributions of CYP2C19 rs4244285 were significantly different between hypertension group and control group. The CYP2C19 *1/*1 genotype was the most predominant among the subjects (40.8%), followed by the CYP2C19 *1/*2 genotype (40.5%). The percentage of CYP2C19*1, *2, and *3 allele was 64.2%, 30.8%, and 5.0%, respectively. The proportion of intermediate metabolizers (IM) (49.3% vs. 42.9%), poor metabolizers (PM) (14.3% vs. 8.9%) (P < 0.001), and CYP2C19*2 allele (33.8% vs. 25.7%, P < 0.001) in hypertension group was significantly higher than that in control group. Multivariate logistic regression (adjusted for gender, age, smoking, and drinking) indicated that CYP2C19 *1/*2, *1/*3, and *2/*2 genotypes may increase susceptibility to hypertension. And the CYP2C19 IM genotype (IM vs. EM: OR 1.514, 95% CI: 1.291–1.775, P < 0.001), PM genotype (PM vs. EM: OR 2.120, 95% CI: 1.638–2.743, P < 0.001), IM + PM genotypes (IM + PM vs. EM: OR 1.617, 95% CI: 1.390–1.882, P < 0.001) may increase risk of hypertension. Conclusions CYP2C19 loss-of-function (IM, PM genotypes) is independent risk factor for hypertension susceptibility. Specifically, the risk genotypes include CYP2C19 *1/*2, *1/*3, and *2/*2.

“…There were differences between programs both in relation to the genes and variants tested (hereafter "targets"), and also with regard to the genetic technology used (Supplementary Table 2). However, the majority of programs adopted array-based platforms (26,36,(41)(42)(43)(44)(45)(46). These ranged from extremely broad systems, with the capacity to flexibly test for many thousands of variants across hundreds of genes, to more targeted gene panels (35).…”

Section: The Genetic Technologymentioning

confidence: 99%

Characterizing pharmacogenetic programs using the consolidated framework for implementation research: A structured scoping review

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et al. 2022

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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.

“…Risk of primary event lower in Ticagrelor arm. Patel et al (2021) [ 77 ] Cohort USA ICAD Clopidogrel + Clopidogrel DAPT 337 IS N/A Yes. [HR 3.4; 95% CI 1.40–8.20] Patel et al (2022) [ 54 ] Cohort USA CAS Clopidogrel and Aspirin 1110 First Time IS Intracranial Hemorrhage Yes.…”

Section: The Evidence For Cyp2c19 Genotyping After Stroke or Tiamentioning

confidence: 99%

“…Using a Cox regression model, they found that carriers of the CYP2C19 *2 allele had an increased risk of further IS compared with non-carriers (HR 2.23, 95% CI 1.17–4.24). A subsequent cohort study, using a similar methodological approach, identified patients who had ICAD, but had not been diagnosed with an IS, meaning they had either had a TIA or were asymptomatic [ 77 ]. Univariate Cox regression revealed that CYP2C19 LoFA carriers had an increased risk of first-time ischemic stroke (HR 2.1, 95% CI 1.1–4.1) if they had previously had a TIA, but not if they were asymptomatic.…”

Section: The Evidence For Cyp2c19 Genotyping After Stroke or Tiamentioning

confidence: 99%

The role of CYP2C19 genotyping to guide antiplatelet therapy following ischemic stroke or transient ischemic attack

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et al. 2022

Expert Review of Clinical Pharmacology

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Introduction Clopidogrel is an antiplatelet agent recommended for secondary prevention of ischemic stroke (IS) and transient ischemic attack (TIA). Conversion of clopidogrel to its active metabolite by hepatic cytochrome P450-2C19 (CYP2C19) is essential for the inhibition of the P2Y12 receptor and subsequent platelet aggregation to prevent thrombotic events. CYP2C19 is highly polymorphic, with over 30 loss of function (LoF) alleles. This review considers whether there is sufficient data to support genotype guided antiplatelet therapy after stroke. Areas covered A systematic literature review retrieved articles, which describe the interaction between CYP2C19 genotype and clinical outcomes following IS or TIA when treated with clopidogrel. The review documents efforts to identify optimal antiplatelet regimens and explores the value genotype guided antiplatelet therapy. The work outlines the contemporary understanding of clopidogrel metabolism and appraises evidence linking CYP2C19 LoF variants with attenuated platelet inhibition and poorer outcomes. Expert opinion There is good evidence that CYP2C19 LoF allele carriers of Han-Chinese ancestry have increased risk for further vascular events following TIA or IS when treated with clopidogrel. The evidence base is less certain in other populations. The expansion of pharmacogenetics into routine clinical practice will facilitate further research and help tailor other aspects of secondary prevention.

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