CYP2C19 Genotype Prevalence and Association With Recurrent Myocardial Infarction in British–South Asians Treated With Clopidogrel

BACKGROUND: Cytochrome P450 family 2 subfamily C member 19 (CYP2C19) is a hepatic enzyme involved in the metabolism of clopidogrel from a prodrug to its active metabolite. Prior studies of genetic polymorphisms in CYP2C19 and their relationship with clinical efficacy have not included South Asian populations. OBJECTIVES: The objective of this study was to assess prevalence of common CYP2C19 genotype polymorphisms in a British-South Asian population and correlate these with recurrent myocardial infarction risk in participants prescribed clopidogrel. METHODS: The Genes & Health cohort of British Bangladeshi and Pakistani ancestry participants were studied. CYP2C19 diplotypes were assessed using array data. Multivariable logistic regression was used to test for association between genetically inferred CYP2C19 metabolizer status and recurrent myocardial infarction, controlling for known cardiovascular disease risk factors, percutaneous coronary intervention, age, sex, and population stratification. RESULTS: Genes & Health cohort participants (N = 44,396) have a high prevalence (57%) of intermediate or poor CYP2C19 metabolizers, with at least 1 loss-of-function CYP2C19 allele. The prevalence of poor metabolizers carrying 2 CYP2C19 loss-of-function alleles is 13%, which is higher than that in previously studied European (2.4%) and Central/South Asian populations (8.2%). Sixty-nine percent of the cohort who were diagnosed with an acute myocardial infarction were prescribed clopidogrel. Poor metabolizers were significantly more likely to have a recurrent myocardial infarction (OR: 3.1; P = 0.019). CONCLUSIONS: A pharmacogenomic-driven approach to clopidogrel prescribing has the potential to impact significantly on clinical management and outcomes in individuals of Bangladeshi and Pakistani ancestry

British South Asian ancestry participants views of pharmacogenomics clinical implementation and research: a thematic analysis.

BACKGROUND: South Asian ancestry populations are underrepresented in genomic studies and therapeutics trials. British South Asians suffer from multi-morbidity leading to polypharmacy. Our objective was to elucidate British South Asian ancestry community perspectives on pharmacogenomic implementation and sharing pharmacogenomic clinical data for research. METHODS: Four focus groups were conducted (9-12 participants in each). Two groups were mixed gender, while one group was male only and one was female only. Simultaneous interpretation was available to participants in Urdu and Bengali. Focus groups were recorded and abridged transcription and thematic analysis were undertaken. RESULTS: There were 42 participants, 64% female. 26% were born in the UK or Europe. 52% were born in Bangladesh and 17% in Pakistan. 36% reported university level education. Implementation of pharmacogenomics was perceived to be beneficial to individuals but pose a risk of overburdening resource limited systems. Pharmacogenomic research was perceived to be beneficial to the community, with concerns about data privacy and misuse. Data sharing was desirable if the researchers did not have a financial stake, and benefits would be shared. Trust was the key condition for the acceptability of both clinical implementation and research. Trust was linked with medication compliance. Education, outreach, and communication facilitate trust. CONCLUSIONS (SIGNIFICANCE AND IMPACT OF THE STUDY): Pharmacogenomics implementation with appropriate education and communication has the potential to enhance trust and contribute to increased medication compliance. Trust drives data sharing, which would enable enhanced representation in research. Representation in scientific evidence base could cyclically enhance trust and compliance

CYP2C19 Genotype Prevalence and Association With Recurrent Myocardial Infarction in British-South Asians Treated With Clopidogrel.

BACKGROUND: Cytochrome P450 family 2 subfamily C member 19 (CYP2C19) is a hepatic enzyme involved in the metabolism of clopidogrel from a prodrug to its active metabolite. Prior studies of genetic polymorphisms in CYP2C19 and their relationship with clinical efficacy have not included South Asian populations. OBJECTIVES: The objective of this study was to assess prevalence of common CYP2C19 genotype polymorphisms in a British-South Asian population and correlate these with recurrent myocardial infarction risk in participants prescribed clopidogrel. METHODS: The Genes & Health cohort of British Bangladeshi and Pakistani ancestry participants were studied. CYP2C19 diplotypes were assessed using array data. Multivariable logistic regression was used to test for association between genetically inferred CYP2C19 metabolizer status and recurrent myocardial infarction, controlling for known cardiovascular disease risk factors, percutaneous coronary intervention, age, sex, and population stratification. RESULTS: Genes & Health cohort participants (N = 44,396) have a high prevalence (57%) of intermediate or poor CYP2C19 metabolizers, with at least 1 loss-of-function CYP2C19 allele. The prevalence of poor metabolizers carrying 2 CYP2C19 loss-of-function alleles is 13%, which is higher than that in previously studied European (2.4%) and Central/South Asian populations (8.2%). Sixty-nine percent of the cohort who were diagnosed with an acute myocardial infarction were prescribed clopidogrel. Poor metabolizers were significantly more likely to have a recurrent myocardial infarction (OR: 3.1; P = 0.019). CONCLUSIONS: A pharmacogenomic-driven approach to clopidogrel prescribing has the potential to impact significantly on clinical management and outcomes in individuals of Bangladeshi and Pakistani ancestry

Health equality, race and pharmacogenomics

Pharmacogenomics is increasingly moving into mainstream clinical practice. Careful consideration must be paid to inclusion of diverse populations in research, translation and implementation, in the historical and social context of population stratification, to ensure that this leads to improvements in healthcare for all rather than increased health disparities. This review takes a broad and critical approach to the current role of diversity in pharmacogenomics and addresses potential pitfalls in order to raise awareness for prescribers. It also emphasizes evidence gaps and suggests approaches that may minimize negative consequences and promote health equality

Use of Genomics to Develop Novel Therapeutics and Personalize Hypertension Therapy.

Hypertension is a prevalent public health problem, contributing to >10 million deaths annually. Though multiple therapeutics exist, many patients suffer from treatment-resistant hypertension or try several medications before achieving blood pressure control. Genomic advances offer mechanistic understanding of blood pressure variability, therapeutic targets, therapeutic response, and promise a stratified approach to treatment of primary hypertension. Cyclic guanosine monophosphate augmentation, aldosterone synthase inhibitors, and angiotensinogen blockade with silencing RNA and antisense therapies are among the promising novel approaches. Pharmacogenomic studies have also been done to explore the genetic bases underpinning interindividual variability in response to existing therapeutics. A polygenic approach using risk scores is likely to be the next frontier in stratifying responses to existing therapeutics

Prescribing direct-acting oral anticoagulants - Mind the evidence gap.

Direct-acting oral anticoagulants (DOACs) are licensed for the prevention of thromboembolism in non-valvular atrial fibrillation, amongst other indications. Prescribers use information derived from the summary of product characteristics which is based on the key trials supporting the DOAC's market authorisation. However, prescribers may not be aware of the limitations within these trials regarding underrepresentation of patient populations commonly encountered in clinical practice and how this may adversely impact them. This review highlights the gaps in the licensing evidence using four clinical vignettes that explore prescribing challenges in older adults, female patients, patients with obesity and patients from non-Europid ethnic backgrounds

The Interface of Therapeutics and Genomics in Cardiovascular Medicine

Pharmacogenomics has a burgeoning role in cardiovascular medicine, from warfarin dosing to antiplatelet choice, with recent developments in sequencing bringing the promise of personalised medicine ever closer to the bedside. Further scientific evidence, real-world clinical trials, and economic modelling are needed to fully realise this potential. Additionally, tools such as polygenic risk scores, and results from Mendelian randomisation analyses, are only in the early stages of clinical translation and merit further investigation. Genetically targeted rational drug design has a strong evidence base and, due to the nature of genetic data, academia, direct-to-consumer companies, healthcare systems, and industry may meet in an unprecedented manner. Data sharing navigation may prove problematic. The present manuscript addresses these issues and concludes a need for further guidance to be provided to prescribers by professional bodies to aid in the consideration of such complexities and guide translation of scientific knowledge to personalised clinical action, thereby striving to improve patient care. Additionally, technologic infrastructure equipped to handle such large complex data must be adapted to pharmacogenomics and made user friendly for prescribers and patients alike

An Academic Clinician's Road Map to Hypertension Genomics: Recent Advances and Future Directions MMXX.

At the dawn of the new decade, it is judicious to reflect on the boom of knowledge about polygenic risk for essential hypertension supplied by the wealth of genome-wide association studies. Hypertension continues to account for significant cardiovascular morbidity and mortality, with increasing prevalence anticipated. Here, we overview recent advances in the use of big data to understand polygenic hypertension, as well as opportunities for future innovation to translate this windfall of knowledge into clinical benefit

UK Prescribing Safety Assessment (PSA): The development, implementation and outcomes of a national online prescribing assessment.

The United Kingdom (UK) Prescribing Safety Assessment (PSA) is a 2-hour online assessment of prescribing competence. It has been undertaken by students and doctors in UK medical and foundation schools for the past decade. This study describes the academic characteristics and performance of the assessment; longitudinal performance of candidates and schools; stakeholder feedback; and surrogate markers of prescribing safety in UK healthcare practice. It demonstrates the feasibility, high-quality and reliability of an online prescribing assessment, uniquely providing a measure of prescribing competence against a national standard. Most candidates pass the PSA on their first attempt, while a minority are identified for further training and assessment. Most responders to a national survey agreed that the PSA is a useful instrument for assessing prescribing competence, and an independent review has recommended adding the PSA to the Medical Licensing Assessment. Surrogate markers suggest there has been improvement in prescribing safety in practice, temporally associated with the introduction of the PSA but other factors could be influential too. National systems should be developed to identify and report prescribing errors and the harm they cause, enabling the impact of educational interventions to be measured