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1. Pharmacogenomic polygenic response score predicts ischaemic events and cardiovascular mortality in clopidogrel-treated patients

Author

Michiaki Kubo, Tobias Geisler, Dimitrios Alexopoulos, Gian Franco Gensini, Kiyuk Chang, Jean-Luc Reny, Joshua P. Lewis, Meinrad Gawaz, Elke Schaeffeler, Kevin P. Bliden, Stefan Winter, Eun Young Kim, Ruth E. Pakyz, Paul A. Gurbel, Rossella Marcucci, Israel Fernandez-Cadenas, Joan Montaner, Nadia Paarup Dridi, Li Gong, Jae-Gook Shin, Matthias Schwab, Ryan Whaley, Jurriën M. ten Berg, John H. Cleator, Pierre Fontana, Marco Valgimigli, Russ B. Altman, Ho-Sook Kim, Joshua D. Backman, Jolanta M. Siller-Matula, Daniel Aradi, Braxton D. Mitchell, Betti Giusti, Thomas O. Bergmeijer, Kathleen A. Ryan, Alan R. Shuldiner, Ming-Shien Wen, Jean-Pierre Déry, Marylyn D. Ritchie, Teri E. Klein, Dan M. Roden, Ming Ta Michael Lee, Dietmar Trenk, Gianluca Campo, Lene Holmvang, and Willibald Hochholzer

Subjects
clopidogrel, pharmacogenetics, platelet aggregation, medicine.medical_specialty, CYP2C19, 030204 cardiovascular system & hematology, NO, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Pharmacology (medical), CYP2C9, pharmacogenetics, 030304 developmental biology, clopidogrel, 0303 health sciences, business.industry, Original Articles, Odds ratio, medicine.disease, Clopidogrel, Confidence interval, platelet aggregation, Pharmacogenomics, Cardiology and Cardiovascular Medicine, business, Pharmacogenetics, medicine.drug
Abstract

Aims Clopidogrel is prescribed for the prevention of atherothrombotic events. While investigations have identified genetic determinants of inter-individual variability in on-treatment platelet inhibition (e.g. CYP2C19*2), evidence that these variants have clinical utility to predict major adverse cardiovascular events (CVEs) remains controversial. Methods and results We assessed the impact of 31 candidate gene polymorphisms on adenosine diphosphate (ADP)-stimulated platelet reactivity in 3391 clopidogrel-treated coronary artery disease patients of the International Clopidogrel Pharmacogenomics Consortium (ICPC). The influence of these polymorphisms on CVEs was tested in 2134 ICPC patients (N = 129 events) in whom clinical event data were available. Several variants were associated with on-treatment ADP-stimulated platelet reactivity (CYP2C19*2, P = 8.8 × 10−54; CES1 G143E, P = 1.3 × 10−16; CYP2C19*17, P = 9.5 × 10−10; CYP2B6 1294 + 53 C > T, P = 3.0 × 10−4; CYP2B6 516 G > T, P = 1.0 × 10−3; CYP2C9*2, P = 1.2 × 10−3; and CYP2C9*3, P = 1.5 × 10−3). While no individual variant was associated with CVEs, generation of a pharmacogenomic polygenic response score (PgxRS) revealed that patients who carried a greater number of alleles that associated with increased on-treatment platelet reactivity were more likely to experience CVEs (β = 0.17, SE 0.06, P = 0.01) and cardiovascular-related death (β = 0.43, SE 0.16, P = 0.007). Patients who carried eight or more risk alleles were significantly more likely to experience CVEs [odds ratio (OR) = 1.78, 95% confidence interval (CI) 1.14–2.76, P = 0.01] and cardiovascular death (OR = 4.39, 95% CI 1.35–14.27, P = 0.01) compared to patients who carried six or fewer of these alleles. Conclusion Several polymorphisms impact clopidogrel response and PgxRS is a predictor of cardiovascular outcomes. Additional investigations that identify novel determinants of clopidogrel response and validating polygenic models may facilitate future precision medicine strategies.

Published
2019

2. 1453-P: Adaption of the ACMG/AMP Variant Interpretation Guidelines for GCK, HNF1A, HNF4A-MODY: Recommendations from the ClinGen Monogenic Diabetes Expert Panel

Author

Linda Jeng, Rochelle N. Naylor, Haichen Zhang, Kristin A. Maloney, Miriam S. Udler, Tiinamaija Tuomi, Rinki Murphy, Ruth E. Pakyz, Toni I. Pollin, José P. Miranda, Louis H. Philipson, Jarno Kettunen, Fabrizio Barbetti, Janne Molnes, Siri Atma W. Greeley, Kevin Colclough, Uyenlinh L. Mirshahi, and Sabrina Prudente

Subjects
medicine.medical_specialty, medicine.diagnostic_test, business.industry, Endocrinology, Diabetes and Metabolism, Genetic counseling, Concordance, Type 2 diabetes, Precision medicine, medicine.disease, HNF1A, Minor allele frequency, Internal medicine, Internal Medicine, medicine, Medical genetics, business, Genetic testing
Abstract

Genetic testing for monogenic diabetes, essential for accurate diagnosis and appropriate treatment is underutilized. Obstacles include clinical overlap with type 1 and type 2 diabetes and difficulty distinguishing clinically significant (pathogenic/likely pathogenic; P/LP) from normal (benign/likely benign; B/LB) variation. The ClinGen Monogenic Diabetes Expert Panel (MDEP) was formed to adapt American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) variant interpretation guidelines to monogenic diabetes genes and enable depositing of expert panel variant reviews into ClinVar, a public database relating gene variants to phenotypes. MDEP includes endocrinologists, laboratory directors, genetic counselors, medical geneticists, clinical scientists and researchers from 37 academic and commercial institutions, allowing the panel to benefit from multiple expert perspectives and pooling of case-level data. Currently, MDEP is focusing on the three most commonly implicated monogenic diabetes genes: GCK, HNF1A and HNF4A. MDEP generated gene-specific modifications and/or strength adjustments to existing rules to provide guidance for the use of evidence, including molecular, phenotypic, segregation, functional, and minor allele frequency data. Our guidelines have so far been tested on 98 HNF1A variants, 15 HNF4A variants and 22 GCK variants selected from ClinVar and the literature. Fourteen of 31 variants of uncertain significance (VUS) in ClinVar were re-classified: nine to P/LP (enabling diagnosis and treatment) and five to B/LB (reducing ambiguity). Six LP variants and one LB variant from ClinVar were re-classified to VUS (stimulating further surveillance). MDEP’s work will improve accuracy, standardization and concordance of variant interpretation for monogenic diabetes and support wider implementation of precision medicine in diabetes. Disclosure H. Zhang: None. K.A. Maloney: None. F. Barbetti: Consultant; Self; Amring. S.W. Greeley: None. J.L.T. Kettunen: None. J.P. Miranda: None. U.L. Mirshahi: None. J. Molnes: None. R. Murphy: None. R.N. Naylor: None. R.E. Pakyz: None. L.H. Philipson: None. S. Prudente: None. T. Tuomi: None. M. Udler: None. K. Colclough: None. L. Jeng: None. T.I. Pollin: None. Funding National Institutes of Health (5U24HD093486, R01DK104942, P30DK020595 )

Published
2020

3. 2264-PUB: Progress in Curating Gene–Disease Relationships by the ClinGen Monogenic Diabetes Expert Panel

Author

Siri Atma W. Greeley, Courtney Thaxton, Haichen Zhang, Kristin A. Maloney, Toni I. Pollin, Rochelle N. Naylor, Megan A. Mayers, Kashyap A. Patel, Kevin Colclough, Miriam S. Udler, and Ruth E. Pakyz

Subjects
education.field_of_study, business.industry, Endocrinology, Diabetes and Metabolism, Population, Type 2 diabetes, Disease, medicine.disease, HNF1B, Bioinformatics, Metformin, HNF1A, Diabetes mellitus, Internal Medicine, medicine, education, business, Gene, medicine.drug
Abstract

Diagnosing and distinguishing monogenic diabetes, including some MODY (maturity-onset diabetes of the young), from type 1 or type 2 diabetes can have profound clinical implications: sulfonylureas vs. insulin or metformin for HNF1A- and HNF4A- diabetes, and no treatment for GCK-diabetes. Since 1996, the number of monogenic diabetes genes has expanded from three to 60 or more, with 14 called MODY genes; however newer evidence has called some of these gene associations into question. Monogenic diabetes is currently underdiagnosed, but the decreasing cost of sequencing and the ability to create multi-gene next-generation sequencing panels may increase access to testing and a proper diagnosis. For the testing to be useful, it is important that the genes chosen for these panels have appropriate evidence as causal genes. The NIH Clinical Genome Resource (ClinGen) Monogenic Diabetes Gene Curation Expert Panel was convened to bring together experts in clinical and laboratory aspects of monogenic diabetes and gene curation to publish curations for the ClinGen website based on evidence from clinical and molecular studies and population databases. To date, we have published evidence-based gene curation summaries for Gene-Disease Validity for HNF1A and HNF4A (both classified as Definitive for monogenic diabetes) and are in the process of curating and publishing curations for GCK (Definitive for monogenic diabetes), INS (Definitive for monogenic diabetes and permanent neonatal diabetes), HNF1B (Definitive for renal cysts and diabetes), and KLF11 (Disputed for monogenic diabetes due to limited evidence and high population frequencies of variants previously asserted as causative). Curation of additional genes is in progress. Accurate curations will inform appropriate testing panel content to reduce ambiguous results and assure variants identified are clinically relevant for informing the care of diabetes in patients and their families. Disclosure T.I. Pollin: None. M.A. Mayers: None. S.W. Greeley: None. K.A. Maloney: None. R.N. Naylor: None. R.E. Pakyz: None. K.A. Patel: None. M. Udler: None. H. Zhang: None. K. Colclough: None. C. Thaxton: None. Funding National Institutes of Health (U24HD093486)

Published
2020

4. Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium

Author

Jae-Gook Shin, Dan M. Roden, Stefan Winter, Paul A. Gurbel, Michiaki Kubo, Braxton D. Mitchell, Joshua P. Lewis, Yuki Bradford, Daniel Aradi, Kevin P. Bliden, Jurriën M. ten Berg, Thomas O. Bergmeijer, Kiyuk Chang, Ruth E. Pakyz, Alan R. Shuldiner, Ho-Sook Kim, Jean-Luc Reny, Meinrad Gawaz, Tobias Geisler, Gianluca Campo, Marco Valgimigli, Elke Schaeffeler, Jolanta M. Siller-Matula, Gian Franco Gensini, Lene Holmvang, Willibald Hochholzer, Rossella Marcucci, Betti Giusti, Ming Ta Michael Lee, Jean-Pierre Déry, Dietmar Trenk, Ming-Shien Wen, John M. Wallace, Marylyn D. Ritchie, Teri E. Klein, Israel Fernandez-Cadenas, Dimitrios Alexopoulos, Matthias Schwab, Ryan Whaley, John H. Cleator, Pierre Fontana, Joshua D. Backman, Russ B. Altman, Shefali S. Verma, Eun Young Kim, Nadia Paarup Dridi, Li Gong, and Joan Montaner

Subjects
Male, Pharmacogenomic Variants, medicine.medical_treatment, Coronary Artery Disease, 030226 pharmacology & pharmacy, Coronary artery disease, Cytochrome P-450 CYP2C19/genetics/metabolism, 0302 clinical medicine, Risk Factors, Platelet Aggregation Inhibitors/adverse effects/therapeutic use, Pharmacology (medical), Myocardial infarction, pharmacokinetic, ddc:616, Clopidogrel/adverse effects/therapeutic use, Articles, Middle Aged, Clopidogrel, clinical outcomes, 3. Good health, Treatment Outcome, Cardiovascular Diseases, 030220 oncology & carcinogenesis, Cardiology, Female, percutaneous coronary intervention, clinical outcomes, CYP2C19, pharmacokinetic, medicine.drug, Blood Platelets, medicine.medical_specialty, Acute coronary syndrome, CYP2C19, Polymorphism, Single Nucleotide, Risk Assessment, Blood Platelets/drug effects/metabolism, Article, NO, 03 medical and health sciences, Internal medicine, medicine, Humans, Cardiovascular Diseases/blood/genetics/mortality/prevention & control, cardiovascular diseases, Aged, Pharmacology, Coronary Artery Disease/mortality/therapy, business.industry, Research, Percutaneous Coronary Intervention/adverse effects/mortality, percutaneous coronary intervention, Percutaneous coronary intervention, medicine.disease, Cytochrome P-450 CYP2C19, Pharmacogenetics, Pharmacogenomics, ddc:618.97, business, Platelet Aggregation Inhibitors, Genome-Wide Association Study
Abstract

Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with adverse clinical outcomes. CYP2C19 loss-of-function alleles play an important role in this response, but account for only a small proportion of variability in response to clopidogrel. An aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify other genetic determinants of clopidogrel pharmacodynamics and clinical response. A genomewide association study (GWAS) was performed using DNA from 2,750 European ancestry individuals, using adenosine diphosphate-induced platelet reactivity and major cardiovascular and cerebrovascular events as outcome parameters. GWAS for platelet reactivity revealed a strong signal for CYP2C19*2 (P value = 1.67e−33). After correction for CYP2C19*2 no other single-nucleotide polymorphism reached genomewide significance. GWAS for a combined clinical end point of cardiovascular death, myocardial infarction, or stroke (5.0% event rate), or a combined end point of cardiovascular death or myocardial infarction (4.7% event rate) showed no significant results, although in coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome subgroups, mutations in SCOS5P1, CDC42BPA, and CTRAC1 showed genomewide significance (lowest P values: 1.07e−09, 4.53e−08, and 2.60e−10, respectively). CYP2C19*2 is the strongest genetic determinant of on-clopidogrel platelet reactivity. We identified three novel associations in clinical outcome subgroups, suggestive for each of these outcomes.

Published
2020

5. The Pharmacogenomics Research Network Translational Pharmacogenetics Program: Outcomes and Metrics of Pharmacogenetic Implementations Across Diverse Healthcare Systems

Author

Liewei Wang, Jill M. Pulley, Mark J. Ratain, Julie A. Johnson, Wolfgang Sadee, Rhonda M. Cooper-DeHoff, Teri E. Klein, Ruth E. Pakyz, Julie R. Field, Alan R. Shuldiner, Russ B. Altman, Mary V. Relling, Peter H. O'Donnell, Josh F. Peterson, Samuel K. Handelman, Peter J. Embi, Jasmine A. Luzum, Larisa H. Cavallari, Naveen L. Pereira, Cyrine E. Haidar, Kathleen Palmer, Michelle Whirl-Carrillo, Dan M. Roden, Kristin Weitzel, Robert R. Freimuth, Jonathan S. Schildcrout, Marc Beller, Amanda R. Elsey, and Richard M. Weinshilboum

Subjects
0301 basic medicine, Knowledge management, MEDLINE, Bioinformatics, Article, Translational Research, Biomedical, 03 medical and health sciences, Humans, Medicine, Pharmacology (medical), Implementation, Alleles, Pharmacology, business.industry, United States, 030104 developmental biology, Workflow, National Institutes of Health (U.S.), Pharmacogenetics, Pharmacogenomics, Informatics, Practice Guidelines as Topic, business, Delivery of Health Care, Healthcare system
Abstract

Numerous pharmacogenetic clinical guidelines and recommendations have been published, but barriers have hindered the clinical implementation of pharmacogenetics. The Translational Pharmacogenetics Program (TPP) of the National Institutes of Health (NIH) Pharmacogenomics Research Network was established in 2011 to catalog and contribute to the development of pharmacogenetic implementations at eight US healthcare systems, with the goal to disseminate real-world solutions for the barriers to clinical pharmacogenetic implementation. The TPP collected and normalized pharmacogenetic implementation metrics through June 2015, including gene-drug pairs implemented, interpretations of alleles and diplotypes, numbers of tests performed and actionable results, and workflow diagrams. TPP participant institutions developed diverse solutions to overcome many barriers, but the use of Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provided some consistency among the institutions. The TPP also collected some pharmacogenetic implementation outcomes (scientific, educational, financial, and informatics), which may inform healthcare systems seeking to implement their own pharmacogenetic testing programs.

Published
2017

6. Multi-site Investigation of Outcomes with Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy after Percutaneous Coronary Intervention

Author

Issam Hamadeh, Devon C. Nwaba, Nita A. Limdi, Amer Ardati, Josh F. Peterson, James M. Stevenson, Russell A. Wilke, Craig R. Lee, Kristin Weitzel, Tameka D. Alestock, Yan Gong, Kathleen Palmer, Joshua C. Denny, Stephen E. Kimmel, Almut G. Winterstein, Richard B. Horenstein, Mark R. Vesely, Todd C. Skaar, Caitrin W. McDonough, Supatat Chumnumwat, Dyson T. Wake, James H. Willig, Petr Starostik, Larisa H. Cavallari, Linda J. B. Jeng, Karen E. Weck, Chrisly Dillon, Michael J. Clare-Salzler, D. Max Smith, Jorge A. Alsip, Vindhya B. Sriramoju, Rolf P. Kreutz, Chintan V. Dave, Julie A. Johnson, William B. Hillegass, Victoria M. Pratt, Toni I. Pollin, R. David Anderson, Rhonda M. Cooper-DeHoff, Richard Y. Zhao, Yee Ming Lee, Shawn W. Robinson, Brigitta C. Brott, Deepak Voora, Tomasz Stys, Lindsay J. Hines, Alan R. Shuldiner, Ruth E. Pakyz, Mark D. Kelemen, Alison H. Quinn, Edith A. Nutescu, Shuko Harada, Lawrence Brown, David R. Nelson, Oyunbileg Magvanjav, Philip E. Empey, Lucius A. Howell, Amanda R. Elsey, May E. Montasser, Nicholas Varunok, James C. Coons, Amber L. Beitelshees, George A. Stouffer, Julio D. Duarte, and Jamie Schub

Subjects
Male, Ticagrelor, medicine.medical_specialty, Time Factors, Prasugrel, Ticlopidine, Pharmacogenomic Variants, Genotype, medicine.medical_treatment, Clinical Decision-Making, Drug Resistance, 030204 cardiovascular system & hematology, Risk Assessment, Article, 03 medical and health sciences, 0302 clinical medicine, Percutaneous Coronary Intervention, Predictive Value of Tests, Risk Factors, Internal medicine, Humans, Medicine, cardiovascular diseases, 030212 general & internal medicine, Aged, business.industry, Patient Selection, Hazard ratio, Percutaneous coronary intervention, Middle Aged, Clopidogrel, United States, Confidence interval, Pharmacogenomic Testing, Surgery, Cytochrome P-450 CYP2C19, Treatment Outcome, Pharmacogenetics, Conventional PCI, Platelet aggregation inhibitor, Female, Cardiology and Cardiovascular Medicine, business, Prasugrel Hydrochloride, Platelet Aggregation Inhibitors, medicine.drug
Abstract

Objectives This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype–guided antiplatelet therapy after percutaneous coronary intervention (PCI). Background CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI. Methods After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as myocardial infarction, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights. Results Among 1,815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years; adjusted hazard ratio: 2.26; 95% confidence interval: 1.18 to 4.32; p = 0.013). Similar results were observed among 1,210 patients with acute coronary syndromes at the time of PCI (adjusted hazard ratio: 2.87; 95% confidence interval: 1.35 to 6.09; p = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted hazard ratio: 1.14; 95% confidence interval: 0.69 to 1.88; p = 0.60). Conclusions These data from real-world observations demonstrate a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele if clopidogrel versus alternative therapy is prescribed. A future randomized study of genotype-guided antiplatelet therapy may be of value.

Published
2017

7. Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points-Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC)

Author

Dan M. Roden, Marylyn D. Ritchie, Jae-Gook Shin, Braxton D. Mitchell, Teri E. Klein, Gian Franco Gensini, Jurriën M. ten Berg, Pierre Fontana, Lene Holmvang, Israel Fernandez-Cadenas, Willibald Hochholzer, Stefan Winter, Tabassome Simon, Ruth E. Pakyz, Paul A. Gurbel, Richard B. Horenstein, Ming-Shien Wen, Tobias Geisler, John H. Cleator, Marco Valgimigli, Ho-Sook Kim, Jean-Sébastien Hulot, Jolanta M. Siller-Matula, Dietmar Trenk, Gianluca Campo, Michiaki Kubo, Elke Schaeffeler, Nadia Paarup Dridi, Ming Ta Michael Lee, Li Gong, Joshua P. Lewis, Jean-Pierre Déry, Rossella Marcucci, Kiyuk Chang, Meinrad Gawaz, Kevin P. Bliden, Alan R. Shuldiner, Daniel Aradi, Thomas O. Bergmeijer, Betti Giusti, Russ B. Altman, Dimitrios Alexopoulos, Matthias Schwab, Ryan Whaley, Jean-Luc Reny, Joan Montaner, Eun Young Kim, Reny, Jean-Luc, Fontana, Pierre, Centre de Ressources Biologiques HUEP-UPMC (CRB HUEP-UPMC), UMS omique (OMIQUE), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Oncology, Male, Candidate gene, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Internationality, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Genome-wide association study, 030204 cardiovascular system & hematology, Cardiovascular Medicine, MESH: Risk Assessment, MESH: Receptors, Purinergic P2Y12, 0302 clinical medicine, P2Y12, MESH: Molecular Targeted Therapy, Receptors, Medicine, 030212 general & internal medicine, Molecular Targeted Therapy, MESH: Treatment Outcome, MESH: Genetic Association Studies, Cardiology, Cardiovascular Medicine, MESH: Aged, ddc:616, Acute Coronary Syndrome/diagnosis/drug therapy/mortality, MESH: Middle Aged, Purinergic P2Y12/drug effects/genetics, Middle Aged, Clopidogrel, Prognosis, Receptors, Purinergic P2Y12, 3. Good health, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Survival Rate, Treatment Outcome, Female, Cardiology and Cardiovascular Medicine, medicine.drug, circulatory and respiratory physiology, Acute coronary syndrome, medicine.medical_specialty, MESH: Survival Rate, Cardiology, MESH: Pharmacogenetics, CYP2C19, Clopidogrel/therapeutic use, Risk Assessment, MESH: Prognosis, Article, NO, 03 medical and health sciences, Internal medicine, Humans, cardiovascular diseases, Acute Coronary Syndrome, Genetic Association Studies, Aged, MESH: Humans, business.industry, MESH: Clopidogrel, medicine.disease, Genome-wide association approach, candidate gene approaches, clopidogrel, efficacy, pharmacodynamic, clinical end points, International Clopidogrel Pharmacogenomics Consortium (ICPC), Cardiovascular Medicine, MESH: Acute Coronary Syndrome, MESH: Male, Pharmacogenetics, Pharmacogenomics, MESH: Genome-Wide Association Study, ddc:618.97, MESH: Internationality, business, MESH: Female, Molecular Targeted Therapy/methods, Genome-Wide Association Study
Abstract

RATIONALE: The P2Y(12) receptor inhibitor clopidogrel is widely used in patients with acute coronary syndrome, percutaneous coronary intervention or ischemic stroke. Platelet inhibition by clopidogrel shows wide inter-patient variability and high on-treatment platelet reactivity is a risk factor for atherothrombotic events, particularly in high-risk populations. CYP2C19 polymorphism plays an important role in this variability, but heritability estimates suggest that additional genetic variants remain unidentified. The aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify genetic determinants of clopidogrel pharmacodynamics and clinical response. STUDY DESIGN: Based on the data published on www.clinicaltrials.gov, clopidogrel intervention studies containing genetic and platelet function data were identified for participation. Lead investigators were invited to share DNA samples, platelet function test results, patient characteristics and cardiovascular outcomes, to perform candidate gene and genome-wide association studies. RESULTS: In total, 17 study sites from 13 countries participate in the ICPC, contributing individual patient data from 8,829 patients. Available adenosine diphosphate (ADP) stimulated platelet function tests included Vasodilator-Stimulated Phosphoprotein (VASP) assay, Light Transmittance Aggregometry (LTA) and the VerifyNow P2Y(12) assay. A proof of principle analysis based on genotype data provided by each group showed a strong and consistent association between CYP2C19*2 and platelet reactivity (p-value = 5.1×10(−40)). CONCLUSION: The ICPC aims to identify new loci influencing clopidogrel efficacy by using state-of-the-art genetic techniques in a large cohort of clopidogrel-treated patients in order to better understand the genetic basis of on-treatment response variability.

Published
2017

8. Implementation of pharmacogenetics: The University of Maryland personalized anti-platelet pharmacogenetics program

Author

Nicholas P. Ambulos, Richard Y. Zhao, Mark R. Vesely, Courtney O'Neill, Tameka D. Alestock, Miriam G. Blitzer, Patrick F. McArdle, Toni I. Pollin, Richard B. Horenstein, Ruth E. Pakyz, Lawrence Brown, Shaun Bhatty, Amber L. Beitelshees, Alan R. Shuldiner, Linda J. B. Jeng, Kathleen Palmer, Jamie Schub, Mark D. Kelemen, Shawn W. Robinson, Casey Lynnette Overby, and Kristin A. Maloney

Subjects
medicine.medical_specialty, medicine.diagnostic_test, business.industry, Translational research, Pharmacology, Precision medicine, Clinical decision support system, Pharmacogenomics, Genetics, Platelet aggregation inhibitor, Medicine, Medical physics, Personalized medicine, business, Genetics (clinical), Pharmacogenetics, Genetic testing
Abstract

Despite a substantial evidence base, implementation of pharmacogenetics into routine patient care has been slow due to a number of non-trivial practical barriers. We implemented a Personalized Anti-platelet Pharmacogenetics Program (PAP3) for cardiac catheterization patients at the University of Maryland Medical Center and the Baltimore Veterans Administration Medical Center Patients' are offered CYP2C19 genetic testing, which is performed in our Clinical Laboratory Improvement Amendment (CLIA)-certified Translational Genomics Laboratory. Results are returned within 5 hr along with clinical decision support that includes interpretation of results and prescribing recommendations for anti-platelet therapy based on the Clinical Pharmacogenetics Implementation Consortium guidelines. Now with a working template for PAP3, implementation of other drug-gene pairs is in process. Lessons learned as described in this article may prove useful to other medical centers as they implement pharmacogenetics into patient care, a critical step in the pathway to personalized and genomic medicine. © 2014 Wiley Periodicals, Inc.

Published
2014

9. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Author

Kenneth Rice, Amy J. Swift, Veronique Vitart, Lu Qi, Kaisa Silander, Olivier Le Bacquer, Laura Crisponi, David S. Siscovick, Bo Isomaa, Anne U. Jackson, Anke Tönjes, Richard N. Bergman, Rosa Maria Roccasecca, Luigi Ferrucci, Narisu Narisu, Kari Stefansson, Holly E. Syddall, Giuseppe Paolisso, Kim L. Ward, Paul Elliott, Scott M. Grundy, Paul Johnson, Jerome I. Rotter, Philippe Froguel, James B. Meigs, George Davey Smith, Andrew T. Hattersley, Leena Peltonen, Eric J.G. Sijbrands, Serena Sanna, María TeresaMartínez-Larrad, David Altshuler, Harald Grallert, Caroline S. Fox, Nita G. Forouhi, Dorret I. Boomsma, Harry Campbell, Jean Tichet, Angelo Scuteri, Aroon D. Hingorani, Daniel S. Pearson, Meena Kumari, Silvia Naitza, Shah Ebrahim, Manjinder S. Sandhu, Jose C. Florez, Cyrus Cooper, David M. Nathan, Joseph Hung, Fredrik Karpe, Ozren Polasek, Philip J. Barter, Ruth McPherson, Benjamin F. Voight, Wolfgang Rathmann, Abbas Dehghan, Udo Seedorf, Beverley M. Shields, Antti Jula, Pau Navarro, Josephine M. Egan, Rune R. Frants, Leif Groop, Gunnar Sigursson, Seppo Koskinen, Vincent Mooser, François Pattou, Jing Hua Zhao, Irene Pichler, John F. Peden, Göran Hallmans, Toshiko Tanaka, Ruth J. F. Loos, Peter Kovacs, Andrew D. Morris, Cécile Lecoeur, Jeffrey R. O'Connell, Massimo Mangino, Nicole Vogelzangs, Rhian Gwilliam, Gordon H. Williams, Carina Zabena, Naomi Hammond, Amélie Bonnefond, Björn Zethelius, Joachim Spranger, Nancy L. Pedersen, Christopher J. Groves, Nicholas J. Timpson, George Dedoussis, Veikko Salomaa, Peter Henneman, Andrew Walley, Serge Hercberg, Ian N. M. Day, Simon Heath, Matt Neville, Alex S. F. Doney, Robert Clarke, Olov Rolandsson, Panos Deloukas, Eric Boerwinkle, Y. AnteroKesaniemi, Mike Sampson, Gerard Waeber, Sven Bergmann, Ben A. Oostra, Manuel Serrano-Ríos, Mandy van Hoek, Christine Cavalcanti-Proença, Anna L. Gloyn, Ulla Sovio, Andrew P. Morris, Anneli Pouta, Amanda J. Bennett, Paul Scheet, Peter Schwarz, Jaakko Tuomilehto, Hugh Watkins, Johanna Kuusisto, Denis Rybin, Anna LiisaHartikainen, Maria GraziaFranzosi, Unnur Thorsteinsdottir, Rafn Benediktsson, Alan F. Wright, Colin N. Apalmer, Anuj Goel, Yavuz Ariyurek, Lars Lind, Robert Sladek, Stefan R. Bornstein, Reedik Mägi, Laila Simpson, Tim D. Spector, Paul W. Franks, Nicholas L. Smith, John R. B. Perry, Peter Vollenweider, Suzannah Bumpstead, Ruth E. Pakyz, Christa Meisinger, Alan R. Shuldiner, Josée Dupuis, Man Li, Eric J. Brunner, Francis S. Collins, Torben Hansen, James F. Wilson, Guangju Zhai, Igor Rudan, Nicole L. Glazer, Marco Orrù, Pierre Meneton, Knut Borch-Johnsen, Eleanor Wheeler, Gonçalo R. Abecasis, Mark I. McCarthy, Jouke JanHottenga, Inga Prokopenko, Ping An, Jérôme Delplanque, Albert Hofman, Andrew B. Singleton, Gabe Crawford, Thomas A. Buchanan, Avan Aihie Sayer, Richard M. Watanabe, David Schlessinger, A C Fedson, André G. Uitterlinden, Frank B. Hu, Jaqueline C. MWitteman, Dhiraj Varma, Ingrid B. Borecki, Sutapa Mukherjee, Murielle Bochud, Barbara Thorand, Christian Gieger, Lori L. Bonnycastle, Stephen J. Sharp, Markus Perola, Caroline Hayward, Kristin Ardlie, J. Graessler, Robert W. Mahley, Toby Johnson, Jian'an Luan, Joshua C. Randall, Cornelia M. van Duijn, Samuli Ripatti, Ko Willems van Dijk, Valgerdur Steinthorsdottir, Yurii S. Aulchenko, G. Mark Lathrop, Christian Dina, Eleftheria Zeggini, Cecilia M. Lindgren, Stavroula Kanoni, Timothy M. Frayling, Dawn M. Waterworth, Marika Kaakinen, Timo T. Valle, Diana Zelenika, Yii Der IdaChen, Angela Silveira, Nigel W. Rayner, Aimo Ruokonen, Yun Li, Cristian Pattaro, Annelli Sandbæk, Richa Saxena, Danielle Posthuma, Steven A. McCarroll, Niels Grarup, Samy Hadjadj, Pilar Galan, Xijing Han, Lyle J. Palmer, Ulf Gyllensten, Peter P. Pramstaller, Manuela Uda, Jarred B. McAteer, Brenda W.J.H. Penninx, Debbie A Lawlor, Torben Jørgensen, Beatrice Knight, Yvonne Böttcher, Claudia Langenberg, Nicole Soranzo, Ghislain Rocheleau, Erik Ingelsson, Mario A. Morken, Michael Roden, Felicity Payne, David R. Hillman, Michael Marmot, Karen L. Mohlke, Heather M. Stringham, Bruce M. Psaty, Gudmar Thorleifsson, Yoav Ben-Shlomo, Inês Barroso, W. H. Linda Kao, James S. Pankow, Valeriya Lyssenko, Nicholas J. Wareham, Tiinamaija Tuomi, Ann ChristineSyvänen, Braxton D. Mitchell, Alisa K. Manning, Mika Kivimäki, Peter Wagner, Praveen Sethupathy, G. BragiWalters, Jaakko Kaprio, Kijoung Song, Marjo Riitta-Järvelin, Michael A. Province, Andrew A. Hicks, Marilyn C. Cornelis, Sarah H. Wild, David Meyre, Guillaume Charpentier, Patrik K. E. Magnusson, David Melzer, Jennie Hui, Peter Shrader, Michael Stumvoll, Mark O. Goodarzi, Michael R. Erdos, Oluf Pedersen, Andreas Pfeiffer, Augustine Kong, Christian Herder, Laura J. Scott, John W. GYarnell, Kirsten Ohm Kyvik, Beverley Balkau, Antje Fischer-Rosinsky, Gonneke Willemsen, Thomas Illig, Neelam Hassanali, Markku Laakso, Michael Boehnke, John Beilby, Christopher S. Franklin, Fernando Rivadeneira, M. Carola Zillikens, Michael N. Weedon, Antonio Cao, Mark E. Cooper, Simon C. Potter, Eco J. C. de Geus, H.-Erich Wichmann, Amanda F. Elliott, Lachlan J. McOin, Sophie Visvikis-Siest, Thomas Sparsø, Laura J. McCulloch, Taina K. Lajunen, Peter S. Chines, Nabila Bouatia-Naji, Medical Research Council (MRC), Biological Psychology, Functional Genomics, Neuroscience Campus Amsterdam - Anxiety & Depression, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Mental Health, Ophthalmology, Epidemiology, Clinical Genetics, Dermatology, Internal Medicine, DIAGRAM Consortium, GIANT Consortium, Global BPgen Consortium, Anders Hamsten on behalf of Procardis Consortium, MAGIC investigators, Human genetics, Psychiatry, EMGO - Mental health, NCA - Attention & Cognition, and NCA - Anxiety & Depression

Subjects
Blood Glucose, Netherlands Twin Register (NTR), Candidate gene, Genome-wide association study, Type 2 diabetes, CIRCADIAN CLOCK, TRIGLYCERIDE LEVELS, 0302 clinical medicine, Delta-5 Fatty Acid Desaturase, Databases, Genetic, Homeostasis, GENETICS & HEREDITY, Anders Hamsten on behalf of Procardis Consortium, Child, Genetics, PLASMA-GLUCOSE, 0303 health sciences, Glucokinase regulatory protein, COMMON VARIANTS, 11 Medical And Health Sciences, Fasting, MAGIC investigators, 3. Good health, MODEL ASSESSMENT, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, ESSENTIAL COMPONENTS, Adolescent, DNA Copy Number Variations, Alleles, Blood Glucose/genetics, Blood Glucose/metabolism, DNA Copy Number Variations/genetics, Diabetes Mellitus, Type 2/genetics, Fasting/blood, Gene Expression Regulation, Genetic Loci/genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Homeostasis/genetics, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide/genetics, Quantitative Trait Loci/genetics, Quantitative Trait, Heritable, Reproducibility of Results, Quantitative Trait Loci, 030209 endocrinology & metabolism, Biology, DIAGRAM Consortium, INSULIN-SECRETION, Polymorphism, Single Nucleotide, Article, Fasting glucose, 03 medical and health sciences, Insulin resistance, SDG 3 - Good Health and Well-being, Diabetes mellitus, Internal medicine, genome wide association study, glucose, diabetes type 2, medicine, GIANT Consortium, Allele, GENOME-WIDE ASSOCIATION, Global BPgen Consortium, 030304 developmental biology, Glycemic, Science & Technology, genome-wide association beta-cell dysfunction plasma-glucose insulin-secretion triglyceride levels essential components model assessment common variants circadian clock disease risk, DISEASE RISK, 06 Biological Sciences, medicine.disease, Endocrinology, Diabetes Mellitus, Type 2, Genetic Loci, biology.protein, BETA-CELL DYSFUNCTION, Developmental Biology
Abstract

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46, 186 nondiabetic participants. Follow-up of 25 loci in up to 76, 558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Published
2010
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10. IL28B genotype does not correlate with HIV control in African Americans

Author

Nahzinine Shakeri, Afshin Parsa, Mohammad M. Sajadi, Robert R. Redfield, Ruth E. Pakyz, Charles D. Howell, and Rohit Talwani

Subjects
Adult, Male, Hepatitis C virus, Single-nucleotide polymorphism, HIV Infections, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Cohort Studies, Young Adult, Polymorphism (computer science), Genotype, medicine, SNP, Humans, Genetic Predisposition to Disease, General Pharmacology, Toxicology and Pharmaceutics, Alleles, Research Articles, Aged, Demography, General Neuroscience, Interleukins, virus diseases, General Medicine, Middle Aged, Virology, Black or African American, Immunology, Cohort, Female, Interferons, Viral load, Cohort study
Abstract

Background: HIV-1 natural viral suppressors (NVS) are individuals that control HIV replication without antiretrovirals (also know as HIV elite controllers). We have recently shown that these individuals have an elevated rate of hepatitis C virus (HCV) clearance. Given the association of IL28B genotype, specifically the rs12979860 single nucleotide polymorphism (SNP) based CC genotype, with HCV clearance, we studied its association with HIV control in 172 African American HIV subjects and 173 race-matched controls. Findings: The frequency of the CC genotype was 12.5% in the NVS, 14.7% in the LVL (“low viral load” cohort with 400–20,000 HIV-1 RNA copies/mL), 17.8% in the MHVL (“medium/high viral load” cohort with >20,000 HIV-1 RNA copies/mL), and 11.6% in an HIV-negative cohort. There was no statistical significance in the CC genotype distribution between these cohorts (p= 0.48 between the NVS and non-NVS HIV positive controls, p= 0.85 between NVS and HIV-negatives). We also did not observe any association between CC genotype distribution and HIV RNA viral load, as a continuous measure. Conclusions: The IL28B CC genotype does not account for the noted HIV control in our specific NVS cohort. Further studies will be needed to determine if a common genetic factor can primarily account for any joint clearance of HCV and control of HIV. Clin Trans Sci 2011; Volume 4: 282–284

Published
2011

11. Functional variants in MBL2 are associated with type 2 diabetes and pre-diabetes traits in Pima Indians and the old order Amish

Author

Xiaolian Shi, Leslie J. Baier, Li Bian, Yunhua L. Muller, Clifton Bogardus, Robert L. Hanson, Alan R. Shuldiner, Ruth E. Pakyz, William C. Knowler, and Janel Mack

Subjects
Adult, Male, medicine.medical_specialty, Diabetes risk, Genotype, Endocrinology, Diabetes and Metabolism, Population, 030209 endocrinology & metabolism, Type 2 diabetes, Biology, Mannose-Binding Lectin, Polymorphism, Single Nucleotide, Risk Assessment, White People, Prediabetic State, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Insulin resistance, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Genetics, Humans, education, Promoter Regions, Genetic, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, education.field_of_study, Type 1 diabetes, Genetic Variation, Glucose Tolerance Test, medicine.disease, 3. Good health, Gestational diabetes, Endocrinology, Diabetes Mellitus, Type 2, Protestantism, Old Order Amish, Indians, North American, Female
Abstract

OBJECTIVEMBL2 encodes the mannose-binding lectin, which is a key player in the innate immune system and has recently been found to play a role in insulin resistance and development of type 1 diabetes and gestational diabetes mellitus. To assess the role of MBL2 in diabetes susceptibility, this gene was analyzed in the Pima Indian population, which has a high prevalence of type 2 diabetes.RESEARCH DESIGN AND METHODSNineteen tag single nucleotide polymorphisms (SNPs) were genotyped in a population-based sample of 3,501 full-heritage Pima Indians, and selected SNPs were further genotyped in independent samples of Native American (n = 3,723) and Old Order Amish (n = 486) subjects.RESULTSTwo variants, a promoter SNP (rs11003125) at −550 bp with a risk allele frequency of 0.77 and a Gly54Asp (rs1800450) with a risk allele frequency of 0.83, were associated with type 2 diabetes in the full-heritage Pima Indians (odds ratio 1.30 per copy of the G allele for rs1103125, P = 0.0007, and 1.30 per copy of the glycine allele for rs1800450, P = 0.002, adjusted for age, sex, birth year, and family membership). These associations replicated in an independent Native American sample (1.19, P = 0.04, for rs11003125) and a Caucasian sample, the Old Order Amish (1.51, P = 0.004, for rs1103125 and 2.38, P = 0.003, for rs1800450). Among Pima Indians with normal glucose tolerance, the diabetes risk allele glycine of Gly54Asp was associated with a decreased acute insulin response to an intravenous glucose bolus infusion (P = 0.004, adjusted for age, sex, percent body fat, glucose disposal under physiological insulin stimulation, and family membership).CONCLUSIONSOur data suggest that the functional variants in MBL2 contribute to type 2 diabetes susceptibility in both Native Americans and the Old Order Amish.

Published
2010

12. THE INFLUENCE OF CYTOCHROME P450 2C19*2 AND*17 GENOTYPE, DIPLOTYPE AND METABOLIZER STATUS ON PLATELET REACTIVITY IN PATIENTS ON MAINTENANCE CLOPIDOGREL THERAPY

Author

Paul A. Gurbel, Ruth E. Pakyz, Mark J. Antonino, Alan R. Shuldiner, Udaya S. Tantry, and Kevin P. Bliden

Subjects
Platelet reactivity, medicine.medical_specialty, business.industry, Internal medicine, Genotype, Medicine, In patient, CYP2C19, business, Clopidogrel, Cardiology and Cardiovascular Medicine, Gastroenterology, medicine.drug
Published
2010
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13. Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge

Author

François Pattou, Thomas Sparsø, Eleftheria Zeggini, Michael N. Weedon, J. Graessler, Mandy van Hoek, Suzette J. Bielinski, Amy J. Swift, David S. Siscovick, Michael R. Erdos, Kenneth Rice, Nabila Bouatia-Naji, Benjamin F. Voight, Wolfgang Rathmann, Jarred B. McAteer, Caroline S. Fox, Kari Stefansson, Vincent Mooser, Philippe Froguel, Gordon H. Williams, Mike Sampson, Annelli Sandbæk, Jeffrey R. O'Connell, Stefan R. Bornstein, Robert Sladek, Andrew D. Morris, Torben Jørgensen, Suzannah Bumpstead, Ruth E. Pakyz, James B. Meigs, Denis Rybin, Peter Vollenweider, Valle Tt, Andrew T. Hattersley, Amélie Bonnefond, Knut Krohn, Kijoung Song, Erik Ingelsson, Mario A. Morken, Laura J. Scott, Richard M. Watanabe, Eric J.G. Sijbrands, David Altshuler, Harald Grallert, Vladimir Mayor, Yii-Der Ida Chen, Heather M. Stringham, Bruce M. Psaty, Andrew B. Singleton, Nicole L. Glazer, Peter Schwarz, Jaakko Tuomilehto, Mathieu Firmann, Yvonne Böttcher, Knut Borch-Johnsen, Josée Dupuis, Unnur Thorsteinsdottir, Thomas A. Buchanan, Avan Aihie Sayer, Inga Prokopenko, Thomas Illig, Inês Barroso, Aroon D. Hingorani, Daniel S. Pearson, Luigi Ferrucci, Anna Köttgen, H.-Erich Wichmann, Peter Shrader, Yurii S. Aulchenko, Lu Qi, Olivier Le Bacquer, Eric J. Brunner, Meena Kumari, Karen L. Mohlke, Valgerdur Steinthorsdottir, Laura Pascoe, Lori L. Bonnycastle, Francis S. Collins, Jérôme Delplanque, Guillaume Charpentier, Michael Stumvoll, Mark O. Goodarzi, Felicity Payne, Ruth J. F. Loos, Richard N. Bergman, Gudmar Thorleifsson, Beverley Balkau, Jing Hua Zhao, Timothy M. Frayling, Josephine M. Egan, Kristin Ardlie, Stephen J. Sharp, Jalal Taneera, Mark Walker, W. H. Linda Kao, Nicholas L. Smith, Niels Grarup, Nita G. Forouhi, Oluf Pedersen, Cécile Lecoeur, Andrew Walley, Ann-Christine Syvänen, Eric Boerwinkle, Toby Johnson, Camilla H. Andreasen, Jian Anluan, Dawn M. Waterworth, Toshiko Tanaka, Braxton D. Mitchell, Alisa K. Manning, James S. Pankow, Valeriya Lyssenko, Mika Kivimäki, David Couper, Alex S. F. Doney, Nicholas J. Wareham, Tiinamaija Tuomi, Johanna Kuusisto, Torben Hansen, Christine Cavalcanti-Proença, Richa Saxena, Markku Laakso, James F. Wilson, Bo Isomaa, Marilyn C. Cornelis, David Meyre, Anne U. Jackson, Holly E. Syddall, Alan R. Shuldiner, Michael Boehnke, Peter M. Nilsson, Gabriel Crawford, Claudia Langenberg, Jerome I. Rotter, Peter S. Chines, Cyrus Cooper, Peter Kovacs, Torsten Lauritzen, Christian Dina, Gerard Waeber, Man Li, Anke Tönjes, Narisu Narisu, Jose C. Florez, David M. Nathan, Leif Groop, Claire Levy-Marchal, Cornelia M. van Duijn, Mark I. McCarthy, Frank B. Hu, Trine Welløv Boesgaard, Colin N. Apalmer, Michael Marmot, GIANT consortium, MAGIC investigators, Ophthalmology, Internal Medicine, and Epidemiology

Subjects
Adenylate Cyclase, Male, medicine.medical_specialty, medicine.medical_treatment, Denmark, Incretin, 030209 endocrinology & metabolism, Type 2 diabetes, Biology, Carbohydrate metabolism, Incretins, Polymorphism, Single Nucleotide, Article, Body Mass Index, Receptors, Gastrointestinal Hormone, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Meta-Analysis as Topic, Internal medicine, Diabetes mellitus, medicine, Genetics, Humans, Insulin, RNA, Messenger, 030304 developmental biology, 0303 health sciences, Glucose tolerance test, medicine.diagnostic_test, Gene Expression Profiling, Genetic Variation, Proteins, Glucose Tolerance Test, medicine.disease, Adenylate Cyclase/genetics, Denmark%22">Type="Geographic">Denmark, Diabetes Mellitus, Type 2/genetics, Female, Gene Expression Regulation, Genetic Loci/genetics, Genome-Wide Association Study, Glucose/metabolism, Incretins/genetics, Insulin/metabolism, Polymorphism, Single Nucleotide/genetics, Proteins/genetics, RNA, Messenger/genetics, RNA, Messenger/metabolism, Receptors, Gastrointestinal Hormone/genetics, Receptors, Gastrointestinal Hormone/metabolism, Colaus Study, Glucagon-like peptide-1, Endocrinology, Glucose, Diabetes Mellitus, Type 2, Genetic Loci, TCF7L2, Adenylyl Cyclases
Abstract

Udgivelsesdato: 2010-Feb Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958-30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, beta (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 x 10(-15)). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 x 10(-17); ratio of insulin to glucose area under the curve, P = 1.3 x 10(-16)) and diminished incretin effect (n = 804; P = 4.3 x 10(-4)). We also identified variants at ADCY5 (rs2877716, P = 4.2 x 10(-16)), VPS13C (rs17271305, P = 4.1 x 10(-8)), GCKR (rs1260326, P = 7.1 x 10(-11)) and TCF7L2 (rs7903146, P = 4.2 x 10(-10)) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09-1.15, P = 4.8 x 10(-18)).

Published
2010

14. The effect of elinogrel on high platelet reactivity during dual antiplatelet therapy and the relation to CYP2C19*2 genotype: first experience in patients

Author

Mark J. Antonino, P. B. Conley, Kevin P. Bliden, M. M. Jurek, U. S. Tantry, Alan R. Shuldiner, Ruth E. Pakyz, Paul A. Gurbel, D. D. Gretler, and G. Stephens

Subjects
Male, Platelet Aggregation, Administration, Oral, Coronary Artery Disease, Pharmacology, P2Y12, Gene Frequency, Purinergic P2 Receptor Antagonists, Medicine, Cytochrome P-450 CYP3A, Angioplasty, Balloon, Coronary, Phosphorylation, Sulfonamides, Microfilament Proteins, Hematology, Middle Aged, Clopidogrel, Receptors, Purinergic P2Y12, Thrombelastography, Adenosine Diphosphate, Phenotype, Drug Therapy, Combination, Female, Stents, Aryl Hydrocarbon Hydroxylases, Collagen, Perfusion, medicine.drug, Blood Platelets, Ticlopidine, Genotype, CYP2C19, Pharmacokinetics, Humans, CYP3A5, Blood Coagulation, Aged, Quinazolinones, Polymorphism, Genetic, Aspirin, business.industry, Receptors, Purinergic P2, Phosphoproteins, Cytochrome P-450 CYP2C19, Pharmacodynamics, business, Elinogrel, Cell Adhesion Molecules, Platelet Aggregation Inhibitors
Abstract

Summary. To study the effect of a new direct acting reversible P2Y12 inhibitor, elinogrel (PRT060128), and the relation to cytochrome P450 (CYP) polymorphisms in patients with high platelet reactivity (HPR) on standard dual antiplatelet therapy. Methods and Results: We studied the pharmacodynamic and pharmacokinetic effects of a single 60-mg oral dose of elinogrel in 20 of 45 previously stented stable patients with HPR. We also genotyped for CYP2C19*2,3,5,17 and CYP3A5*3. Platelet reactivity fell within 4 h of dosing, the earliest time point evaluated as measured by the following assays: maximum 5 and 10 μm ADP LTA (P

Published
2009

15. Aspirin Resistance in Healthy Drug-Naïve Men versus Women (From the Heredity and Phenotype Intervention [HAPI] Heart Study)

Author

Ruth E. Pakyz, Mary Ann Drolet, Alan R. Shuldiner, Paul Sack, William R. Herzog, Kathleen A. Ryan, Sylvia Newcomer, Haiqing Shen, Yi-Ju Zhao, Braxton D. Mitchell, Xiaolian Shi, and Heidi Karon

Subjects
Adult, Male, medicine.medical_specialty, Platelet Aggregation, Drug Resistance, Hematocrit, Asymptomatic, Article, Cohort Studies, chemistry.chemical_compound, Sex Factors, Internal medicine, medicine, Prevalence, Humans, Platelet, Whole blood, Aspirin, medicine.diagnostic_test, business.industry, Middle Aged, Thromboxane B2, Drug-naïve, Endocrinology, Phenotype, chemistry, Platelet aggregation inhibitor, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Platelet Aggregation Inhibitors, medicine.drug
Abstract

This study was designed to determine the factors that contribute to interindividual variation in the antiplatelet effects of aspirin. We measured platelet response to aspirin in 745 (400 men and 345 women) drug-naive asymptomatic subjects of the Heredity and Phenotype Intervention (HAPI) Heart Study. Whole blood platelet aggregometry was performed to assess response to arachidonic acid, adenosine diphosphate, and collagen at baseline and after 14 days of aspirin 81 mg/day. There was wide interindividual variation in platelet aggregation in response to aspirin, with no clear biological threshold to define aspirin resistance. Variation in platelet function before and after aspirin was heritable. Women exhibited greater platelet aggregability in response to adenosine diphosphate and collagen at baseline and after aspirin administration. The degree to which aspirin inhibited collagen-induced platelet aggregation was also significantly less in women compared with men (mean +/- SD percent inhibition of collagen-induced [1 microg/ml] platelet aggregation 49.9 +/- 30.9 vs 57.5 +/- 42.5 in women and men, respectively, p = 0.005). Using a cutoff70% inhibition of collagen-induced platelet aggregation, 21% of the total population demonstrated aspirin resistance, which occurred in 30% of women and 16% of men (p = 0.0002). Aspirin-resistant subjects were older, had significantly higher total cholesterol and low-density lipoprotein cholesterol levels, lower hematocrit, and higher platelet count compared with aspirin-sensitive subjects. In conclusion, in this study group, platelet function is heritable. There is wide interindividual variation in platelet response to aspirin as defined by whole blood platelet aggregometry, with women having lower mean percent inhibition of platelet aggregation and greater prevalence of aspirin resistance than men.

Published
2009

16. The Effect of Various Degrees of Unilateral Spermatic Cord Torsion on Fertility in the Rat

Author

M. James Cosentino, Rachel M. Heindel, Ruth E. Pakyz, and Larry N. Reinking

Subjects
Male, medicine.medical_specialty, Time Factors, Urology, media_common.quotation_subject, Physiology, Fertility, Pregnancy, Fertility testing, Testis, otorhinolaryngologic diseases, Animals, Medicine, Spermatic Cord Torsion, Infertility, Male, Organ weight, media_common, business.industry, Torsion (gastropod), Fecundity, Rats, Surgery, body regions, Female, business
Abstract

Unilateral spermatic cord torsion has been shown to cause damage to the contralateral testis in humans and animal models. In an attempt to explain conflicts among various laboratories concerning the extent of this contralateral effect and to determine the importance of the extent of torsion, prepubertal rats (35 to 40 days) were subjected to unilateral spermatic cord torsion of various degrees (zero to 1440 degrees). Sham surgeries were performed and served as controls (0 degrees of torsion). The animals were allowed to recover from the surgeries and to attain puberty before a period of fertility testing. Fertility, fecundity, organ weight and testicular histological data were obtained after the breeding period. Our data indicate that animals undergoing 360 degrees of torsion exhibited no changes in the parameters studied. However, if 720 degrees, 1080 degrees or 1440 degrees of torsion was induced, a significantly lower percentage of fertile males and pregnant females resulted for each of these experimental groups when compared to those values for the 0 degrees controls. These data indicate that the extent of contralateral testicular degeneration is dependent upon the degree of spermatic cord torsion to which the ipsilateral testis is subjected. The induction of unilateral spermatic cord torsion at 720 degrees or more causes a significant reduction of subsequent fertility while torsion of a lesser degree has little or no effect in the development of this phenomenon.

Published
1990

17. Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits: A Multi-Ethnic Meta-Analysis of 45,891 Individuals

Author

Seppo Koskinen, Christian Herder, Daniel I. Chasman, Andrew R. Wood, Jonna L. Grimsby, J.F. Wilson, Day Inm., Massimo Mangino, Gonneke Willemsen, Robert W. Mahley, Cristian Pattaro, Nicole L. Glazer, T.B. Harris, Irene Pichler, M S Sandhu, D. van Heemst, Christine Proença, Martha Ganser, Robert A. Hegele, Richa Saxena, Eleftheria Zeggini, Markku Laakso, Peter Kraft, Judith B. Borja, Karen L. Mohlke, J B Richards, de Geus Ejc., Robert Sladek, Cristen J. Willer, Samy Hadjadj, S.M. Boekholdt, Gina M. Peloso, Kijoung Song, Sutapa Mukherjee, Gudmar Thorleifsson, Winston Hide, Mark I. McCarthy, Ruth E. Pakyz, Marian Beekman, Ayellet V. Segrè, Inga Prokopenko, Ping An, George Dedoussis, Danielle Posthuma, Jeanette Erdmann, Simon J. Griffin, Nilesh J. Samani, Inke R. König, Frank B. Hu, Lokki M-L., David M. Evans, Xiaohui Li, Valgerdur Steinthorsdottir, Aimo Ruokonen, A Pouta, Kerrin S. Small, Cecilia M. Lindgren, O Le Bacquer, Xijing Han, Florian Kronenberg, E Katsareli, Christian Dina, S. Gabriel, Jochen Spranger, James S. Pankow, M. Kloppenburg, Penninx Bwjh., Torben Hansen, Josh Smith, Jennie Hui, Gordon H. Williams, Mark Seielstad, Ingrid B. Borecki, Weihua Zhang, Peter P. Pramstaller, Stephen J. Sharp, Neil R. Robertson, Zee Ryl., Mike Sampson, Angela Silveira, C.M. van Duijn, Anders Hamsten, Peter Shrader, Denis Rybin, Chen Y-Di., Gunnar Sigurdsson, Michael Stumvoll, Russel Tracy, Mark O. Goodarzi, Göran Hallmans, Michael R. Erdos, Valeriya Lyssenko, Juha Saharinen, Sven Bergmann, Jeffrey R. O'Connell, Debbie A Lawlor, Thomas Meitinger, Yvonne Böttcher, Jérôme Delplanque, Sarah G. Buxbaum, Silvia Naitza, Shah Ebrahim, Graham A. Hitman, Angelo Scuteri, Aroon D. Hingorani, Heribert Schunkert, François Pattou, Claudia Lamina, A L Elliott, Sekar Kathiresan, Dawn M. Waterworth, Jennifer A. Brody, Thomas Quertermous, Leena Peltonen, Josephine M. Egan, Daniel J. Rader, J F Peden, Yarnell Jwg., Daniel S. 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Havulinna, Toby Johnson, Samuli Ripatti, Erik Ingelsson, Mario A. Morken, Carl G. P. Platou, Anke Tönjes, Qi Sun, Narisu Narisu, S J Bumpstead, Jose M. Ordovas, Alan B. Feranil, L Groop, P Chines, Sara M. Willems, Perry Jrb., Matthew A. Allison, Jan Scott, Cécile Lecoeur, Kastelein Jjp., Herman A. Taylor, Anyuan Cao, Christopher J. Groves, Lincoln D. Stein, Laura J. Scott, John Beilby, Kristin G. Ardlie, Christopher S. Franklin, Yoav Ben-Shlomo, B M Shields, N J Timpson, Marco Orrù, Amélie Bonnefond, Kiran Musunuru, Murielle Bochud, Udo Seedorf, Yongmei Liu, Guillaume Lettre, Lee J-Y., Alan R. Shuldiner, Ryan P. Welch, David J. Hunter, John Whitfield, Klaus Strassburger, Khaw K-T., Hartikainen A-L., Gunnar Sigurðsson, Lu Qi, Richard N. Bergman, G M Lathrop, Sigrid W. Fouchier, T van Herpt, David S. Siscovick, Igor Rudan, Richard M. Watanabe, Themistocles L. Assimes, Nicholas G. Martin, Ozren Polasek, Dhiraj Varma, K Kim, Oliver Hofmann, Nicholas D. Hastie, S Bumpstead, Jose C. 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S, Vitart, V, Vogelzangs, N, Waeber, G, Wagner, Pj, Walley, A, Ward, Kl, Watkins, H, Wild, Sh, Willemsen, G, Witteman, Jc, Yarnell, Jw, Zelenika, D, Zethelius, B, Zhai, G, Zhao, Jh, Zillikens, Mc, Diagram, Consortium, Giant, Consortium, Global B., Pgen Consortium, Borecki, Ib, Meneton, P, Magnusson, Pk, Nathan, Dm, Williams, Gh, Silander, K, Bornstein, Sr, Schwarz, P, Spranger, J, Karpe, F, Shuldiner, Ar, Cooper, C, Serrano Ríos, M, Lind, L, Palmer, Lj, Hu FB, 1st, Franks, Pw, Ebrahim, S, Marmot, M, Wright, Af, Stumvoll, M, Hamsten, A, Procardis, Consortium, Buchanan, Ta, Valle, Tt, Rotter, Ji, Penninx, Bw, Boomsma, Di, Cao, A, Scuteri, A, Schlessinger, D, Uda, M, Ruokonen, A, Jarvelin, Mr, Peltonen, L, Mooser, V, Magic, Investigator, Glgc, Consortium, Musunuru, K, Smith, Av, Edmondson, Ac, Stylianou, Im, Koseki, M, Pirruccello, Jp, Chasman, Di, Johansen, Ct, Fouchier, Sw, Peloso, Gm, Barbalic, M, Ricketts, Sl, Bis, Jc, Feitosa, Mf, Orho Melander, M, Melander, O, Li, X, Cho, Y, Go, Mj, Kim, Yj, Lee, Jy, Park, T, Kim, K, Sim, X, Ong, Rt, Croteau Chonka, Dc, Lange, La, Smith, Jd, Ziegler, A, Zhang, W, Zee, Ry, Whitfield, Jb, Thompson, Jr, Surakka, I, Smit, Jh, Sinisalo, J, Scott, J, Saharinen, J, Sabatti, C, Rose, Lm, Roberts, R, Rieder, M, Parker, An, Pare, G, O'Donnell, Cj, Nieminen, M, Nickerson, Da, Montgomery, Gw, Mcardle, W, Masson, D, Martin, Ng, Marroni, F, Lucas, G, Luben, R, Lokki, Ml, Lettre, G, Launer, Lj, Lakatta, Eg, Laaksonen, R, König, Ir, Khaw, Kt, Kaplan, Lm, Johansson, Å, Janssens, Ac, Igl, W, Hovingh, Gk, Hengstenberg, C, Havulinna, A, Hastie, Nd, Harris, Tb, Haritunians, T, Hall, A, Groop, Lc, Gonzalez, E, Freimer, Nb, Erdmann, J, Ejebe, Kg, Döring, A, Dominiczak, Af, Demissie, S, de Faire, U, Caulfield, Mj, Boekholdt, Sm, Assimes, Tl, Quertermous, T, Seielstad, M, Wong, Ty, Tai, E, Feranil, Ab, Kuzawa, Cw, Taylor HA, Jr, Gabriel, Sb, Holm, H, Gudnason, V, Krauss, Rm, Ordovas, Jm, Munroe, Pb, Tall, Ar, Hegele, Ra, Kastelein, Jj, Schadt, Ee, Strachan, Dp, Reilly, Mp, Samani, Nj, Schunkert, H, Cupples, La, Ridker, Pm, Rader, Dj, Kathiresan, S., Medical Research Council (MRC), Perry, John [0000-0001-6483-3771], Wareham, Nicholas [0000-0003-1422-2993], Langenberg, Claudia [0000-0002-5017-7344], Semple, Robert [0000-0001-6539-3069], Griffin, Simon [0000-0002-2157-4797], Barroso, Ines [0000-0001-5800-4520], Soranzo, Nicole [0000-0003-1095-3852], Wheeler, Eleanor [0000-0002-8616-6444], Luan, Jian'an [0000-0003-3137-6337], Forouhi, Nita [0000-0002-5041-248X], Sharp, Stephen [0000-0003-2375-1440], Sovio, Ulla [0000-0002-0799-1105], Zhao, Jing Hua [0000-0003-4930-3582], Luben, Robert [0000-0002-5088-6343], Khaw, Kay-Tee [0000-0002-8802-2903], Sandhu, Manjinder [0000-0002-2725-142X], Apollo - University of Cambridge Repository, Biological Psychology, Functional Genomics, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Lifestyle, Overweight and Diabetes, Other departments, Experimental Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Cardiology, Human genetics, Psychiatry, NCA - Attention & Cognition, EMGO - Lifestyle, overweight and diabetes, Lääketieteen yksikkö - School of Medicine, University of Tampere, Institute for Molecular Medicine Finland, Hjelt Institute (-2014), Clinicum, Department of General Practice and Primary Health Care, Department of Public Health, Haartman Institute (-2014), Transplantation Laboratory, Biostatistics Helsinki, Quantitative Genetics, Complex Disease Genetics, Genetic Epidemiology, DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Procardis Consortium, MAGIC investigators, GLGC Consortium, Olson, J., Kronmal, R., Robbins, J., Chaves, PH., Burke, G., Kuller, LH., Tracy, R., Gottdiener, J., Prineas, R., Becker, JT., Enright, P., Klein, R., and O'Leary, DH.

Subjects
Netherlands Twin Register (NTR), Male, Insulin Resistance/genetics, VARIANTS, 0302 clinical medicine, POPULATION, African Americans, blood/genetics, 0303 health sciences, education.field_of_study, Adiponectin/blood, Adiponectin/genetics, Asian Continental Ancestry Group, Cholesterol, HDL/genetics, Diabetes Mellitus, Type 2/genetics, European Continental Ancestry Group, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucose Tolerance Test, Humans, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Waist-Hip Ratio, Global B Pgen Consortium, MAGIC investigators, 3. Good health, Cholesterol, Medicine, Adiponectin, Type 2, medicine.medical_specialty, HDL, Biolääketieteet - Biomedicine, Single-nucleotide polymorphism, DIAGRAM Consortium, White People, Molecular Genetics, GLGC Consortium, 03 medical and health sciences, Asian People, SDG 3 - Good Health and Well-being, GIANT Consortium, Diabetes Mellitus, Genetics, DIAGRAM+ Consortium, GENOME-WIDE ASSOCIATION, Polymorphism, education, Biology, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 0604 Genetics, Science & Technology, GLGC Investigators, nutritional and metabolic diseases, ta3121, medicine.disease, Obesity, Black or African American, blood/genetics, African Americans, Asian Continental Ancestry Group, Cholesterol, genetics, Diabetes Mellitus, genetics, European Continental Ancestry Group, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Glucose Tolerance Test, Humans, Insulin Resistance, genetics, Male, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Waist-Hip Ratio, Endocrinology, Diabetes Mellitus, Type 2, Developmental Biology, Type 2/genetics, Cancer Research, Type 2 diabetes, QH426-470, 030204 cardiovascular system & hematology, LIPID CONCENTRATIONS, GENETICS & HEREDITY, Genetics (clinical), RISK, 2. Zero hunger, INSULIN-RESISTANCE, Glucose tolerance test, medicine.diagnostic_test, MAGIC Consortium, Single Nucleotide, ADIPOSE-TISSUE, CORONARY-ARTERY-DISEASE, Life Sciences & Biomedicine, Research Article, Clinical Research Design, GENETIC-BASIS, Population, Insulin resistance, Internal medicine, Diabetes mellitus, medicine, ddc:610, 030304 developmental biology, RECEPTOR, Cholesterol, HDL, Human Genetics, HDL/genetics, 3121 General medicine, internal medicine and other clinical medicine, MuTHER Consortium, 3111 Biomedicine, Procardis Consortium, Insulin Resistance
Abstract

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8–1.2×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p, Author Summary Serum adiponectin levels are highly heritable and are inversely correlated with the risk of type 2 diabetes (T2D), coronary artery disease, stroke, and several metabolic traits. To identify common genetic variants associated with adiponectin levels and risk of T2D and metabolic traits, we conducted a meta-analysis of genome-wide association studies of 45,891 multi-ethnic individuals. In addition to confirming that variants at the ADIPOQ and CDH13 loci influence adiponectin levels, our analyses revealed that 10 new loci also affecting circulating adiponectin levels. We demonstrated that expression levels of several genes in these candidate regions are associated with serum adiponectin levels. Using a powerful novel method to assess the contribution of the identified variants with other traits using summary-level results from large-scale GWAS consortia, we provide evidence that the risk alleles for adiponectin are associated with deleterious changes in T2D risk and metabolic syndrome traits (triglycerides, HDL, post-prandial glucose, insulin, and waist-to-hip ratio), demonstrating that the identified loci, taken together, impact upon metabolic disease.

Published
2012

18. Association of Cytochrome P450 2C19 Genotype With the Antiplatelet Effect and Clinical Efficacy of Clopidogrel Therapy

Author

William R. Herzog, Richard B. Horenstein, Kathleen A. Ryan, Braxton D. Mitchell, Kevin P. Bliden, Jeffrey R. O'Connell, Alan R. Shuldiner, Afshin Parsa, Quince Gibson, Nauder Faraday, Udaya S. Tantry, Coleen M. Damcott, Wendy S. Post, Toni I. Pollin, Amish Gandhi, Paul A. Gurbel, and Ruth E. Pakyz

Subjects
Adult, Male, medicine.medical_specialty, Ticlopidine, Genotype, Platelet Aggregation, medicine.medical_treatment, Coronary Artery Disease, CYP2C19, Polymorphism, Single Nucleotide, Coronary artery disease, Internal medicine, Ethnicity, medicine, Humans, cardiovascular diseases, Platelet activation, Angioplasty, Balloon, Coronary, Aged, Clinical Trials as Topic, Chromosomes, Human, Pair 10, business.industry, Percutaneous coronary intervention, General Medicine, Middle Aged, Clopidogrel, medicine.disease, Surgery, Cytochrome P-450 CYP2C19, Treatment Outcome, Pharmacogenetics, Cardiology, Platelet aggregation inhibitor, Female, Aryl Hydrocarbon Hydroxylases, business, Elinogrel, Platelet Aggregation Inhibitors, Genome-Wide Association Study, medicine.drug
Abstract

Clopidogrel therapy improves cardiovascular outcomes in patients with acute coronary syndromes and following percutaneous coronary intervention by inhibiting adenosine diphosphate (ADP)-dependent platelet activation. However, nonresponsiveness is widely recognized and is related to recurrent ischemic events.To identify gene variants that influence clopidogrel response.In the Pharmacogenomics of Antiplatelet Intervention (PAPI) Study (2006-2008), we administered clopidogrel for 7 days to 429 healthy Amish persons and measured response by ex vivo platelet aggregometry. A genome-wide association study was performed followed by genotyping the loss-of-function cytochrome P450 (CYP) 2C19*2 variant (rs4244285). Findings in the PAPI Study were extended by examining the relation of CYP2C19*2 genotype to platelet function and cardiovascular outcomes in an independent sample of 227 patients undergoing percutaneous coronary intervention.ADP-stimulated platelet aggregation in response to clopidogrel treatment and cardiovascular events.Platelet response to clopidogrel was highly heritable (h(2) = 0.73; P.001). Thirteen single-nucleotide polymorphisms on chromosome 10q24 within the CYP2C18-CYP2C19-CYP2C9-CYP2C8 cluster were associated with diminished clopidogrel response, with a high degree of statistical significance (P = 1.5 x 10(-13) for rs12777823, additive model). The rs12777823 polymorphism was in strong linkage disequilibrium with the CYP2C19*2 variant, and was associated with diminished clopidogrel response, accounting for 12% of the variation in platelet aggregation to ADP (P = 4.3 x 10(-11)). The relation between CYP2C19*2 genotype and platelet aggregation was replicated in clopidogrel-treated patients undergoing coronary intervention (P = .02). Furthermore, patients with the CYP2C19*2 variant were more likely (20.9% vs 10.0%) to have a cardiovascular ischemic event or death during 1 year of follow-up (hazard ratio, 2.42; 95% confidence interval, 1.18-4.99; P = .02).CYP2C19*2 genotype was associated with diminished platelet response to clopidogrel treatment and poorer cardiovascular outcomes.

Published
2009

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