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Pharmacogenetics in Warfarin Therapy

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Pharmacogenetics in Warfarin Therapy PHARMACOGENETICS IN WARFARIN THERAPY Thesis submitted in accordance with the requirements of the University of Liverpool for the degree of Doctor in Philosophy by Azizah Ab Ghani December 2013 DECLARATION This thesis is the result of my own work. The material contained within this thesis has not been presented, nor is currently being presented, either wholly or in part for any other degree of qualification. Azizah Ab Ghani This research was carried out in the Department of Molecular and Clinical Pharmacology, in the Institute of Translational Medicine, at The University of Liverpool ii CONTENTS ABSTRACT iv ACKNOWLEGEMENTS v ABBREVIATIONS vi CHAPTER 1: General introduction 1 CHAPTER 2: Development and validation of a warfarin dosing algorithm 47 CHAPTER 3: Incorporating genetic factor into HAS-BLED, a bleeding risk score 75 CHAPTER 4: Pharmacogenetics of warfarin in a paediatric population 102 CHAPTER 5: Warfarin pharmacogenetic in children: A genome-wide association study 135 CHAPTER 6: Validation of a novel point of care Hybeacon® genotyping method on prototype PCR instrument Genie 1 for CYP2C9 and VKORC1 alleles 155 CHAPTER 7: Final discussion 178 BIBLIOGRAPHY 189 iii ABSTRACT Warfarin is a challenging drug to dose accurately, especially during the initiation phase because of its narrow therapeutic range and large inter-individual variability. Therefore, the aim of this thesis was to investigate the use of pharmacogenetics and clinical data to improve warfarin therapy. Genetic variants in cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) are known to influence warfarin dose. Therefore we developed a pharmacogenetic dosing algorithm to predict warfarin stable dose prospectively in a British population based on 456 patients who started warfarin in a hospital setting and validated it in 262 retrospectively recruited patients from a primary care setting. The pharmacogenetic algorithm which included CYP2C9*2, CYP2C9*3 and VKORC1-1693 together with body surface area, age and concomitant amiodarone use, explained 43% of warfarin dose variability. The mean absolute error of the dose predicted by the algorithm was 1.08 mg/day (95% CI 0.95-1.20). 49.6% of patients were predicted accurately (predicted dose fell within 20% of the actual dose). The HAS-BLED score, a bleeding risk score has recently been suggested for use in the management of patients with atrial fibrillation. We validated HAS-BLED performance in predicting major bleeding using a prospective cohort with 6 months follow-up (n=482) (c-statistic 0.80 95% CI (0.71-0.90). Factors significantly associated with major bleeding in our cohort (p≤0.1) were concurrent amiodarone use, labile INR, concurrent clopidogrel use, bleeding predisposition, concurrent aspirin use and CYP2C9*3. Adding a genetic covariate (CYP2C9*3) to the HAS-BLED score did not significantly improve its performance in predicting major bleeding. Considering CYP2C9*3 is a rare allele, our study was underpowered and requires further investigation in a larger cohort. A retrospective study of 97 Caucasian children was conducted to gain greater understanding of the factors that affect warfarin anticoagulant control and response in children. Results from multiple regression analysis of genetic and non-genetic factors showed that indication for treatment (Fontan or non-Fontan group), VKORC1 -1693, and INR group explained 20.8% of variability in proportion time in which INR measurements fell within the target range (PTTR); CYP2C9*2 explained 6.8% of the variability in INR exceeding target range within the first week of treatment; CYP2C9*2, VKORC1 -1693, age and INR group explained 41.4% of warfarin dose variability and VKORC1 -1693 explained 8.7% of haemorrhagic events. The contributions of CYP2C9 and VKORC1 polymorphism were small in the above outcomes. We therefore went onto explore other genetic markers using genome-wide scanning. Two SNPs on chromosome 5, rs13167496 and rs6882472 were found to be significantly associated at a genome-wide significance level with PTIR. However, none of SNPs were significantly associated with warfarin stable dose, INR values exceeding the target range within the first week of treatment and bleeding complications. Because of our small sample size, these findings will need to be validated in a replication cohort. Finally, we have validated and evaluated the performance of Genie HyBeacon®, a point of care therapy (POCT) instrument to genotype 135 samples for CYP2C9*2, CYP2C9*3 and VKORC1 -1693. We showed that the instrument accuracy was >98% (agreement with ABI Taqman® genotyping), it was relatively simple to use and had a good turn-around time (1.6 hours) making it suitable for clinical use. In conclusion, the results presented in this thesis demonstrate how knowledge of pharmacogenetics may help in assessing improvement in the quality of care of patients on warfarin. However, for personalized medicine to be widely adopted in clinical practice, payers need evidence of clinical- and cost-effectiveness. How such evidence is produced and evaluated varies in different healthcare settings, which further increases the challenge of implementing personalised medicine into the clinic. iv ACKNOWLEDGEMENT First and foremost, I would like to express my sincere gratitude to my supervisors Professor Munir Pirmohamed, Dr Andrea Jorgensen and Dr Ana Alfirevic for all their invaluable support, assistance and guidance throughout my PhD studies. Their expertise and directions enabled me to complete the work presented in this thesis. I would also like to acknowledge the Malaysia Ministry of Health for giving me the funding. My special thanks to Dr Eunice Zhang for her invaluable assistance, encouragement, advice and helpful suggestion throughout my degree. A big thank you to all the clinicians and nurses and the patients for taking part in the study, without whom, the study would never have never been possible. Many thanks to Dr Laura Sutton who provided superb statistical expertise with all analysis undertaken in children study. I am also grateful for support, friendship and assistance in the lab offered by the other members of The Wolfson Centre for Personalised Medicine. You have all made my stay in Liverpool unforgettable. Finally, words of thanks will never enough for my husband for his patience, sacrifice and tremendous support throughout the project until completion of this thesis. My love and thanks also goes to my children who give me strength and courage to go on. Lastly but not the least, I owe deep gratitude towards my family especially my beloved mum and dad for their endless support, patience and encouragement throughout this research work. v ABBREVIATION ABCB1 ATP binding cassette, subfamily B, member 1 AF atrial fibrillation bp base pairs CALU calumenin CEU Caucasians in Utah, USA CHB Han Chinese in Beijing, China CI confidence interval CIVC cysteine132-isoleucine-valine-cysteine135 CPIC Clinical Pharmacogenetics Implementation Consortium CYP1A1 cytochrome P450, family 1, subfamily A, polypeptide 1 CYP1A2 cytochrome P450, family 1, subfamily A, polypeptide 2 CYP2C18 cytochrome P450, family 2, subfamily C, polypeptide 18 CYP2C19 cytochrome P450, family 2, subfamily C, polypeptide 19 CYP2C8 cytochrome P450, family 2, subfamily C, polypeptide 8 CYP2C9 cytochrome P450, family 2, subfamily C, polypeptide 9 CYP3A4 cytochrome P450, family 3, subfamily A, polypeptide 4 CYP3A5 cytochrome P450, family 3, subfamily A, polypeptide 5 CYP4F2 cytochrome P450, family 4, subfamily F, polypeptide 12 DNA deoxyribonucleic acid EDTA ethylenediaminetetraacetic acid EPHX1 epoxide hydrolase 1 Factor II/FII coagulation factor 2 Factor IX/FIX coagulation factor 9 Factor VII/FVII coagulation factor 7 Factor X/FX coagulation factor 10 FDA Food and Drug Administration GGCX -glutamyl carboxylase GGCX gamma-glutamyl carboxylase gla gamma-carboxyglutamic acid glu glutamic acid vi GWAS genome-wide association study HWE hardy–weinberg equilibrium IBD identity by descent INR international normalised ratio - ratio IWPC International Warfarin Pharmacogenetics Consortium JPT Japanese in Tokyo, Japan K1 vitamin K1 (phyloquinone) KH2 reduced vitamin K, or hydroquinone KH2 reduced vitamin K or hydroquinone KO vitamin K 2,3 epoxide (oxidised vitamin K) LD linkage disequilibrium MAF minor allele frequency MK-4 vitamin K2 (Menoquinone or MK-n) homologous. MK-n has a variables side chain length of isoprene units an ‘n’ stands for the number of isoprenoid residues in the chain M-PVA polyvinyl alcohol particles NCBI National Center for Biotechnology Information NSAIDs nonsteriodal anti-inflammatory drugs OAC oral anticoagulant PBX3 Pre-B-Cell Leukemia Homeobox 3 PCR polymerase chain reaction POCT point of care therapy PTTR percentage or proportion time that a patient was within targeted therapeutic range RCT randomised control trial RCT randomised controlled trial ROC receiver operating curves SNPs single polymorphisms ST18 Suppression of tumorigenicity 18 TF tissue factor TIFAB TRAF-Interacting Protein With Forkhead-Associated Domain, Family Member B VKA vitamin K anticoagulant vii VKORC vitamin K epoxide reductase complex YRI Yoruba in Ibadan, Nigeria viii Chapter 1 General Introduction 1 CHAPTER 1 CONTENTS 1.1 THE GENETIC BASIS OF INTER-INDIVIDUAL DIFFERENCES IN DRUG RESPONSE .......... 3 1.1.1 Genetic variants ........................................................................................... 3 1.1.2 Pharmacogenetics and pharmacogenomics ................................................. 4 1.2 WARFARIN
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