Proefschrift Bas Nieuw Def.Indd

METHODOLOGICAL APPROACHES TO THE PHARMACOGENOMICS OF STATINS Bas Peters Photographs cover: MJ Photography (front) and Don Vladimir (back) (www.Istockphoto.com) Cover Design: Lodewijk Slippens Lay-out: Bas Verweij Printed by: Optima Grafische Communicatie, Rotterdam The work presented in this thesis was performed at the Division of Pharmacoepidemiology and Clinical Pharmacology of the Utrecht Institute for Pharmaceutical Sciences (UIPS), Faculty of Science, Utrecht University. The contributions of the study participants, pharmacists and other health care providers involved to the Utrecht Cardiovascular Pharmacogenetics studies are gratefully acknowledged. CIP-gegevens Koninklijke Bibliotheek, Den Haag Peters, B.J.M. Methodological approaches to the pharmacogenomics of statins Thesis Utrecht University – with ref. – with summary in Dutch ISBN/EAN: 978-90-8559-277-8 © 2010 B.J.M. Peters METHODOLOGICAL APPROACHES TO THE PHARMACOGENOMICS OF STATINS METHODOLOGISCHE BENADERINGEN TER BESTUDERING VAN DE FARMACOGENETICA VAN STATINES (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. J.C. Stoof, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op maandag 21 december 2010 des middags te 4.15 uur door Bas Johannes Maria Peters Geboren op 28 september 1982 te Veghel Promotor Prof.dr. A. de Boer Co-promotoren Dr. A.H. Maitland-van der Zee Dr. O.H. Klungel CONTENTS 7 1. General Introduction 11 2. Background papers 2.1 Pharmacogenetics of cardiovascular drug therapy 2.2 Methodological and statistical issues in pharmacogenomics 53 3. Single SNP candidate gene approach to the pharmacogenetics of statins 3.1 Effectiveness of statins in the reduction of the risk of myocardial infarction is modified by the GNB3 C825T variant 3.2 The effect of nine common polymorphisms in coagulation factor genes (F2, F5, F7, F12 and F13) on the effectiveness of statins: the GenHAT study 81 4. Tagging SNP candidate gene/pathway approach to the pharmacogenetics of statins 4.1 Pharmacogenetic interactions between ABCB1 and SLCO1B1 tagging SNPs and the effectiveness of statins in the prevention of myocardial infarction 4.2 Variants of ADAMTS1 modify the effectiveness of statins in reducing the risk of myocardial infarction 4.3 The PCSK9 E670G variant and reduced statin effectiveness 131 5. Cosmopolitan tagging approach of cardiovascular implicated loci and the response to statins 5.1 A cardiovascular gene-centric 50 K SNP array and the response to statins: A pilot study 141 6. Genetics of statin-induced myopathy 6.1 Pharmacogenomic insights into treatment and management of statin-induced myopathy 6.2 The SLCO1B1 gene and discontinuation of statin treatment 159 7. General discussion 175 8. Summary/Samenvatting 183 9. Dankwoord/List of publications/About the author GENERAL 1INTRODUCTION GENERAL INTRODUCTION GENERAL INTRODUCTION Around 1900, the relationship between genes and proteins, and the phenomena of biochemical individuality of humans was first proposed by the British physician Garrod. Long after, it was postulated that genetic variations could affect response to drugs, a phenomenon called pharmacogenetics.1 Throughout the second half of the 20th century, an increasing number of pharmacogenetic discoveries have been reported over time. Starting point was the discovery of N-acetyltransferase 2 (encoded by NAT2) variability and the capacity to N-acetylate isoniazid in the early 1950s. Soon after, glucose-6-phosphat dehydrogenase (encoded by G6PD) deficiency, pseudocholinesterase deficiency, cytochrome P450 2D6 (encoded by CYP2D6) and thiopurine methyltransferase (encoded by TPMT) were linked to interindividual variability in response to a variety of drugs. The invention of the polymerase chain reaction (PCR) in 1983 by Nobel Prize winner Kary Mullis heralded a new era in (pharmaco)genetics. The PCR made it possible to identify disease loci and to investigate responders and non-responders to drugs based on their genotype rather than their phenotype. A fair amount of articles in the field of pharmacogenetics of cardiovascular medicine have been published in the 90’s. These studies included mostly a one Single Nucleotide Polymorphism (SNP) in a candidate gene that was hypothesized to affect the response to the drug of interest. With the introduction of relatively cheap high throughput genotyping techniques and the launching of the human genome project2 and International HapMap Project,3 the start of the 21st century was characterized by a tremendous surge in the field of (pharmaco)genetic research.4 METHODOLOGICAL CHALLENGES IN PHARMACOGENETIC RESEARCH Discovery of the promising CETP taq1B and ADD1 Gly460Trp treatment interactions, with the cholesterol lowering drug pravastatin5 and the antihypertensive agent hydrochlorothiazide,6 respectively, initially led to speculations about genotype guided pharmacotherapy. However, numerous subsequent studies that have been published to date have still not been able to pass judgment on the exact role of these polymorphisms in the efficacy of these widely prescribed cardiovascular drugs. Unfortunately, non replication and inconclusiveness about the exact mechanism and implication of many pharmacogenetic interactions seems to be more the rule than the exception. On a brighter note, there are also successful examples of pharmacogenetic research such as the aforementioned (TPMT, CYP2D6, and G6PD) examples. Another successful example of explaining interindividual variability in response to the anticoagulants coumarins with genetics, is the implication of the metabolizing enzyme encoded by CYP2C9 that has consistently been associated with drug safety.7 In fact, genotype guided coumarin dosing has already been tested in a small trial.8 Current pharmacogenetic research greatly benefits from the advances in technology. Nonetheless, the problem of non replication and inconclusiveness about many pharmacogenetic interaction remains present. This common pattern may be attributed to a range of characteristics of the pharmacogenetic research that has been conducted to date, among which power problems, small magnitude of effects, (single) SNP approach, poor understanding of biological mechanisms, and study design. 8 GENERAL INTRODUCTION PHARMACOGENETICS OF STATINS Worldwide, statins are among the most prescribed drugs. Statins are highly effective in reducing the risk of cardiovascular events,9 primarily by lowering low density lipoprotein (LDL) cholesterol. In addition, there is overwhelming evidence that statins do not solely lower cholesterol, but also exert beneficial non-lipid or pleiotropic effects,10 with anti- inflammatory actions as the principal component. The most convincing example for statin pharmacogenetics involves the APOE gene: Carriers of the APOE2 allele may have a better LDL response to statin treatment compared to APOE3 and/or APOE4 carriers.11 However, the field of the pharmacogenetics of statins is no exception with respect to the aforementioned challenges that pharmacogenetic research is facing.11 It is recognized that future research will have to find a way to combine different methods and different disciplines to make real progress. Certainly, much progress has been made, but the scientific community realizes full well that genetics comes with great complexity. Therefore new initiatives are needed that combine genomics with disciplines such as epigenetics, proteomics, bioinformatics, etcetera to aim for a system’s biology approach. OBJECTIVES OF THIS THESIS The subject of this thesis is “methodological approaches to the pharmacogenetics of statins”. The first main objective is to study common genetic variability in genes involved in the pharmacokinetics, cholesterol lowering pathway of statins, the non-lipid pathway of statins, and cardiovascular candidate genes in more general for modification of the response to statins. The response of statin includes both the protective effect of statins against myocardial infarction (MI) and the risk of discontinuation (as a proxy for adverse drug reactions/ineffectiveness). The second main objective is to test and improve new methods that can be used in multi-locus approaches in (pharmaco-) genetic research. OUTLINE OF THIS THESIS This thesis starts off with a review of the current knowledge of the pharmacogenetics of the four mostly prescribed cardiovascular drugs (coumarins, statins, antihypertensives, and platelet aggregation inhibitors). In addition, the same chapter describes a review of the methodological and statistical challenges pharmacogenetics research is facing. Chapter 3 focuses on Single Nucleotide Polymorphisms (SNPs) that are candidates for modification of statin effectiveness. In Chapter 3.1, we conducted an observational study to investigate the effect of the well known functional C825T polymorphism in the G protein beta polypeptide 3 (GNB3) gene. In Chapter 3.2, nine SNPs in coagulation genes were tested for their effect on statin effectiveness in a post-hoc analysis of the Genetics of Hypertension Associated Treatment (GenHAT) trial. Chapter 4 describes studies that consider all common variability in candidate genes within the pharmacokinetic, cholesterol lowering, and non-lipid pathway of statins, for the pharmacogenetics of statins, instead of a single SNP approach as described in Chapter 3. The pathways that are included in Chapter 4.1, 4.2, and 4.3 are a pharmacokinetic, anti-inflammatory, and cholesterol

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