Translating pharmacogenetics to primary care
Swen, J.J.
Citation
Swen, J. J. (2011, December 21). Translating pharmacogenetics to primary care. Retrieved from https://hdl.handle.net/1887/18263
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General Introduction 1
Drug response is a complex trait that shows significant interpatient variability. It has been suggested that response rates to major therapeutic classes of drugs range from 25 to 60 percent [1]. To a certain extent this variability may be explained by genetic variation. The concept of interindividual differences in drug response was proposed as early as 1909 [2]. However, current clinical practice hardly considers genetic variation a relevant factor during the processes of drug prescribing and dispensing. Pharmacogenetics is the study of variations in DNA sequence as related to drug response [3]. The ultimate goal of pharmacogenetics is to predict and thereby improve drug response in the individual patient.
After the completion of the Human Genome Project in 2003, genomics has become a mainstay of biomedical research and pharmacogenetics has been forecasted to be one of the first clinical applications arising from the new knowledge [4]. Indeed, the research efforts in the field of pharmacogenetics expressed as the number of publications listed on PubMed have steadily increased until leveling out in 2009 at 1100-1200 publication per year (Figure 1.1) [5].
By contrast, the clinical use of pharmacogenetic testing did not meet the initial high expectations and has lagged considerably behind, despite the significant body of evidence supporting its usefulness. As a result of the unmet promises many clinicians have become somewhat disillusioned regarding pharmacogenetics in recent years. Indeed, expectations of the effect of a single polymorphism on drug response were unrealistically high [6]. Still, pharmacogenetics holds the promise of advancing drug therapy.
The aim of this thesis is to identify the reasons for the slow clinical translation of pharmacogenetics and to explore and expand possible solutions to address these obstacles.
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Figure 1.1 Hits on PubMed using the search string “pharmacogenetics OR pharmacogenomics”.
Basic principles of pharmacogenetics
A gene is a part of the DNA that codes for a type of protein or for a RNA chain that has a specific function in the organism. There are two alleles per autosomal gene (one paternal and one maternal) with one allele on each of the two chromosomes of a chromosome pair [7]. Together the two alleles form the genotype. Heterozygotes have two different alleles, and homozygotes have two of the same alleles. Genetic variation can consist of deletions, insertions, inversions, and copy number variation [8]. Most sequence variations are single nucleotide polymorphisms (SNPs), a single DNA base pair substitution that may result in a different gene product. As a result of this genetic variation many genes have multiple variants. The most common allele in a population is referred to as the wild type. Some of the variant alleles code for non-functional or decreased functional proteins.
Allele frequencies can vary greatly in different ethnic populations. Phenotype refers to the trait resulting from the protein product encoded by the gene.
Outline of the thesis
This thesis is divided into four parts. The first part aims at identifying obstacles and possible solutions for the clinical implementation of pharmacogenetics. In the second part, issues related to the quality control of pharmacogenetic testing are discussed. In the third part the influence of genetic variation on the response to sulfonylureas (SUs), a class of commonly used oral antidiabetic drugs used in the treatment of Type 2 diabetes mellitus (T2DM) patients, is used as a case model to investigate the possibilities for pharmacogenetics in primary care. The fourth part contains the general discussion and summary.
In Chapter 2 possible obstacles for the clinical implementation of pharmacogenetics are investigated and solutions to overcome these obstacles are identified. In the next chapter one of the identified solutions, the development of clinical guidelines to aid the use of pharmacogenetic tests, is investigated in detail (Chapter 3). Chapter 4 describes the results of a pilot experiment to investigate the technical feasibility of pharmacogenetic screening in primary care. In this chapter also the potential impact of the pharmacogenetic guidelines described in Chapter 3 is investigated.
The application of pharmacogenetics in clinical practice may result in the adjustment of
treatment of individual patients. Therefore, genotyping of patients in a routine clinical
setting requires robust and reliable genotyping methods and good quality control is of great
importance. Chapter 5 discusses the use of plasmid-derived samples as quality controls. A
second issue related to quality control of pharmacogenetic tests is the exclusion of SNPs
because of poor genotyping. Several studies have reported difficulties in genotyping
rs757210, a SNP in the gene coding for hepatocyte nuclear factor 1β. Chapter 6 describes
our experiments to find alternative methods to genotype this SNP.
The third part of this thesis is devoted to the investigation of the influence of genetic variation on the response to SUs. SUs are part of the mainstay of treatment with oral antidiabetic drugs. We selected SU treatment as a case model to investigate the potential role of pharmacogenetics in primary care for three reasons. First, most T2DM patients are treated in primary care. Secondly, there is significant interpatient variability in response to SUs, with approximately 10-20% of the patients experiencing primary failure. Thirdly, SUs are metabolized by the polymorphic enzyme CYP2C9. This enzyme also plays an important role in the metabolism of many other drugs frequently used in primary care.
Chapter 7 describes the application of the classic candidate gene approach to investigate the effect of SNPs in CYP2C9 on the response to SUs. In Chapter 8 a different approach is applied. In 2007, multiple T2DM risk alleles have been identified from genome-wide association studies. From the identified T2DM risk alleles a panel of 20 consistently replicated SNPs appears of which the majority has been associated with the process of insulin release from the pancreatic beta-cells. We hypothesized that this panel of 20 SNPs not only confers to an increased risk for T2DM but also influences response to SU treatment. Finally the results from the presented studies are put into perspective and a future outlook is described in Chapter 9.
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REFERENCES
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JAMA 2001;285(5):540-544.
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