Ellen M. McDonagh

Pharmacogenomics Knowledge for Personalized Medicine

The Pharmacogenomics Knowledgebase (PharmGKB) is a resource that collects, curates, and disseminates information about the impact of human genetic variation on drug responses. It provides clinically relevant information, including dosing guidelines, annotated drug labels, and potentially actionable gene–drug associations and genotype–phenotype relationships. Curators assign levels of evidence to variant–drug associations using well‐defined criteria based on careful literature review. Thus, PharmGKB is a useful source of high‐quality information supporting personalized medicine–implementation projects.

Incorporation of pharmacogenomics into routine clinical practice: the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline development process.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes genotype-based drug guidelines to help clinicians understand how available genetic test results could be used to optimize drug therapy. CPIC has focused initially on well-known examples of pharmacogenomic associations that have been implemented in selected clinical settings, publishing nine to date. Each CPIC guideline adheres to a standardized format and includes a standard system for grading levels of evidence linking genotypes to phenotypes and assigning a level of strength to each prescribing recommendation. CPIC guidelines contain the necessary information to help clinicians translate patient-specific diplotypes for each gene into clinical phenotypes or drug dosing groups. This paper reviews the development process of the CPIC guidelines and compares this process to the Institute of Medicine’s Standards for Developing Trustworthy Clinical Practice Guidelines.

Nomenclature for alleles of the thiopurine methyltransferase gene

The drug-metabolizing enzyme thiopurine methyltransferase (TPMT) has become one of the best examples of pharmacogenomics to be translated into routine clinical practice. TPMT metabolizes the thiopurines 6-mercaptopurine, 6-thioguanine, and azathioprine, drugs that are widely used for treatment of acute leukemias, inflammatory bowel diseases, and other disorders of immune regulation. Since the discovery of genetic polymorphisms in the TPMT gene, many sequence variants that cause a decreased enzyme activity have been identified and characterized. Increasingly, to optimize dose, pretreatment determination of TPMT status before commencing thiopurine therapy is now routine in many countries. Novel TPMT sequence variants are currently numbered sequentially using PubMed as a source of information; however, this has caused some problems as exemplified by two instances in which authors’ articles appeared on PubMed at the same time, resulting in the same allele numbers given to different polymorphisms. Hence, there is an urgent need to establish an order and consensus to the numbering of known and novel TPMT sequence variants. To address this problem, a TPMT nomenclature committee was formed in 2010, to define the nomenclature and numbering of novel variants for the TPMT gene. A website (http://www.imh.liu.se/tpmtalleles) serves as a platform for this work. Researchers are encouraged to submit novel TPMT alleles to the committee for designation and reservation of unique allele numbers. The committee has decided to renumber two alleles: nucleotide position 106 (G>A) from TPMT*24 to TPMT*30 and position 611 (T>C, rs79901429) from TPMT*28 to TPMT*31. Nomenclature for all other known alleles remains unchanged.

Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for human leukocyte antigen B (HLA-B) genotype and allopurinol dosing: 2015 update.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for HLA‐B*58:01 Genotype and Allopurinol Dosing was originally published in February 2013. We reviewed the recent literature and concluded that none of the evidence would change the therapeutic recommendations in the original guideline; therefore, the original publication remains clinically current. However, we have updated the Supplemental Material and included additional resources for applying CPIC guidelines into the electronic health record. Up‐to‐date information can be found at PharmGKB (http://www.pharmgkb.org).

Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for rasburicase therapy in the context of G6PD deficiency genotype.

Glucose‐6‐phosphate dehydrogenase (G6PD) deficiency is associated with development of acute hemolytic anemia (AHA) induced by a number of drugs. We provide guidance as to which G6PD genotypes are associated with G6PD deficiency in males and females. Rasburicase is contraindicated in G6PD‐deficient patients due to the risk of AHA and possibly methemoglobinemia. Unless preemptive genotyping has established a positive diagnosis of G6PD deficiency, quantitative enzyme assay remains the mainstay of screening prior to rasburicase use. The purpose of this article is to help interpret the results of clinical G6PD genotype tests so that they can guide the use of rasburicase. Detailed guidelines on other aspects of the use of rasburicase, including analyses of cost‐effectiveness, are beyond the scope of this document. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines are published and updated periodically on https://www.pharmgkb.org/page/cpic to reflect new developments in the field.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Ivacaftor Therapy in the Context of CFTR Genotype

Cystic fibrosis (CF) is a life‐shortening disease arising as a consequence of mutations within the CFTR gene. Novel therapeutics for CF are emerging that target CF transmembrane conductance regulator protein (CFTR) defects resulting from specific CFTR variants. Ivacaftor is a drug that potentiates CFTR gating function and is specifically indicated for CF patients with a particular CFTR variant, G551D‐CFTR (rs75527207). Here, we provide therapeutic recommendations for ivacaftor based on preemptive CFTR genotype results.

PharmGKB summary: very important pharmacogene information for N-acetyltransferase 2

Departments of Genetics, Bioengineering, Stanford University, Palo Alto, California, Department of Pharmacology and Toxicology and James Graham Brown Cancer Center, University of Louisville, Kentucky, USA, Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece and Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Stockholm, Sweden

PharmGKB summary: caffeine pathway

Departments of Genetics, Bioengineering, Stanford University Medical Center, Stanford, California, USA and Division of Clinical Pharmacology, Karolinska Institute, Stockholm, Sweden Correspondence to Dr Teri E. Klein, PhD, Department of Genetics, Stanford University Medical Center, 300 Pasteur D. Lane L301, Mail Code 5120, Stanford, CA 94305-5120, USA Tel: + 1 650 725 0659; fax: + 1 650 725 3863; e-mail: feedback@pharmgkb.org

PharmGKB summary: very important pharmacogene information for G6PD

Glucose-6-phosphate dehydrogenase (G6PD) was one of the first genes found to be associated with variable drug response. It is also very polymorphic, with G6PD deficiency found in more than 300 million people worldwide [1]. Here, we provide an overview of G6PD as a very important pharmacogene, and detail genetic variants and haplotypes associated with drug response (Although most G6PD variants are caused by single nucleotide polymorphisms (SNPs) in the coding region of the G6PD gene at the X chromosome, due to the heterogeneity of alleles causing G6PD deficiency; here, we use the term ‘haplotype’ to define the set of linked SNPs in a G6PD variant that are inherited together and that may or may not produce G6PD deficiency). A more in-depth report, with interactive links to individual literature annotations, can be found at http://www.pharmgkb.org/gene/PA28469.

PharmGKB summary: uric acid-lowering drugs pathway, pharmacodynamics.

Disorders involving uric acid including gout, hyperuricemia and resultant kidney failure are prevalent. There are three main groups of pharmaceuticals used for modulating uric acid: 1. Drugs that reduce the generation of uric acid (allopurinol and febuxistat), 2. Those that increase the removal of uric acid (rasburicase, pegloticase), (both depicted in Figure 1) or 3. Those that inhibit the reabsorption of uric acid (depicted in Figure 3). This summary briefly describes the mechanisms of action and the candidate genes and genetic variants associated with response to these drugs. Clinically relevant genetic variants have been identified for allopurinol and rasburicase, and CPIC guidelines have been published that recommend selection of alternative treatments for some individuals. A more extensive description and interactive version can be found for each pathway at www.pharmgkb.org. Figure 1 Uric acid-lowering drugs pathway, Pharmacodynamics Figure 3 Uricosurics pathway, Pharmacodynamics 1) Drugs that reduce the generation of uric acid: allopurinol and febuxostat Pharmacodynamics Allopurinol is a drug indicated for the treatment of gout, prophylaxis of hyperuricemia in patients undergoing chemotherapy, and prevention of kidney stones recurrence [1]. Allopurinol and its metabolite oxypurinol are analogues of hypoxanthine and xanthine, respectively, and work by binding to and inhibiting xanthine dehydrogenase (XDH), preventing the formation of uric acid (Figure 1) [1–5]. Hypoxanthine and xanthine are cleared in the urine or reutilized in the synthesis of nucleotides and nucleic acids [1, 6]. Febuxostat (Uloric®) is a non-purine inhibitor of XDH that can bind to and inhibit both oxidized or reduced forms of XDH (Figure 1) [2, 7, 8]. It is indicated for the treatment of hyperuricemia in patients with gout (but not for asymptomatic hyperuricemia) [9], and is an alternative therapy for patients where allopurinol has been contraindicated due to allergic responses [7, 8, 10]. A downside to allopurinol/febuxostat treatment is that existing high levels of plasma uric acid are not cleared and, as xanthine is less soluble than uric acid, xanthine kidney stones or xanthine nephropathy may result [3, 6].