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Rare Genetic Variants in Cellular Transporters, Metabolic Enzymes, and Nuclear Receptors Can Be Important Determinants of Interindividual Differences in Drug Response

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Rare Genetic Variants in Cellular Transporters, Metabolic Enzymes, and Nuclear Receptors Can Be Important Determinants of Interindividual Differences in Drug Response ORIGINAL RESEARCH ARTICLE © American College of Medical Genetics and Genomics Rare genetic variants in cellular transporters, metabolic enzymes, and nuclear receptors can be important determinants of interindividual differences in drug response Mikael Kozyra, Medical student1, Magnus Ingelman-Sundberg, PhD1 and Volker M. Lauschke, PhD1 Purpose: In this study we characterized the genetic variability of respectively. Additionally, by analyzing variation patterns across 146 clinically relevant genes influencing drug pharmacokinetics in these populations, we pinpointed potential priority genes for popula- African and European subpopulations, which are key determinants tion-adjusted genetic profiling strategies. Furthermore, we estimated, for interindividual variations in drug efficacy and adverse drug based on our variant frequency analyses, that approximately 30–40% reactions. of functional variability in pharmacogenes can be attributed to rare variants. Methods: By integrating data from the 1000 Genomes Project (n = 1,092 individuals) and the Exome Sequencing Project (ESP; n = 6,503 Conclusions: Our results indicate that these clinically important individuals), single-nucleotide variants (SNVs) were identified and genes are genetically highly variable and differ considerably between analyzed regarding frequency, functional consequences, and ethnic populations. Furthermore, the large extent of rare variants empha- diversity. sizes the need for sequencing-based approaches and effective func- Results: In total, we found 12,152 SNVs in exons, 312 of which were tionality predictions to allow for true personalized medicine. novel. The majority of variants were rare (minor allele frequency Genet Med advance online publication 21 April 2016 (MAF) <1%; 92.9%) and nonsynonymous (56.2%). We calculated that individuals of European and African descent harbor, on aver- Key Words: drug development; genetic variation; personalized age, 100.8 and 121.4 variants across the 146 pharmacogenes ­studied, medicine; pharmacogenes; rare variants INTRODUCTION the European Medicines Agency4 to optimize drug treatment. The development of next-generation sequencing platforms and These studies also uncovered a vast repertoire of genetic vari- the mapping of the human genome have transformed the field ants with profound impact on drug metabolism, some of which of pharmacogenetics into pharmacogenomics, thus expanding have been successfully translated in clinical practice.5 its scope from a candidate-driven approach to genome-wide Much research has been focused on the cytochrome P450 studies of associations. The vast amount of genetic information (CYP) superfamily of genes because these are major contribu- opens new possibilities to describe and categorize the extent of tors to drug metabolism, primarily in the liver. The impact of genetic polymorphisms in the human genome at the popula- this variation on drug response and ADRs is extensive; recently, tion level. a comprehensive overview of the genetic variability within the Interindividual differences in drug pharmacokinetics (PK) CYP super gene family with important implications for person- and pharmacodynamics (PD) can cause the loss of treatment alized medicine was published.6 Yet, a plethora of other genes efficacy or give rise to adverse drug reactions (ADRs) with neg- such as other phase I enzymes, phase II conjugation enzymes, ative consequences for patients. In addition, ADRs can be as transporters, cytochrome reductases, and nuclear receptors, costly for society when they occur with the initial treatment for hereafter jointly termed “pharmacogenes,” also impact PK and symptoms.1 They are the prime cause of drug withdrawal from PD directly or indirectly and can cause ADRs.7 the market, resulting in significant costs for the pharmaceutical Genes encoding transporter proteins belong primarily to industry that have been calculated as approximately US$2.6 bil- two large gene families: the ATP-binding cassette (ABC) super- lion per new drug.2 In recent decades, much research has aimed family, whose members export substances out of cells, and to identify the genetic basis for interindividual differences in the solute carrier (SLC) superfamily, which mostly mediate drug response and toxicity; in particular, this work has resulted molecule influx. They can translocate a vast variety of com- in a series of genomic drug labels by the Food and Drug pounds like xenobiotics and drugs, thereby impacting PD and Administration (FDA)3 (http://www.fda.gov/drugs/sciencere- PK.8 Transporters of the ABC family are important in cancer search/researchareas/pharmacogenetics/ucm083378.htm) and therapy because they can confer resistance to chemotherapy by 1Section of Pharmacogenetics, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. Correspondence: Volker M. Lauschke ([email protected]) Submitted 26 November 2015; accepted 2 February 2016; advance online publication 21 April 2016. doi:10.1038/gim.2016.33 20 Volume 19 | Number 1 | January 2017 | GEnEticS in mEdicinE Genetic variability in pharmacogenes | KOZYRA et al ORIGINAL RESEARCH ARTICLE extruding chemotherapeutic drugs; thus, they are associated ucm083378.htm), a comprehensive overview of the inventory with poor prognosis.9 of genetic variation on a population level is still lacking. Here, The SLC transporter family contains more than 300 genes we present an extensive data set of human polymorphisms with selectivity to structurally diverse compounds whose vari- within important pharmacogenes based on two population ants impact drug PK. One such example is given by genetic sequencing projects: the ESP of the National Heart, Lung, and polymorphisms in SLCO1B1, a gene encoding the cellular Blood Institute22 and the 1000 Genomes Project.23 We provide transporter OATP1B1 that mediates influx of a wide variety of an overview and classification of variants across populations pharmaceutical substances like various statins, bosentan, and and assess the contribution of rare variants to overall functional troglitazone.10 The single-nucleotide variant (SNV) rs4149056 variability. Furthermore, the data presented here deliver new in SLCO1B1 (SLCO1B1*5) has been shown to profoundly influ- insights into genetic variants that potentially affect drug effi- ence statin uptake, resulting in lower inhibition of HMG-CoA cacy and can thus incentivize the adoption of this knowledge and increased blood cholesterol levels.11 Furthermore, the into clinical practice. rs4363657 variant, which is in almost complete linkage dis- equilibrium with rs4149056, showed a strong association with MATERIAL AND METHODS statin-induced myopathy.12 Inversely, treatment efficacy of the Data collection and filtration antidiabetes drug repaglinide is increased in variant carriers A list of important pharmacogenes was collected from http:// because hepatic uptake primes the compound for biotransfor- www.pharmaadme.org and expanded with genes from the liter- mation into inactive metabolites.13 ature that could play a role in the PK or PD. Data on each of the In addition to transporters, phase II enzymes constitute an 146 genes were collected from ESP database (http://www.nhlbi. important class of pharmacogenes that are responsible for nih.gov/) release ESP6500SI-V222 and from 1000 Genomes the detoxification and inactivation of drugs, mostly by trans- Project release 20130502 (http://www.ncbi.nlm.nih.gov/varia- fer of chemical moieties that render the drug, toxin, or hor- tion/tools/1000genomes).23 Information regarding variants was mone more hydrophilic and facilitate excretion. Major phase retrieved from NCBI dbSNP release 134 (http://www.nlm.nih. II pathways include conjugation with glucuronides by UDP- gov/SNP/), Ensembl variation (http://www.ensembl.org/info/ glucuronosyltransferases (UGTs), the addition of glutathione genome/variation/index.html), and UCSC genome browser by glutathione-S-transferases (GSTs), and sulfonation cata- (http://genome.ucsc.edu/). Variation rates were calculated as lyzed by sulfotransferases (SULTs). UGTs contribute to the bio- follows: transformation of drugs and other exogenous substances, such SUMM()AF ×+nnSUMM()AF × as tobacco smoke carcinogens as well as environmental and VR = EA EA AA AA +× dietary pollutants.14 Kinetics of these detoxification processes ()nnEA AA 100 influence exposure to toxic or carcinogenic substances and thus where SUM(MAF) is the aggregated minor allele frequen- can modify the susceptibility to exposure-induced diseases cies and n is the allele sample size for European Americans such as cancer.14 Furthermore, genetic variants can influence or African Americans, respectively. All chromosome files the susceptibility to drug-induced toxicity, as exemplified by were obtained from http://ftp.1000genomes.ebi.ac.uk/vol1/ ADRs seen upon treatment with irinotecan.15 GSTs catalyze the ftp/phase1/analysis_results/supporting/accessible_genome_ transfer of reduced glutathione to unipolar compounds such as masks/ and analyzed using UGENE (http://ugene.unipro.ru). halogenonitrobenzenes, quinones, and unsaturated carbonyls.16 Gene coordinates were obtained from GeneCards (version Genetic variants in GSTs affect the metabolism of busulfan and 3.12.396 26 May 2015). cyclophosphamide, two compounds with narrow therapeutic ranges used in conditioning prior to hematopoietic stem cell Quality assessment of sequencing methods transplantations.17 Sulfonation of drugs, environmental chemi- The suitability of short-read sequencing technologies
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