Personalized Medicine in Vascular Medicine

Pharmacogenomics in Personalized Medicine
Reference work entry
First Online:

Abstract

Genetic polymorphisms and mutations in drug-metabolizing enzymes, transporters, receptors, and other drug targets (e.g., toxicity targets) are linked to interindividual differences in the efficacy and toxicity of medications as well as risk of genetic diseases. The interindividual variation in the rate of drug metabolism has been known for many years. Pharmacogenomics dealing with heredity and response to drugs is part of science that attempts to explain variability of drug responses and to search for the genetic basis of such variations or differences. Validation of clinically important genetic polymorphisms and development of new technologies are critical issues for advancing personalized medicine. The practice of personalized medicine is urgently needed to circumvent drug-induced adverse reactions for elderly patients in several countries where the number of elderly with age of over 65 years old is rapidly increasing. Cost-effective methods should be developed for genotyping, and it would be desirable to include genetic information into the patient’s record as guidance for physicians to individualize the therapeutic intervention.

Keywords

Personalized Medicine Information Communication Technology TPMT Activity Warfarin Dose Requirement Companion Diagnostics 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Glossary of Terms

SNP

(single nucleotide polymorphism) is a DNA sequence variation occurring when a single nucleotide in the genome (or other shared sequence) differs between members of a biological species or paired chromosomes in a human. SNPs have been used as high-resolution markers in gene mapping related to diseases or normal traits.

GWAS

(genome-wide association study) is an examination of many common genetic variants in different individuals to see if any variant is associated with a trait. A Manhattan plot demonstrates several strongly associated risk loci, where each dot represents an SNP, with the X-axis showing genomic location and Y-axis showing association level.

CYPs

(cytochrome P-450 s) form a large and diverse family of heme-containing enzymes that catalyze the oxidation of organic compounds. CYPs are the major enzymes involved in drug metabolism and bioactivation, accounting for about 75 % of the total number of different metabolic reactions.

VKORC1

(vitamin K epoxide reductase complex subunit 1) is responsible for reducing vitamin K 2,3-epoxide to the form of vitamin K that is required for the carboxylation of glutamic acid residues in certain blood-clotting proteins. Fatal bleeding can be caused by vitamin K deficiency and by the vitamin K antagonist warfarin. In humans, mutations in the VKORC1 gene can be associated with deficiencies in vitamin-K-dependent clotting factors.

TPMT

(thiopurine methyltransferase) plays a role in the metabolism of the thiopurine drugs, such as azathioprine, 6-mercaptpurine (6-MP), and 6-thiouanine. TPMT catalyzes the S-methylation of thiopurine drugs. Defects in the TPMT gene lead to decreased methylation and decreased inactivation of 6-MP, leading to enhanced bone marrow toxicity which may cause myelosuppression, anemia, bleeding tendency, leukopenia, and infection.

PK

(pharmacokinetics) describes the profile of absorption, distribution, metabolism, and excretion (ADME) of a drug after administration.

PD

(pharmacodynamics) describes the biochemical and pharmacological effects of a drug on the body, the mechanisms of drug action, and the relationship between drug concentration and effect.

EM

(extensive metabolizer) is the major population that normally metabolizes a drug.

PM

(poor metabolizer) is a subpopulation that poorly metabolizes a drug as compared with the majority of the population, which is due to homozygous mutation or genetic polymorphism in the gene encoding a specific drug-metabolizing enzyme.

IM

(intermediate metabolizer) is a subpopulation that metabolizes a drug at an intermediate rate between EM and PM. This phenotype is due to heterozygous alleles, one of which carries a mutation or genetic polymorphism in the gene encoding a specific drug-metabolizing enzyme.

UM

(ultraextensive metabolizer) is the subpopulation that metabolizes a drug more rapidly than does the majority of the population, which is due to gene amplification of a specific drug-metabolizing enzyme.

MALDI-TOF MS

(matrix-assisted laser desorption/ionization time-of-flight mass spectrometry) is a relatively novel technique in which a coprecipitate of a UV-light-absorbing matrix and a biomolecule is irradiated by a nanosecond laser pulse. Most part of the laser energy is absorbed by the matrix, which prevents unwanted fragmentation of the biomolecule. The ionized biomolecules are accelerated in an electric field and enter the flight tube. During the flight in this tube, different molecules are separated according to their mass to charge ratio and reach the detector at different times. In this way each molecule yields a distinct signal. The method is used for detection and characterization of biomolecules, such as proteins, peptides, oligosaccharides, and oligonucleotides, with molecular masses between 400 and 350,000 Da.

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Further Reading

  2. Table of pharmacogenomic biomarkers in drug labels. http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm. Accessed 30 Oct 2013

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.RIKEN Center for Life Science TechnologiesYokohamaJapan

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