**4. Genes and drugs**

genetics, it makes reference to the different alleles or variants of a gene related to a drug interaction with the body. The frequency of the less common allele in the population must not be higher than 1%. The two main groups of genetic polymorphisms are Single Nucleotide Polymorphisms (SNPs) and Lenght Polymorphisms (repetitions of nucleotide groups). The first group represents 90% of genetic variability in our genome, and each nucleotide change appears approximately in 1 every 1000 nucleotides. Length polymorphisms represent more extensive changes in the DNA sequence and approximately are the remaining 10% of poly‐

The NCBI SNP database (www.ncbi.nlm.nih.gov/snp) contains all the SNPs described, ar‐ ranged by their Reference number, which names all SNPs starting with the letters "rs", followed by a number code, but also including some classical names that had already been given to some SNPs. By clicking on a SNP code, one can get more information and several links, one of them is called "diversity" and shows the different allele frequencies found depending on the study and especially, depending on the sample's ethnicity. There are polymorphic sites with allelic frequencies quite well conserved amongst differ‐ ent ethnicities, but others have relevant differences and we must always pay attention to

The exact biological difference in meaning between "polymorphism" and "mutation" is not always clearly defined. The term "mutation" is classically associated with pathologi‐ cal significance, while "polymorphism" usually refers to a genetic change without health consequences. The problem is that "polymorphism" has also been employed to describe mostly any newly described genetic variant, without having studied it enough to know if it has a pathological consequence or not. The international research project 1000 ge‐ nomes (www.1000genomes.org) has been a great effort to sequence the whole genome of a thousand different people, so we are still attending to well quantified frequencies of genetic variants, that in some cases will still be measured in not sufficient people and so, knowing exactly the population frequencies of all our genome variants is still a chal‐ lenge, moreover due to the fact that the frequencies vary amongst different human eth‐ nicities. In conclusion, we must be cautious when interpreting the term "polymorphism" and not assume that it is just a genetic change without any biological consequences, as it

The genetic variants that can influence the behavior of a drug in the body, are mainly re‐ lated to the interaction of the drug with the receptor/ligand involved in their pharmaco‐ logical action and/or with the systems involved in its pharmacokinetic process of absorption, distribution, metabolism and excretion. So, transport, metabolism and drug target genes are the three groups of genes whose polymorphisms are of interest in phar‐ macogenetics. In a very simplistic way, an individual carrying a significant polymorphic variant will suffer from different effects from those suffered by the individuals carrying the "normal" variant at the same polymorphic site, but just in the case of being treated with the particular drug affected by that variant. If that individual is not treated with

that drug, he may not manifest any effects related to that polymorphism.

morphic variability in our genomes.

290 Current Issues and Future Direction in Kidney Transplantation

may has not been well characterized yet.

this point.

After understanding the basic concepts, we can now enter the approach to the best known gene-drug relationships. There are currently different reference sources that help us in this welter of information, such as the aforementioned HapMap project, the SNP database of NCBI and, to our knowledge, the best pharmacogenetics website which is the Pharmacogenomics Knowledge Base, PharmGKB (www.pharmgkb.org). This latter website, is a very intuitive way of learning and consulting about gene-drug relationships, by performing searches based on gene, SNP, drug or disease; with research and clinical information, and lots of links to external related sites. There we can find a table of the "well-known drug-gene pharmacogenomics associations" which represents the drugs whose relationship with some polymorphic gene has been clearly defined in the literature and is academically accepted, based on extensive reviews of all available information.

The United States Food and Drug Administration (FDA, www.fda.gov) also publishes a list of drugs where a genetic test is recommended or mandatory for the drug administration, explaining which section of the drug label has the genetic-related information.


**DRUG BIOMARKER DRUG BIOMARKER** Exemestane ER &/ PgR receptor Ticagrelor CYP2C19 Fluorouracil DPD Tolterodine CYP2D6 Fluoxetine CYP2D6 Tositumomab CD20 antigen Fluoxetine and Olanzapine CYP2D6 Tramadol and Acetaminophen CYP2D6 Flurbiprofen CYP2C9 Trastuzumab Her2/neu Fluvoxamine CYP2D6 Tretinoin PML/RARα Fulvestrant ER receptor Trimipramine CYP2D6

Gefitinib EGFR Vemurafenib BRAF Iloperidone CYP2D6 Venlafaxine CYP2D6

**Table 1.** FDA Pharmacogenomic biomarkers in drug labels (adapted from www.fda.gov)

Imipramine CYP2D6 Warfarin CYP2C9, VKORC1

Imatinib C-Kit, Ph Chromosome, PDGFR,

**4.1. Genes and drugs in transplantation**

Indacaterol UGT1A1

designed studies [8].

FIP1L1-PDGFRα

Galantamine CYP2D6 Valproic Acid UCD (NAGS; CPS; ASS; OTC; ASL;

Practical Pharmacogenetics and Single Nucleotide Polymorphisms (SNPs) in Renal Transplantation

There is certainly a lot of work done, but there is still much to do. Today, there are many publications and many research articles in the area, and the field is growing exponentially, but most of these studies reflect data from very specific conditions, where sets of patients with convenient features and sometimes far from the clinical reality, where included. It is necessary to validate the actual utility of pharmacogenetics in routine medical practice with serious, well-

In the pharmacogenetics of transplantation, as in other therapeutic areas, three groups of genes specifically involved in the response to immunosuppressive therapy have been identified: the genes encoding drug transporter proteins, inward or outward of the cells; the genes encoding metabolic enzymes involved in drug biotransformation and, finally; those encoding receptors or drug targets. Although the great majority of immunosuppressive drugs are transported and metabolized by a limited set of enzymes which mostly are known genes, the interpretation of the results observed in transplanted patients is complicated in many times. One reason for this is that these patients are highly subjected to polytherapy, and so interactions, both pharma‐ cokinetic and pharmacodynamic, may have great significance and may condition the response to treatment. Another important aspect to consider when interpreting the observed response is the fact that each patient actually contains two different genetic entities: the donor and the recipient. This phenomenon is particularly relevant when the transplanted organs are the liver or the kidney. In these types of transplantation, it must be considered that the drugs admin‐ istered to the recipient will be metabolized or excreted by the transplanted organ from the donor. In fact, more and more studies in transplantation pharmacogenetics consider both the

donor and recipient genotypes to evaluate the response to treatment [9-12].

ARG)

http://dx.doi.org/10.5772/54733

293

Voriconazole CYP2C19


**Table 1.** FDA Pharmacogenomic biomarkers in drug labels (adapted from www.fda.gov)

There is certainly a lot of work done, but there is still much to do. Today, there are many publications and many research articles in the area, and the field is growing exponentially, but most of these studies reflect data from very specific conditions, where sets of patients with convenient features and sometimes far from the clinical reality, where included. It is necessary to validate the actual utility of pharmacogenetics in routine medical practice with serious, welldesigned studies [8].
