**3. What are genetic polymorphisms?**

effective doses and to minimize adverse effects. Many publications, including our own, have found statistically significant correlations between (SNPs) and tacrolimus and/or cyclosporine dose-corrected blood levels. There are also works correlating certain variants in SNPs with safety and efficacy of the treatment. Even some researchers, working groups and consortia

Pharmacogenetic tests are becoming cheaper every day, so the cost of performing these assays is getting more assumable, especially when clinically relevant complications are demonstrated. The incorporation of pharmacogenetic studies to the real clinical practice will depend on the creation of well-designed sets of SNPs that, in a cost-effectiveness manner, could correlate clinical complications with genotypes, taking into consideration the whole and complicated treatment in polymedicated patients. Many results contribute to highlight the need of prospective controlled studies, with pharmacogenetic analysis prior to transplantation. This will probably be the critical point for the regulatory agen‐ cies to settle the most relevant polymorphisms as validated biomarkers to be widely

For all this reasons, our aim in this chapter is to provide an easy explanation about what a polymorphism is and an updated view of the most relevant SNPs with evidence of their implication in safety and efficacy of immunosuppressive treatment in renal transplantation. The final goal is to give a summary from basic knowledge to concrete examples that help to improve the medical doctors' knowledge of the clinical impact of Pharmacogenetics in their

The term "Personalized Medicine" was not long ago some "scifi" concept, just express‐ ing the best wishes of the scientific community with an aim of adjusting the pharmaco‐ therapy as best as possible to each single patient. However, in the last years we have seen real advances in this area that have brought to the real clinical practice in most of the "first world" countries, a set of new analysis under the same principle: offering an

In order to understand this new approach in medicine and put it into practice, we necessarily have to take genetics in consideration, and particularly, we have to pay attention to the individual differences that make each patient respond in a different way to a given pharma‐ cological treatment. Here, we arrive to the concepts of Pharmacogenetics and Pharmacoge‐ nomics, that can be heard in more and more places each day. They are, and for sure will be, components to be considered in the medical practice. We can define them in many ways, and traditionally they have been employed interchangeably although there are differences between them. They are different but complementary disciplines. The European Medicines Agency, EMA, takes their definitions from The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), this is a project with regulatory authorities from Europe, Japan and USA, together with experts from pharmaceut‐

recommend guidelines for initial dosing adjust regarding this SNPs.

used in the clinical transplantation setting.

288 Current Issues and Future Direction in Kidney Transplantation

**2. Personalized medicine and pharmacogenetics**

individualized therapy to each different patient.

daily practice.

We also must review some other basic concepts in genetics and, extensively, pharmacogenetics in order to understand the following information. The most relevant one is Polymorphism, which is defined as a mendelian monogenic character that appears in the population with the presence of more than one allele in the same genetic locus. Applying the term to pharmaco‐ 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‐ morphic variability in our genomes.

Other relevant concepts to understand pharmacogenetics are Haplotipe and Linkage Dise‐ quilibrium (LD). Haplotype refers to those alleles of a chromosome, or part thereof, which are physically close and that tend to be inherited together. In our field, it is especially important that more and more frequently the research is focused not on single SNPs, but on combinations of them, forming haplotypes. Although many research has been simplified, studying SNPs analyzed one by one, the real biological significance of these genetic changes must be seen in the resulting effect of groups of SNPs, since the individual effects of each one can be enhanced, reduced or offset by the effects of others. In addition, the linkage disequilibrium, is the situation in which some alleles are present together in a higher frequency than expected, due to its close location in the chromosomes. This is important in SNPs research, since one can study a SNP that is well know and easy to determine, instead of studying another SNP linked to the first, that is more difficult to assess, and the results can be correlated. For instance, in some cases one SNP, with not known biological significance, is correlated with certain clinical conse‐ quence, and after a deeper research it is found that actually that first SNP is in fact in linkage disequilibrium with another SNP, unknown or non studied before, that is directly related to

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

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

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In relation to these concepts, we can now understand that SNPs that have not got a clearly studied functional meaning, for example they do not alter the amino acid sequence or are not regulatory in intronic regions, are usually included in research projects. Maybe these SNPs are linked to others that are not taken into consideration but that do produce a direct effect on the gene product. These studies will be completed when information of LD blocks, provided for instance in public consultation databases as HapMap (www.hapmap.org), would be included. These final integrative approaches require powerful statistical and *in silico* analysis, correlating

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

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.

that clinical consequence.

**4. Genes and drugs**

of all available information.

the large amount of information obtained.

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 this point.

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 may has not been well characterized yet.

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.

Other relevant concepts to understand pharmacogenetics are Haplotipe and Linkage Dise‐ quilibrium (LD). Haplotype refers to those alleles of a chromosome, or part thereof, which are physically close and that tend to be inherited together. In our field, it is especially important that more and more frequently the research is focused not on single SNPs, but on combinations of them, forming haplotypes. Although many research has been simplified, studying SNPs analyzed one by one, the real biological significance of these genetic changes must be seen in the resulting effect of groups of SNPs, since the individual effects of each one can be enhanced, reduced or offset by the effects of others. In addition, the linkage disequilibrium, is the situation in which some alleles are present together in a higher frequency than expected, due to its close location in the chromosomes. This is important in SNPs research, since one can study a SNP that is well know and easy to determine, instead of studying another SNP linked to the first, that is more difficult to assess, and the results can be correlated. For instance, in some cases one SNP, with not known biological significance, is correlated with certain clinical conse‐ quence, and after a deeper research it is found that actually that first SNP is in fact in linkage disequilibrium with another SNP, unknown or non studied before, that is directly related to that clinical consequence.

In relation to these concepts, we can now understand that SNPs that have not got a clearly studied functional meaning, for example they do not alter the amino acid sequence or are not regulatory in intronic regions, are usually included in research projects. Maybe these SNPs are linked to others that are not taken into consideration but that do produce a direct effect on the gene product. These studies will be completed when information of LD blocks, provided for instance in public consultation databases as HapMap (www.hapmap.org), would be included. These final integrative approaches require powerful statistical and *in silico* analysis, correlating the large amount of information obtained.
