**5.3. Barriers for the clinical application of Pharmacogenetics**

The introduction in the medical practice of new strategies is always difficult, among other reasons due to economic factors and the inertia of much of the professional sector, which is typically conservative. But in the particular case of pharmacogenetics, and genomics in general, there are other social factors that we will now comment, that hinder the implemen‐ tation of these new techniques.

of "omics" referring to global studies, "whole set", where we pass from the analysis of specific phenomena to the search of the interrelationship of phenomena, where we must integrate not only genomics but also proteomics (the sequences and expression patterns of all proteins), me‐ tabolomics (identification and quantification of all metabolites) and even transcriptomics (se‐ quences and expression patterns of all transcripts) and to close the circle, reach the interactome (full set of physical interactions between proteins, DNA sequences and RNA). The review of T.

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

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

301

In relation to this need for training and knowledge, we will introduce one of the biggest problems facing the Pharmacogenetics and Pharmacogenomics application in our society: as in any area of knowledge that directly affects Health and Drugs, clinical applications arising from Pharmacogenetics should be well regulated and should be given proper use. Both the patient and the doctor must be well informed of the scope and meaning of the data that can be obtained. It is crucial to know what to expect of a pharmacogenetic analysis, realistically,

It is said that in a couple of years, the cost for sequencing a complete human genome will be about 1,000\$. It is not difficult to imagine that there will soon be many patients who will consult their physicians with their genome sequence in their hand, asking whether they will have cancer or Alzheimer's or not, according to what is written in their genes. Are we prepared to deal with these situations? The New England Journal of Medicine published a series of articles and editorials addressing these issues on the occasion of the first decade of the publication of the human genome, with very interesting articles written by experts in the field, as the great

And, if we are not prepared for this new tool yet, how will we discriminate between reliable and fraudulent information? Who should be responsible for setting common guidelines to drive us in making decisions about which tests are acceptable and which are not? We think that the key are not only the regulatory agencies, which do not always agree with each other when defining whether a marker is valid or not. However, other agents, Industry, and especially the scientific societies, should be the ones to influence education on these issues and

At the academic level, many efforts have been demanded to these disciplines because they generated great expectations that were not met as fast as expected. Now, regulatory agencies require a greater statistical significance than that of many other types of studies, to accept the validity of a new marker. That is why well designed clinical studies and meta-analyses are necessary for the agencies to accept new validated markers. We must also be aware of the alarm triggered in relation to commercial proposals that are clearly misleading the consumer. Just a quick search on the Internet to realize that they are on sale genotyping chips that offer scientifically implausible predictions, such as predicting vulnerability to sudden death in athletes, obesity, the ability to succeed at school, etc. The U.S. committee SACGHS (the Secretary's Advisory Committee on Genetics, Health and Society) has already issued several reports concerning with the issue and stressing the need to regulate this area of biomedicine in order to not leave the consumer completely unprotected. There are two excellent publica‐

Manolio [57] is very useful for understanding the current situation of genomic studies.

without creating false hopes.

review of Collins and coworkers [58].

serve as a reference under the most rigorous scientific method.

tions from Dr. JP Evans, illustrating this problem [59, 60].

Contrary to what has usually happened in other fields of biomedicine, in this one we have the paradox that technological progress has gone faster than the advancement of knowledge. Today's technology platforms can just bring in a few days the data that used to take months or even years to achieve. The advances in knowledge of the human genome sequence have been really quick, especially since in February 2001 Nature and Science published simultane‐ ously the results of the Human Genome Project. The enormous progress in data collection through technology could not be accompanied by a corresponding advance in the association of the data with biological effects or implications for medical treatments [56]. A great amount of research investment is still necessary in order to understand and take advantage of this huge avalanche of data.

Clearly, every great discovery is preceded by circumstances that make it possible, and for the deciphering of the human genome, and overall progress of genomics, including Pharmacoge‐ netics-omics, milestones were achieved with the confluence of three fundamental aspects: the opportunity of high performance technologies (high throughput), the multidisciplinary working groups and the development of bioinformatics.

Investment in technology and the big bet of different private companies have been crucial for the rapid performance rate of genetic sequences data collection. In fact, as we have already mentioned, more and more individual human sequences have been obtained, demonstrating the variability of our genome and even small errors in the initial sequencing generations. Anyway, such data cannot give us more information than little white dots on a blackboard, with sometimes very specific information on diseases or even just some predispositions, but little conclusive information for the moment. This is mainly due to two major keys in genetics and biology: the first is that rarely a single gene is responsible for a disease, usually diseases result from the interaction of many genes, with particular variants or defects. The second key is that our phenotype is not an exclusive product of the expression of our genes, instead it is the gene-environment combination. In most cases, the weight of each of the two components in a given disease is difficult to decipher.

Moreover, not only the gene-environment relationship offers serious knowledge gaps, but also the relationships between genes. Everyone knows that life is the result of Systems Biology, wa‐ terfalls of activation or repression of components that influence each other. That is the kind of approach that we have to tend to, once we have more experience and results in reductionist studies. Biological systems are complex networks of thousands of routes, many of which are in‐ terconnected, biosynthetic pathways, signal transduction pathways, routes of regulating the expression of genes. The integration, representation and modeling of the interconnections of biological information analysis require global, systemic analyses. This is how we enter the era of "omics" referring to global studies, "whole set", where we pass from the analysis of specific phenomena to the search of the interrelationship of phenomena, where we must integrate not only genomics but also proteomics (the sequences and expression patterns of all proteins), me‐ tabolomics (identification and quantification of all metabolites) and even transcriptomics (se‐ quences and expression patterns of all transcripts) and to close the circle, reach the interactome (full set of physical interactions between proteins, DNA sequences and RNA). The review of T. Manolio [57] is very useful for understanding the current situation of genomic studies.

**5.3. Barriers for the clinical application of Pharmacogenetics**

300 Current Issues and Future Direction in Kidney Transplantation

working groups and the development of bioinformatics.

in a given disease is difficult to decipher.

tation of these new techniques.

avalanche of data.

The introduction in the medical practice of new strategies is always difficult, among other reasons due to economic factors and the inertia of much of the professional sector, which is typically conservative. But in the particular case of pharmacogenetics, and genomics in general, there are other social factors that we will now comment, that hinder the implemen‐

Contrary to what has usually happened in other fields of biomedicine, in this one we have the paradox that technological progress has gone faster than the advancement of knowledge. Today's technology platforms can just bring in a few days the data that used to take months or even years to achieve. The advances in knowledge of the human genome sequence have been really quick, especially since in February 2001 Nature and Science published simultane‐ ously the results of the Human Genome Project. The enormous progress in data collection through technology could not be accompanied by a corresponding advance in the association of the data with biological effects or implications for medical treatments [56]. A great amount of research investment is still necessary in order to understand and take advantage of this huge

Clearly, every great discovery is preceded by circumstances that make it possible, and for the deciphering of the human genome, and overall progress of genomics, including Pharmacoge‐ netics-omics, milestones were achieved with the confluence of three fundamental aspects: the opportunity of high performance technologies (high throughput), the multidisciplinary

Investment in technology and the big bet of different private companies have been crucial for the rapid performance rate of genetic sequences data collection. In fact, as we have already mentioned, more and more individual human sequences have been obtained, demonstrating the variability of our genome and even small errors in the initial sequencing generations. Anyway, such data cannot give us more information than little white dots on a blackboard, with sometimes very specific information on diseases or even just some predispositions, but little conclusive information for the moment. This is mainly due to two major keys in genetics and biology: the first is that rarely a single gene is responsible for a disease, usually diseases result from the interaction of many genes, with particular variants or defects. The second key is that our phenotype is not an exclusive product of the expression of our genes, instead it is the gene-environment combination. In most cases, the weight of each of the two components

Moreover, not only the gene-environment relationship offers serious knowledge gaps, but also the relationships between genes. Everyone knows that life is the result of Systems Biology, wa‐ terfalls of activation or repression of components that influence each other. That is the kind of approach that we have to tend to, once we have more experience and results in reductionist studies. Biological systems are complex networks of thousands of routes, many of which are in‐ terconnected, biosynthetic pathways, signal transduction pathways, routes of regulating the expression of genes. The integration, representation and modeling of the interconnections of biological information analysis require global, systemic analyses. This is how we enter the era In relation to this need for training and knowledge, we will introduce one of the biggest problems facing the Pharmacogenetics and Pharmacogenomics application in our society: as in any area of knowledge that directly affects Health and Drugs, clinical applications arising from Pharmacogenetics should be well regulated and should be given proper use. Both the patient and the doctor must be well informed of the scope and meaning of the data that can be obtained. It is crucial to know what to expect of a pharmacogenetic analysis, realistically, without creating false hopes.

It is said that in a couple of years, the cost for sequencing a complete human genome will be about 1,000\$. It is not difficult to imagine that there will soon be many patients who will consult their physicians with their genome sequence in their hand, asking whether they will have cancer or Alzheimer's or not, according to what is written in their genes. Are we prepared to deal with these situations? The New England Journal of Medicine published a series of articles and editorials addressing these issues on the occasion of the first decade of the publication of the human genome, with very interesting articles written by experts in the field, as the great review of Collins and coworkers [58].

And, if we are not prepared for this new tool yet, how will we discriminate between reliable and fraudulent information? Who should be responsible for setting common guidelines to drive us in making decisions about which tests are acceptable and which are not? We think that the key are not only the regulatory agencies, which do not always agree with each other when defining whether a marker is valid or not. However, other agents, Industry, and especially the scientific societies, should be the ones to influence education on these issues and serve as a reference under the most rigorous scientific method.

At the academic level, many efforts have been demanded to these disciplines because they generated great expectations that were not met as fast as expected. Now, regulatory agencies require a greater statistical significance than that of many other types of studies, to accept the validity of a new marker. That is why well designed clinical studies and meta-analyses are necessary for the agencies to accept new validated markers. We must also be aware of the alarm triggered in relation to commercial proposals that are clearly misleading the consumer. Just a quick search on the Internet to realize that they are on sale genotyping chips that offer scientifically implausible predictions, such as predicting vulnerability to sudden death in athletes, obesity, the ability to succeed at school, etc. The U.S. committee SACGHS (the Secretary's Advisory Committee on Genetics, Health and Society) has already issued several reports concerning with the issue and stressing the need to regulate this area of biomedicine in order to not leave the consumer completely unprotected. There are two excellent publica‐ tions from Dr. JP Evans, illustrating this problem [59, 60].
