Current Pharmacogenomics - Volume 4, Issue 1, 2006

Transposable elements (TEs), which occupy nearly 40% of eukaryotic DNA, are selfish repetitive sequences, able to proliferate in the host genomes via either their DNA copies or RNA intermediates utilizing the mechanism termed 'reverse transcription' and the RNA-dependant DNA polymerase enzyme, called reverse transcriptase. The newly formed DNA copy of the element then integrates into the genome, using a combination of host and self-encoded proteins, depending on the transposable element origin. Being important model objects for the study of many fundamental molecular biology processes and by actively participating in the gene regulation network, TEs are of great interest for basic researches in molecular genetics and genomics. Their practical use, however, is limited now to some fields of forensic sciences, phylogenetic studies and population genetics. In this mini-review I have tried to put together both theoretical, experimental and speculative data on the use of the transposable elements as tools for the gene delivery into the host eukaryotic genomes, producing stable transgene transformants. The strength of the TE-based constructions as compared with popular viral vectors would be the predictable, genomic target sequence-specific transgene integration, mediated by the enzymatic machinery of some TEs. These and other implications of transposable elements in biomedical sciences will be discussed.

The toxicity that can result from the exposure to numerous xenobiotics can vary greatly for each individual. This is mainly due to differences in the activity of xenobiotic metabolizing enzymes (XME) that participate in the disposal of toxic xenobiotics from the human body. The genes that encode XMEs present a variety of polymorphisms that occur in the promoter or coding regions, resulting in differences in the amount or in the catalytic activities of the enzymes. Human populations differ regarding the frequency of alleles and haplotypes that are present in a given geographic region. Genetic background and ancestry are the main reasons for such variability. South America, due to an extensive colonization period, is populated by descendents of Amerindians, Africans and Europeans. The admixtures that happened in each country, however, vary according to historical and geographical conditions. Brazil, for example, has one of the world's most admixed populations with genetic contributions from several tribes of Amerindians, many still existent, from Africans, and from various waves of European immigrants. In this review we will discuss the frequency of genetic polymorphisms of XMEs, particularly Cytochrome P450s and Glutathione S-transferases, found in different populations of South American countries. The genetic background and degree of population admixture of each country is taken under consideration in a discussion of the difficulties generated by enzyme polymorphisms in the treatment of individuals within such populations.

Alcohol dependence is a frequent and complex disorder involving both genetic (h2≈ 0.5) and environmental factors. The definition of what is inherited with alcohol dependence is still unknown. Shared liability has been detected with other addictive disorders (mainly nicotine dependence), and certain psychiatric disorders (such as bipolar disorder) and/or personality disorders (specifically antisocial personality). Such a broad spectrum may also explain the development of antidepressants, mood regulators and/or anti-impulsive drugs in the treatment of alcohol dependence. Genome wide scans, analyses of alcohol metabolism and reward circuits have identified many candidate genes or locations. Some genes linked to the reward pathway of alcohol, may have pharmacogenetic relevancy, such as the GABRA6 gene (regarding the role of benzodiazepine in alcohol withdrawal), SLC6A4 gene (as serotonin reuptake inhibitors may reduce alcohol intake in subgroups of patients), CB1 gene (because the CB1 agonists modify alcohol consumption, at least in rodents), and the OPRM1 gene (the 118G allele being associated with increased chances of Naltrexone efficacy). High-throughput approach for genotyping of polymorphisms, transcriptomics, and proteomics are useful tools that will help to identify susceptibility and protection genes for alcohol diseases. Together, these tools could be used to develop a rational pharmacogenomics strategy to test specific individual treatment for alcohol dependence.

The molecular biology era has allowed the exact definition of the disease-associated-proteins (DAPs). The computational era has analyzed full-length DAPs by antigenicity prediction algorythms based on physico-chemical parameters. Today, proteomics is providing a global comprehensive analysis of defined peptide portions of DAPs. The fine profiling of the disease-associated peptide repertoire is of particular importance in the definition of qualities as antigenicity and immunogenicity, and is a concrete promise of a bench-to-bedside translational research. Identifying the peptide sequences within the DAPs, which may potentially provoke (auto)immune responses, more than ever emerges as the key strategy for effective immunotherapeutical treatments in cancer diseases as well as infectious or autoimmune pathologies. Here I draw a schematic picture of the experimental attempts to define immunogenic peptide portions, describe the principle of sequence uniqueness as a rationale for the subproteomic analysis of DAPs and delineate the possible advantages of a peptide-vaccine approach to the treatment of degenerative, infectious and autoimmune diseases that might be effective and devoid of collateral harmful effects.

Drug response is a complex process determined by both genetic and non-genetic factors. Factors that control drug response can be divided into those that affect the systemic distribution and the concentration of drug at its target (pharmacokinetics) and those associated with drug targets and cellular downstream effectors (pharmacodynamics). Most pharmacogenetic studies to date have focused on the influence of genetic variation in determinants of drug distribution. Consistent associations between host polymorphisms in drug metabolising enzymes, including UGT1A1, TPMT and DPD and patient toxicity or response to chemotherapies have been demonstrated. Less is known about the cellular events following exposure to anticancer agents that lead to DNA repair or cell death, making them more difficult to study. Genetic variation in these downstream effectors is a potential source of interindividual differences in tumoral response. Exciting associations between tumor sensitivity to tyrosine kinase inhibitors and somatic mutations in their drug targets (for example epidermal growth factor receptor (EGFR)) have recently been demonstrated. These findings take us closer to personalized therapy. This paper reviews the latest advances in cancer pharmacogenetics with an emphasis on genetic variation in drug targets and mediators of cellular events that occur following drug-target interactions.

Proton pump inhibitors (PPI) are widely used for the treatment of gastroesophageal reflux disease (GERD), and in combination with antibiotics for the treatment of Helicobacter pylori infection. PPI are mainly metabolized by the polymorphic cytochromes P450 2C19 and 3A4. Genetic polymorphisms of these genes with resulting different enzyme activities may have an impact on the clinical efficacy of PPI-based therapies. There is increasing evidence that in Asian patient populations the efficacy of PPI-based eradication therapies is influenced by the patients CYP2C19 metabolizer status. Also two European studies report on CYP2C19-dependent eradication rates of H. pylori. In slow metabolizers, the AUC of oral PPI are higher in comparison to extensive metabolizers resulting in a stronger suppression of intragastric acid secretion. Recent studies suggest that the healing rate of erosive GERD is also influenced by the CYP2C19 metabolizer status. This review focuses on the relationship between CYP2C19 polymorphisms and clinical outcome after PPI based therapies in H. pylori eradication and GERD.

The antimetabolite 5-fluorouracil (5-FU) is widely used in combination treatment of patients with advanced stages of colorectal cancer. In the last decade, several studies focused on genetically determined variability in function of certain enzymes that are involved in the metabolism of 5-fluoropyrimidines. Polymorphisms and mutations within the thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR) and dihydropyrimidine dehydrogenase (DPD) genes have been associated with response to or toxicity from treatment with 5-FU. Pharmacogenetic studies could therefore identify genetic markers that can be used to guide the treatment for each individual patient. However, the predictive role of these genetic markers is not straightforward. Controversial data have been found for polymorphisms in the TS gene. Similarly, the role of MTHFR is not clear. Mutations in the DPD gene seem more suitable to predict toxicity in part of the cases but seems less suitable for prediction of response. These inconsistencies across the literature regarding the impact of identified TS, MTHFR and DPD polymorphisms on enzyme levels and response to 5-FU-based drugs will be discussed in this review. More comprehensive genetic evaluation by combined analysis of several parameters is needed. To achieve this novel approaches such as expression array and array-CGH offer the best perspective.

Type 2 diabetes is a complex and heterogeneous metabolic condition that has reached epidemic proportions, affecting more than 150 million individuals worldwide. Maintenance of near-normal glucose control in patients with type 2 diabetes been shown to be associated with a reduced risk of microvascular complications as well as a trend toward reduction of macrovascular events. Treatment with antihyperglycemic agents is initially successful in type 2 diabetes, but it is often associated with a high secondary failure rate, and the addition of insulin is eventually necessary to restore acceptable glycemic control for many patients. The molecular reasons for the different responses to antidiabetic therapy are not clear, and the possibility that genetic factors may predispose to failure to respond adequately to oral antidiabetic agents remains an open question. Pharmacogenetics is an emerging discipline that involves the search for genetic polymorphisms, commonly observed among the general population, which influence drug response. Interesting candidate genes belong to three main groups: 1) genes encoding for drug metabolizing enzymes and/or transporters that influence pharmacokinetics; 2) genes encoding for targets and/or receptors of drugs that influence pharmacodynamics; and 3) genes encoding for proteins that are involved in the causal pathway of disease and are able to modify the effects of drugs. In this review, we will discuss our current understanding of genetic polymorphisms that may affect responses of patients with type 2 diabetes to antidiabetic oral treatment as well as the main challenges, which should be addressed in order to translate pharmacogenetics principles into widespread clinical practice.