Current Pharmacogenomics - Volume 4, Issue 4, 2006

Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing a person to an in-creased risk of fracture. The overall rate of osteoporosis is increasing annually around the world, especially among the elderly people, resulting in heavier social-economic burden. Till now, certain anti-osteoporosis medications have been ap-plied to prevent and/or treat osteoporosis by the mechanism of either decreasing excessive bone resorption or promoting bone formation. However, the efficacy of those therapies varies among people, sometimes causing unnecessary medical cost or even unwanted side-effects. Therefore, more cost-effective and subject-specific prevention and treatment of osteo-porosis is needed. In such context, pharmacogenomic studies of osteoporosis are of particular importance since it has been widely shown that genetic factors play a role in the efficacy of osteoporosis treatment. The goal of osteoporosis pharma-cogenomics is to optimize drug development and customize personalized treatment according to the specific genetic background. Herein, we discussed the application of genetic and genomic approaches to osteoporosis clinics, which held the promise to revolutionize the way we understand, prevent and treat osteoporosis.

Pharmacogenomic studies in the field of colorectal cancer have recently emerged as tools to benefit patients in receiving tailored chemotherapy and potentially improved therapeutic benefit. 5-fluorouracil/oxalplatin combination che-motherapy has been approved in the United States and Europe for the treatment of advanced colorectal cancer. However, overall efficacy may be compromised by dose-limiting toxicity and varying inter-individual responses to treatment. De-termining who is most likely to benefit from 5-FU/oxaliplatin is of great importance, and may be determined in part by pharmacogenomic studies. Genes involved in the cytotoxic and metabolic pathways of 5FU and oxaliplatin may be pre-dictive and prognostic markers for colorectal cancer. Examining polymorphic variants leading to altered function of these relevant genes offers an approach to further individualize chemotherapeutic treatment. A number of studies have impli-cated significant genes in altered clinical outcome, indicating the need for an established comprehensive genetic profile to predict efficacy of 5-FU/oxaliplatin. In addition to polymorphic studies, array-based technology has recently emerged as a tool to examine global gene expression in predicting outcome to chemotherapy. The ultimate goal of pharmacogenomic studies in colorectal cancer is to develop a genetic profile to tailor chemotherapeutics to the individual patient. With an in-creased knowledge of why patients have altered responses to 5-FU/oxaliplatin, there can be greater accuracy in selecting the most appropriate therapy.

Pharmacogenetics represents the study of variability in drug response due to genetic variations. Inflammatory bowel disease (IBD, i.e. primarily Crohn's disease and ulcerative colitis) is characterized by a chronic or relapsing in-flammation of the digestive tract. The thiopurines 6-mercaptopurine (6-MP) and azathioprine (AZA), an imidazol deriva-tive and pro-drug of 6-MP, are widely used in IBD, particularly in Crohn's disease. The metabolism of thiopurines is complexand individually variable. Thiopurine methyltransferase (TPMT) is a key enzyme in this metabolism and exhibits a genetic variability due to a number of variant alleles coding for a defective enzyme. The formation of biologically active thioguanine nucleotides (TGN) and methylated metabolites may vary considerably due to the TPMT activity. Patients with decreased TPMT activity are at increased risk of developing severe side effects if treated with conventional thio-purine doses, due to the accumulation of toxic metabolites. Determination of the TPMT phenotype or genotype is often used to identify individuals with increased risk for adverse events. Twenty-one variant TPMT alleles have been described, of which three are more common than the others. An association between inosine triphosphate pyrophosphatasepolymor-phisms and adverse events during thiopurine treatment has also been proposed. In this review, the clinical value of TPMT status determination and pharmacological monitoring of thiopurine metabolites are discussed as well as the increased in-terest in the use of 6-thioguanine, a thiopurine with a less complex metabolism, as an alternative for patients who do not tolerate AZA or 6-MP. It can be concluded that TPMT determination before start of thiopurine therapy is of value to iden-tify individuals with increased risk for adverse reactions due to genetic enzyme deficiency. However, large prospective studies are still needed to evaluate the true benefit of monitoring thiopurine metabolites during thiopurine treatment.

The management of inflammatory bowel disease (IBD) remains challenging due to the varied clinical manifes-tations of Crohn's disease (CD) and ulcerative colitis (UC). The development of new modalities in therapy is promising, with immunomodulator-based approaches rising to a more prominent position in our armamentarium. Mutations in a vari-ety of genes have been shown to be associated with IBD and specific phenotypes of disease. The CARD15/NOD2 protein has been associated with the sensing of, and tolerance to, intraluminal bacteria. Patients with specific NOD2 mutations have an increased risk for the development of CD, and certain mutations have been associated with specific disease sub-types, including fibrostenotic and penetrating disease, and the likelihood of surgical intervention. Mutations in the Toll-like receptor 4 (TLR4) gene have been associated with inflammatory or stenotic disease. Other susceptibility loci, includ-ing OCTN and the IBD loci, are associated with increased severity and early onset of disease. The elucidation of muta-tions in enzymatic pathways might predict who will respond to specific pharmacotherapies, and those at risk for treat-ment-associated adverse effects. Single nucleotide polymorphisms in the thiopurine methyltransferase (TPMT) gene, with lowered enzymatic activities, may predict patients who require lower doses of immunomodulatory therapies and those who are at increased risk for myelosuppression and hepatitis. Patients with mutations in the N-acetyltransferases may be at increased risk for adverse effects of aminosalicylates. Overall, our understanding of the genetics of susceptibility, and of the likelihood of response to specific therapies, may be beneficial in refining the medical approach to the complex man-agement of IBD.

Rheumatoid arthritis (RA) is a systemic inflammatory disorder that mainly affects the joints. When left un-treated, the disease can be aggressive resulting in irreversible joint damage with high morbidity and mortality. Disease modifying anti-rheumatic drugs (DMARDS) are the cornerstones of treatment in RA. In recent times, a new class of dis-ease-modifying medications, the biologics, has been added to the therapeutic armamentarium in RA. DMARDs not only ameliorate the clinical signs and symptoms of disease, but also prevent the radiographic progression of joint damage. However, there is significant variability in patients' response to these agents, both in terms of efficacy and toxicity. At thepresent time, there are no reliable means of predicting, a priori, an individual patient's response to a given DMARD. In this review, the current published literature on the pharmacogenetics of traditional DMARDS and the newer biological DMARDs is highlighted. Pharmacogenetics may be a powerful tool for optimizing drug therapy in patients with rheuma-toid arthritis.

Pharmacogenomics holds the promise that drugs might one day be tailor-made for individuals and adapted to each person's own genetic makeup. The field of pharmacogenomics in regards to severe infections is a growing and im-portant field in modern medicine. Severe infections, like severe community acquired pneumonia (CAP) or sepsis have a great impact in morbidity and mortality and consume a great amount of sanitary resources. Those infections have not been analyzed properly under the point of view of pharmacogenomics. The genomes of both the host and the pathogen are key points in this field. There are specific mutations in the host genome associated with adverse outcomes (genes of antigen recognition molecules, pro-inflammatory cytokines, anti-inflammatory cytokines, and effectors molecules). Those muta-tions could define a genetic profile of high risk patient in whom a specific treatment should be added urgently. In addition, some adverse effects to antibiotics can be predicted performing genetic testing. As the concept one-drug-fits-all approach is no longer appropriate in medicine, the genetic profile is discussed like useful tool to make important clinical decisions regarding treatment and to design clinical trials. Moreover, the genome of the host could help us to know if nonresponding patients to vaccine are genetically pre-programmed to be nonresponders or whether failure to respond is a random event. On the other hand, genome of pathogen could have advantages in the clinical management establishing a definitive diag-nosis, determining antimicrobial resistance and/or following the response to treatment.

Members of the ATP binding cassette transporter family are responsible for the cellular efflux of a broad range of endogenous compounds and xenobiotics in multiple tissues. The ABCG2 (ABCP, BCRP, MXR) protein, which is highly expressed in the gastrointestinal tract and liver as well as numerous multi-drug resistant cancer cells, is considered to be of particular importance in governing drug absorption, elimination and cellular sensitivity to a wide variety of clini-cally important drugs. A wealth of recent literature has also indicated that inhibition of this transporter may result in drug-drug interactions. Furthermore, genetic polymorphisms in the gene encoding ABCG2 have been described, which can sig-nificantly affect expression, cellular localization, and/or substrate recognition in vitro and in vivo. Alteration of ABCG2 transporter function by either of these mechanisms has been demonstrated to contribute to interindividual variability in drug disposition and treatment outcome (toxicity or response) with certain, but not all, substrates for ABCG2. In this re-port, we provide an update on this rapidly emerging field.

The inter-individual and inter-ethnic variations in phase I enzyme activity is largely attributed to gene poly-morphisms. The distribution and clinical consequences of these variations have been extensively studied in Africans, Asians, and Caucasians. However, information is still lacking regarding the frequency and the impact of these variations on xenobiotic metabolism and disease processes in Mexican Americans. Therefore, this review addresses the polymor-phisms of genes encoding phase I enzymes in Mexican Americans; these include: cytochrome P450 (CYP) 2C19,CYP2D6,CYP2E1, alcohol dehydrogenase (ADH), and aldehyde dehydrogenase (ALDH). This review article summarizes the association between phenotype (drug metabolism) and genotype for CYP2C19 and CYP2D6 as well as the role of ge-netic variations in CYP2E1,ADH, and ALDH as potential risk factors for alcoholism in the Mexican American population. The major findings are as follows: (1) Mexican Americans have unique genetic patterns compared with other ethnic groups; (2) In general, Mexican Americans tend to be extensive metabolizers of substrates for CYP2C19 and CYP2D6; (3) Genotypes of CYP2D6 can be used to predict phenotypes in Mexican Americans; and (4) Variations in alcohol me-tabolizing genes contribute to alcoholism in the Mexican American population.