Current Pharmacogenomics - Current Issue

Evidence is beginning to accumulate that not only development and progression of left ventricular hypertrophy (LVH) in hypertension is genetically predisposed, but its regression during therapy has several genetic determinants. Renin-angiotensin system (RAS) is generally considered to be the major contributor to LVH development. I/D polymorphism of angiotensin-converting enzyme (ACE) gene was shown to determine plasma ACE concentrations and LVH severity in hypertension. Several studies have also documented association of angiotensin II type I receptor gene (AT1R) polymorphism (A1166C) with LVH. Impact of angiotensinogen (ATG) genetic polymorphisms (-6G/A or M235T) in LVH is not so well established. Gene-gene interactions between these genes are also described. Since pharmacogenetic approach has been introduced to testing of antihypertensive drug efficacy, the influence of RAS genetic polymorphisms on LVH regression during treatment was also analyzed in several studies. The data obtained nowadays are rather controversial. Large proportion of studies documented lower LVH regression in patients carrying D allele (or DD genotype) of ACE gene. C allele of AT1R gene is also shown to influence LVH reversal during treatment. However, major clinical studies concerning effects of different drugs on hypertensive LVH did not include genetic investigations; the existing data are obtained on rather small patient samples, do not take into account gene-environmental interactions, and need to be tested in larger trials.

Colorectal cancer (CRC) is one of the most frequently occurring malignancies worldwide, and the second leading cause of cancer related death in the Western World. Although early stage disease is curable by surgical resection alone, one half of patients with CRC will present with metastatic disease at some stage in the course of their disease. The most active drug in the treatment of CRC is 5-fluorouracil (5-FU) which is used in both the adjuvant and advanced settings. The use of adjuvant therapy is of proven benefit in Stage III CRC, however, its role in Stage II disease is less clear. There is therefore a need to identify those patients with early stage disease who will develop recurrent disease, and who would therefore benefit most from adjuvant treatment. In the advanced setting, the use of irinotecan and oxaliplatin in combination with 5-FU has proven beneficial, with yet further improvements in survival reported with the addition of new targeted agents such as bevacizumab. Despite this, a significant number of patients with advanced disease do not derive any benefit from the chemotherapy they receive, highlighting a need for the development of molecular or genomic markers predictive of response to these chemotherapeutic agents. This review will evaluate the recent advances in pharmacogenomics in CRC, in particular the development of predictive markers of response to chemotherapy. The successful identification of these markers of response will herald an era of personalised treatment, reducing treatment-related toxicity and improving outcome of patients with CRC.

Sulfate (SO4 2-) is an abundant nutrient in the blood and is essential for normal growth and development. SO4 2- is conjugated (sulfonated) to many compounds in the body, including glycosaminoglycans, steroid hormones and bile acids. Sulfonation also plays an important role in the metabolism of xenobiotics and certain drugs, such as acetaminophen. SO4 2- enters and exits cells via plasma membrane SO4 2- transporters. To date, ten human SO4 2- transporters belonging to the Solute Linked Carrier 13 (SLC13) or 26 (SLC26) gene families have been identified. Clinical interest has focused on two SLC26 SO4 2- transporters which are associated with recessive human disorders: SLC26A2 is defective in four different chondrodysplasias (MED, DTD, AO2 and ACG1B) and SLC26A3 is associated with congenital chloride diarrhea (CLD). Ongoing studies are focused on the physiological significance of the other eight SO4 2- transporters (SLC13A1, A4, and SLC26A1, A6, A7, A8, A9, A11), yet to be characterized in human diseases. Our Slc13a1 null (Nas1-/-) mouse studies, have revealed several pathophysiological features associated with this transporter: hyposulfatemia, hypersulfaturia, reduced growth, seizures, behavioural abnormalities, hypercholesterolemia, fatty liver, reduced fertility and enhanced acetaminophen-induced hepatotoxicity. These findings can be relevant to single nucleotide polymorphisms (SNPs) in human SLC13A1, which lead to changes in SO4 2- transport function. This paper summarises non-synonymous SNPs (nsSNPs) found in the sulfate transporters SLC13A1, A4, and SLC26A1, A6, A7, A8, A9, A11, with a special focus on SLC13A1, which we have identified to be responsible for maintaining blood SO4 2- concentrations.

Rheumatoid arthritis (RA) is a chronic inflammatory disease which affects approximately 1% of the world population. A considerable effort has been put into understanding the genetic factors associated with this complex disease. Sequencing of the human genome has opened new prospects for the detection of genetic variants associated with increased susceptibility, poor prognosis and inadequate response to therapy. One of the most promising candidate genes is TNFα, not only due to its pivotal role in the inflammatory process, but also because anti-TNFα drugs have become the golden standard in RA therapy. Of particular interest are the highly abundant single nucleotide polymorphisms (SNPs), particularly when they occur in regulatory regions, such as the promoter of the gene, upregulating or downregulating the production of TNFα by changing the affinity of transcription factors to their binding sites. In this review, we address the influence exerted by TNFα gene promoter SNPs in RA, focusing particularly on their effect on TNFα production. Subsequently, we review the results of association studies addressing the influence of these polymorphisms on RA susceptibility, prognosis and response to therapy, with special concern on specific anti-TNFα drugs.

This review brings together evidence to show that chemotherapy agents that cause DNA double strand breaks have increased success in treating model cancers with deficits in the pathway containing BRCA1/2 proteins. In people who do not have BRCA1 or BRCA2 gene mutations, the encoded proteins prevent breast/ovarian cancer. However BRCA1 and BRCA2 proteins have multiple functions including participating in a pathway that mediates error-free repair of DNA double strand breaks. Inactivation of BRCA1, BRCA2 or any other critical protein within this “BRCA pathway” due to a gene mutation should inactivate this error-free repair process. DNA fragments produced by double strand breaks are then left to non-specific processes that rejoin them without regard for preserving normal gene regulation or function, so rearrangements and deletions of DNA segments are more likely. This mechanism contributes to the gross chromosomal rearrangements found in a large majority of human cancers. In many cancers, gene rearrangements and deletions are believed to be critical events so a compromised BRCA pathway increases cancer risk in general. Mutation specifically of the BRCA1 or the BRCA2 gene increases risk as much as about 8 times for subsets of numerous cancers including stomach, pancreas, prostate, colon, etc. as reported in epidemiologic studies. Moreover, inactivating virtually any gene within a model for the BRCA pathway increases risk up to nearly 2000 fold for a subset of leukemias and lymphomas that frequently contain gene rearrangements. In tumor cells, the status of the BRCA pathway may be important during chemotherapy. Some chemotherapy agents cause chromosome breaks as they destroy tumor cells but other types of chemotherapy depend on different mechanisms. A damaged BRCA pathway may make subgroups of tumors unable to correctly repair broken chromosomes. Because normal error- free repairs are no longer assured, sensitivity to chemotherapy drugs that cause DNA double strand breaks should especially increase. The end result specifying tumor resistance vs. tumor sensitivity to chemotherapy is complicated and may be modified by additional mechanisms. Nevertheless this review of the literature shows that the status of the BRCA pathway is a broadly useful criterion in selecting chemotherapy agents for model tumors derived from a variety of different organs. These preclinical models show real gains depending on the chemotherapy regimen selected. If the models are appropriate predictors in cancer patients, then identifying patients more likely to respond to a given chemotherapy agent should minimize serious adverse effects and prolong survival times.

Flavin-containing monoooxygenases (FMOs) are a family of enzymes involved in the metabolism of foreign chemicals, including many therapeutic drugs. In this review we focus on the functional FMOs of humans (FMOs 1, 2, 3, 4 and 5). For each FMO we describe its gene organization, developmental- and tissue-specific pattern of expression, substrate specificity and the identity, frequency and functional effect of polymorphic variants. We also review the consequences of genetic variation in the FMOs for the metabolism of therapeutic drugs and the implications of this for drug efficacy and response. Some key points are: the majority of humans are homozygous for an allele (FMO2ast;2) that encodes a truncated, non-functional polypeptide, but a substantial proportion of individuals of African descent possess a copy of the functional ancestral (FMO2*1) allele and thus are predicted to respond differently to drugs and other foreign chemicals that are substrates for FMO2; FMO3 polymorphisms that decrease catalytic activity have been linked to increased drug efficacy; rare mutations in FMO3 are causative of the disorder trimethylaminuria; and the role of FMO1 and FMO3 in the oxidation of the antiestrogen tamoxifen and the antitubercular drug thiacetazone are discussed.

Cellular homeostasis in many organs is maintained via gap junctions composed of connexin (Cx), a large protein family with a number of subtypes. In fact, gap junctional intercellular communication (GJIC) is actively involved in all aspects of the cellular life cycle, ranging from cell growth to cell death. It has been well known that Cx genes act as tumor suppressor genes in GJIC-dependent and GJIC-independent manners. Actually, cancers have two different phenotypes on Cx expression and localization in cells; one shows complete silencing of Cx gene, other shows normal expression of Cx gene but disruption of localization of Cx protein. The former has the down-regulation of Cx functions as GJICdependent transformation, and the latter has disruption of Cx localization as GJIC-independent transformation. Thus, in order to restore Cx-dependent functions in cancers and establish the new cancer therapy based on tumor-suppressive effects of Cx gene, we should develop different procedures on each cancer which has the two different phenotypes. In this mini-review, we summarize the tumor-suppressive effects of Cx genes and refer to a possibility of development of a new cancer therapy based on the restoration of the tumor-suppressive effects.