Current Pharmacogenomics, Vol. 3, No. 3, 2005
Contents
Genetic
Susceptibility to Risk for Bladder Cancer in Individuals Working in High Risk
Occupations Pp.165-175
Robert A. Branch, Nancy Paulsen, Raj A. Persad, Patrick J.B.
Smith, Christopher Collins, Ann Schwartz, Al Cecchetti, Vincent C. Arena,
Kendra Jones and Marjorie Romkes
Application of
Pharmacogenomic Approaches in the Study of Drug Response in Complex Diseases
Pp.177-190
Eva Halapi and Hakon Hakonarson
Molecular Genetics
and Epidemiology of Japanese Type 1 Diabetes Pp.191-199
Eiji Kawasaki and Katsumi Eguchi
The Role of
DNA-Microarray in Translational Cancer Research Pp.201-216
Sonke Korfee, Wilfried Eberhardt, Yasuhiro Fujiwara and
Kazuto Nishio
Thermodynamic and
Kinetic Analyses of Nucleic Acid Structures for Pharmacogenomics Pp.217-236
Daisuke Miyoshi and Naoki Sugimoto
Single Nucleotide
Polymorphisms (SNPs): History, Biotechnological Outlook and Practical
Applications Pp.237-245
Shelina Kassam, Peter Meyer, Anthony Corfield, Gregor
Mikuz and Consolato Sergi
Abstracts
[Back
to top] Genetic Susceptibility to Risk for
Bladder Cancer in Individuals Working in High Risk Occupations
Robert A. Branch, Nancy Paulsen, Raj A. Persad, Patrick J.B. Smith, Christopher Collins, Ann Schwartz, Al Cecchetti, Vincent C. Arena, Kendra Jones and Marjorie Romkes
We investigated the relative contribution of a pharmacogenomic measure of slow acetylation phenotype to susceptibility for bladder cancer in subjects with a history of high risk occupational exposure. The dapsone –acetylation was determined in 107 incident patients with transitional cell bladder cancer (organ-confined, non-aggressive cancer (n=43), organ-confined, aggressive cancer (n=32), non-organ-confined, aggressive cancer (n=32) and age, sex matched controls (n=85). Adjusting for age, sex, alcohol consumption and smoking habits, the slow acetylator phenotype and history of occupational exposure were independent; significant risk factors in at least one of the three subgroups of bladder cancer. In each cancer group, the combination of slow acetylation and occupational exposure conferred significant increases in risk with a synergistic substantially greater increase in non-organ-confined, aggressive bladder cancer. The frequency of occupational exposure and slow acetylator phenotype in the control group was 6% while this combination was present in 86% of patients with non-organ-confined, aggressive bladder cancer. These results support the hypothesis that slow acetylators exposed to high-risk occupations are at increased risk for the subsequent development of non-organ-confined, aggressive bladder cancer.
[Back
to top] Application of Pharmacogenomic
Approaches in the Study of Drug Response in Complex Diseases
Eva Halapi and Hakon Hakonarson
Single nucleotide polymorphisms (SNP) in genes encoding drug receptors, transporters, metabolizing enzymes or DNA repair genes are known to influence the toxicity and efficacy profile of drugs. While the transition of this information to DNA-based tests in order to improve drug selection, identify optimal dosing, maximize drug efficacy or minimize the risk of toxicity has been slow coming, recent advances in molecular biology have yielded new diagnostic assays, some of which have already been incorporated into therapeutic guidelines such as testing for Herceptin protein in breast cancer patients. Moreover, new high-throughput screening methods and data mining approaches have emerged that could revolutionalise the drug development process and reduce the risk of drug failure, while both lowering costs and delivering faster and better results. In this regard, the powerful coupling of linkage to ultra-high throughput genotyping, gene array or proteomics technology, together with innovative bioinformatics resources, provides a focused integrative strategy for pinpointing disease-causing genes that may generate validated drug targets and genes that are responsible for differential drug response. The new information generated has already sparked the initiation of novel strategies and diagnostic approaches in clinical development that are anticipated to ultimately lead to safer and more efficacious drugs.
[Back to top] Molecular Genetics and
Epidemiology of Japanese Type 1 Diabetes
Eiji Kawasaki and Katsumi Eguchi
Type 1 diabetes is an organ-specific autoimmune disease characterized by T-cell mediated destruction of pancreatic b-cells. A variety of environmental and genetic factors are involved in the development of the disease. The human leukocyte antigen (HLA) class II genes (termed IDDM1) are the major genes associated with susceptibility to type 1 diabetes. The highest risk for type 1 diabetes in Caucasian population is associated with individuals expressing both DRB1*0301-DQB1*0201 and DRB1*0401-DQB1*0302. However, HLA-DRB1*0405-DQB1*0401, HLA-DRB1*0901-DQB1*0303 and HLA-DRB1*0802-DQB1*0302 are three major susceptible haplotypes in Japanese patients with type 1 diabetes. In contrast, the most protective HLA DR-DQ haplotype, DRB1*1501-DQB1*0602, is universal. Other genetic factors reported in type 1 diabetes include the polymorphisms in insulin gene (IDDM2), CTLA4 gene (IDDM12), PTPN22 gene, IL-18 gene, TNF-a gene, Neuro D/BETA 2 gene, Vitamin D receptor gene, and SDF-1 gene. Within the last decade, a number of immunological and environmental manipulations in animal models of type 1 diabetes, NOD mouse and BB rat, have been reported. In humans, two major trials have been conducted to try to prevent type 1 diabetes with administration of insulin and nicotinamide (DPT-1 and ENDIT). To date, no treatment has been shown to prevent human type 1 diabetes. However, if a safe and effective therapy is identified, one should consider the use of agent for high risk individuals to prevent diabetes, as well as for the patients with type 1 diabetes in adults who are often diagnosed as having type 2 diabetes to preserve residual b-cell function based on the findings of both immunogenetic and pharmacogenetic testing to predict responders from non-responders.
[Back to
top] The Role of DNA-Microarray in Translational Cancer Research
Sonke Korfee, Wilfried Eberhardt, Yasuhiro Fujiwara and
Kazuto Nishio
The overall prognosis for the majority of cancer patients remains poor. Current conventional strategies in clinical cancer research are unable to adequately answer a large number of important unsolved questions. Although some patients achieve substantial benefits from classical cytotoxic chemotherapy, others will not. The mechanisms behind this phenomenon are still not identified in detail. Furthermore, the activity of promising novel molecular targeting anticancer agents like tyrosinkinase inhibitors is currently not predictable within the individual patient. The biological background for this clinical and prognostic heterogeneity in behavior is more or less the large individual variation in the biological nature of tumors within the same classified histological subgroup. The overall usefulness of conventional histopathological classifications to adequately predict patient prognosis or response to chemotherapy is limited. The most promising way to solve this issue is to found clinical research strategies on basic biological evidence. New genomic technologies have been developed within recent years. These techniques are able to analyze thousands of genes and their expression profiles simultaneously. An increasing number of investigations has reported applications of these novel technologies within clinical trials settings. The aim of this approach is to identify new subsets of cancer patients, to improve prediction of their clinical outcome or response to treatment and select new targets for innovative therapeutic drugs based on the findings from gene expression profiles. Results of these gene expression profile studies could potentially lead to more individually tailored systemic cancer therapy. In the recent years, a remarkable number of studies based on these techniques have already been reported. Although the published results are clearly impressive and highly promising, a lot of work remains to be done. Moreover, there is a strong need for an increase in reliability and reproducibility of such gene expression profiling techniques and thus introduction of reproducible quality control in the performance of these assays. Although a large number of issues remain to be clarified prior to a more general application of genomic profiling techniques in clinical cancer research, this strategy will eventually turn out as a promising approach to improve successful management of cancer patients.
[Back
to top] Thermodynamic and Kinetic Analyses of Nucleic
Acid Structures for Pharmacogenomics
Daisuke Miyoshi and Naoki Sugimoto
The critical role of nucleic acids, DNA and RNA, is to store and process genetic information that includes all needs for life. The Human Genome Project (HGP) showed that about 98% of the human genome does not code for protein expression, and the role of these noncoding sequences remains unknown. The HGP also showed that repetitive DNA sequences, including dinucleotide repeats, trinucleotide repeats, and telomeric, and centromeric sequences, are widely distributed in the human genome. Most of the repetitive DNA potentially can fold into noncanonical structures via both Watson-Crick and non-Watson-Crick base pairs. These structures should have discernible conformational signals in nucleic acid-nucleic acid, nucleic acid-protein, and nucleic acid-drug interactions. The structural polymorphism of these nucleic acids is generated by not only their sequence but also by their surrounding conditions. In this review, the characteristics of the nucleic acid structures, their thermodynamic and kinetic properties, and their importance in pharmacology and medicine will be discussed.
[Back
to top] Single Nucleotide Polymorphisms (SNPs): History, Biotechnological
Outlook and Practical Applications
Shelina Kassam, Peter Meyer, Anthony Corfield, Gregor Mikuz and Consolato Sergi
The recent introduction of molecular biology methods to pharmacology, to assess how DNA sequence variations can influence the response of an individual to a drug, has opened new dimensions in the evidence based analysis of goals, risks and benefits of drug therapy. The development of diagnostic test systems to identify patients at increased risk of adverse drug reactions, the application of genomic technologies to drug development, and the clarification of the mechanisms of drug action on cells represent actual challenges for both clinicians and researchers. In this review, we emphasize on the investigative tools of molecular biology-based pharmacology with particular reference to the development of single nucleotide polymorphisms (SNPs) and new developing trends of this technology.