Pharmacogenomics and infectious diseases: impact on drug response and applications to disease management.

The impact of pharmacogenomics on the prevention, diagnosis, and treatment of infectious diseases is discussed. The application of pharmacogenomics to infectious diseases requires consideration of the genomes of both the pathogen and the host. The pathogen's genome may be used for antigen identification, to identify infecting organisms, and to determine antimicrobial resistance. Diagnostic tool development and vaccine design can be aided by knowing which portions of a pathogen are important antigenic determinants. The unique genetic makeup of a pathogen can facilitate its identification as an augmentation to the traditional culture. Important genes conferring resistance to antibiotics can be detected, and this information can be used to choose appropriate antibiotic therapy. The genome of the host may reveal susceptibility genes and new drug targets that may be used in the treatment of infectious diseases. Thus far, polymorphisms in genes of the host immune system have been associated with susceptibility to infections and response to treatment. Examples of these findings will be described. Pharmacogenomics has the potential to revolutionize the prevention, diagnosis, and treatment of infectious diseases.     

Diversity of human immune system multigene families and its implication in the genetic background of rheumatic diseases

A large number of molecules in the immune system are encoded by multigene families. These genes are rich in pairs of activating and inhibitory receptors that share the same ligands, thereby playing a crucial role in immunoregulation. Furthermore, multigene families tend to be highly polymorphic. Thus, multigene families are strong candidates for containing genes that enhance susceptibility to immune system-related diseases. Here, we review studies from our group, as well as other investigators, on three multigene families that belong to the immunoglobulin (Ig) - like receptor superfamily: Fcgamma receptor (FCGR), killer cell Ig-like receptor (KIR) and leukocyte Ig-like receptor (LILR) families. FCGR genes have been implicated in susceptibility to systemic lupus erythematosus (SLE). In FCGR2B encoding an inhibitory receptor expressed in B cells, monocytes and dendritic cells, a polymorphism within the transmembrane region, Ile232Thr, was identified and found to be associated with susceptibility to SLE in three Asian populations. Functional analyses revealed that SLE-associated FcgammaRIIb-232Thr was less efficient in entering the membrane lipid raft, and exhibited reduced inhibitory potential against B cell receptor signaling. Although the frequency of this polymorphism was low in Caucasians, another polymorphism within the promoter region was reported to be associated with SLE. KIR/HLA combinations have been shown to be associated with various autoimmune and infectious diseases. Recently, LILR families have also been found to be highly polymorphic, and association with several diseases has been identified. These results emphasize the role of multigene families in the diversity of human immune response and susceptibility to diseases.     

Commonalities and differences between Crohn's disease and ulcerative colitis: the genetic clues to their interpretation

Traditional knowledge of clinical, laboratorial, and endoscopic orders regarding ulcerative colitis and Crohn's disease has begun to be implemented by the revolutionary data from genetic studies. Ever since many decades ago it has been clear that inflammatory bowel diseases are complex multifactorial disorders wherein gut-confined and/or environmental factors must synergize with genetic components to effect the full-blown disorder. The sequencing of the human genome and the generation of public resources of single nucleotide polymorphisms permitted the conduction of powerful population based genome-wide association studies. The latter have increased the number of the identified susceptibility loci to 99. In this review we touched on two pathways that make true susceptibility genes for inflammatory bowel diseases; gene loci that confer specific risk for ulcerative colitis and Crohn's disease were discussed in detail.     

Modelling the epidemiology of infectious diseases for decision analysis: a primer

The number of economic evaluations related to infectious disease topics has increased over the last 2 decades. However, many such evaluations rely on models that do not take into account unique features of infectious diseases that can affect the estimated value of interventions against them. These include their transmissibility from infected to susceptible individuals, the possibility of acquiring natural immunity following recovery from infection and the uncertainties that arise as a result of their complex natural history and epidemiology. Modellers conducting economic evaluations of infectious disease interventions need to know the main features of different types of infectious disease models, the situations in which they should be applied and the effects of model choices on the cost effectiveness of interventions.     

Recent advances in the administration of vaccines for infectious diseases: microneedles as painless delivery devices for mass vaccination

Despite remarkable progress in the control of infectious diseases through vaccination, better delivery systems have been poorly explored. There is renewed interest in the discovery of novel vaccines and adjuvants owing to emerging and reemerging diseases and the burden and complexity of chronic infectious diseases. Conversely, the need for rapid local, regional, mucosal or parenteral bioavailability has led to advances in delivery systems and devices. Here, we present recent developments in the field of non-invasive cutaneous delivery of vaccines for infectious diseases. Transdermal delivery using microneedles could revolutionize the way prophylactic interventions for infectious diseases are carried out in the future.     

The role of infectious agents in pulmonary and systemic vascular disease

With emphasis on the pulmonary circulation, three general types of vascular disease are discussed: fibroproliferative (atherosclerosis), cellular proliferative (endothelial neoplasms) and inflammatory (granulomatous vasculitis). The causes of these phenotypic responses are invariably multifactorial, but infectious agents including viruses, Chlamydia, Helicobacter, Rickettsia, mycobacteria and other infectious agents have been increasingly implicated in the pathophysiology. The classifications of vascular diseases are complicated and confusing and many eponymous diseases are specific variations of more general disease processes. The pivotal role of the monocyte/macrophage and T-cells is discussed, particularly with regard to intracellular infections. In addition to antimicrobial therapy, modifications of macrophage function by IFN-γ and blockade of TNF are attractive areas for therapeutic research. Diseases with many synergistic causes will probably also require multifaceted therapeutic interventions.     

Candidate Genes for Atopic Asthma

Atopic asthma is one of the most common childhood diseases in developed countries. Asthma is characterized by reversible airway obstruction, bronchial hyper-responsiveness, and airway inflammation. Atopy in childhood is considered the strongest predisposing factor for asthma. The etiology of asthma is complex and is thought to involve the interaction of multiple genes and a variety of environmental factors such as allergens and viral and bacterial infections. To identify genes conferring susceptibility for asthma and atopy, many genome-wide screens for asthma and its associated traits have now been carried out, and genetic linkage has been consistently identified in several regions. Several independent genome-wide screens found regions of linkage with asthma on chromosomes 5, 6, 11, 12, 13, 16 and 19, identifying candidate susceptibility genes including FCER1B, the IL-4 gene cluster, TNFalpha, HLA loci and others. However, the evidence for linkage is still only suggestive for most regions. In an effort to clarify the mechanism underlying the development of asthma, further studies utilizing new technologies and data from the Human Genome Project are ongoing. It is hoped that this accumulation of data will lead to improved genetic testing and assist in the development of new drugs.     

The role of infectious agents in pulmonary and systemic vascular disease

With emphasis on the pulmonary circulation, three general types of vascular disease are discussed: fibroproliferative (atherosclerosis), cellular proliferative (endothelial neoplasms) and inflammatory (granulomatous vasculitis). The causes of these phenotypic responses are invariably multifactorial, but infectious agents including viruses, Chlamydia, Helicobacter, Rickettsia, mycobacteria and other infectious agents have been increasingly implicated in the pathophysiology. The classifications of vascular diseases are complicated and confusing and many eponymous diseases are specific variations of more general disease processes. The pivotal role of the monocyte/macrophage and T-cells is discussed, particularly with regard to intracellular infections. In addition to antimicrobial therapy, modifications of macrophage function by IFN-gamma and blockade of TNF are attractive areas for therapeutic research. Diseases with many synergistic causes will probably also require multifaceted therapeutic interventions.     

Genetics and ulcerative colitis: what are the clinical implications?

Substantial progress has been made in the last years in characterizing the susceptibility genes involved in IBD pathogenesis, especially for Crohn's disease. Although some genetic factors associated with Crohn's disease also predispose individuals to ulcerative colitis, markers specific only for ulcerative colitis have been found. Recent genome-wide association studies in ulcerative colitis have identified several new loci, and suggested many new potential pathways. The identified susceptibility genes and their variants could be useful to predict disease course and to improve stratification of patients, when correlated with other subphenotypes. Moreover, understanding the biological pathways involved in the disease could lead to the development of new treatments and molecules that specifically target such pathways, discover different therapeutic approaches and eventually progress to personalized treatment.     

Microdialysis assessment of drug delivery systems for vitreoretinal targets

Posterior segment drug delivery challenges inherent in the treatment of many sight-threatening diseases have become increasingly apparent. Therapeutic interventions for ocular diseases such as neovascular retinopathies, inflammatory and/or infectious diseases may involve drug delivery to vitreoretinal targets. An important part of successful therapeutic strategies for such diseases involves verification that efficacious concentrations of the pharmacological agent are achieved within relevant intraocular regions. Microdialysis has been effectively employed for characterizing intraocular disposition in both anterior and posterior segments, providing important documentation of successful drug delivery to desired targets. Recent papers that showcase the maturation in the model development of microdialysis approaches for estimating posterior segment pharmacokinetics and further validation of the methodology are described in this review. Special problems examined include anterior and posterior ocular clearance mechanisms, intraocular metabolism and active transport of drugs.     

Obesity and diabetes gene discovery approaches

New treatments are currently required for the common metabolic diseases obesity and type 2 diabetes. The identification of physiological and biochemical factors that underlie the metabolic disturbances observed in obesity and type 2 diabetes is a key step in developing better therapeutic outcomes. The discovery of new genes and pathways involved in the pathogenesis of these diseases is critical to this process, however identification of genes that contribute to the risk of developing these diseases represents a significant challenge as obesity and type 2 diabetes are complex diseases with many genetic and environmental causes. A number of diverse approaches have been used to discover and validate potential new targets for obesity and diabetes. To date, DNA-based approaches using candidate gene and genome-wide linkage analysis have had limited success in identifying genomic regions or genes involved in the development of these diseases. Recent advances in the ability to evaluate linkage analysis data from large family pedigrees using variance components based linkage analysis show great promise in robustly identifying genomic regions associated with the development of obesity and diabetes. RNA-based technologies such as cDNA microarrays have identified many genes differentially expressed in tissues of healthy and diseased subjects. Using a combined approach, we are endeavouring to focus attention on differentially expressed genes located in chromosomal regions previously linked with obesity and/or diabetes. Using this strategy, we have identified Beacon as a potential new target for obesity and diabetes.     

Genetic susceptibility to infectious diseases

The clinical outcome of infectious disease (ID) is determined by a complex interaction between microorganism, host genetic factors and environment.

Epidemiological studies have revealed differences within and between populations exposed to the same infectious agent, and in the prevalence or severity of the disease, underlying the relevance of the genetic background. Population genetic studies have estimated the genetic component (susceptibility) in the ID determination and have identified some susceptibility gene(s)/polymorphism(s).

This paper describes the methods used in genetic epidemiology. Complex segregation analysis is used to define genetic models. Parametric linkage analysis and association studies are used to identify polymorphisms strongly linked to the disease. Genome-wide scan and microarray technology are used to map and identify major genes for ID. Future developments will identify subgroups of subjects at different risks of developing ID     

Bayesian Decomposition Analysis of Bacterial Phylogenomic Profiles

BACKGROUND: The past two decades have seen the appearance of new infectious diseases and the reemergence of old diseases previously thought to be under control. At the same time, the effectiveness of the existing antibacterials is rapidly decreasing due to the spread of multidrug-resistant pathogens. AIM: The aim of this study was to the identify candidate molecular targets (e.g. enzymes) within essential metabolic pathways specific to a significant subset of bacterial pathogens as the first step in the rational design of new antibacterial drugs. METHODS: We constructed a dataset of phylogenomic profiles (vectors that encode the similarity, measured by BLAST scores, of a gene across many species) for a series of 31 pathogenic bacteria of interest with 1073 genes taken from the reference organisms Escherichia coli and Mycobacterium tuberculosis. We applied Bayesian Decomposition, a matrix decomposition algorithm, to identify functional metabolic units comprising overlapping sets of genes in this dataset. RESULTS: Although no information on phylogeny was provided to the system, Bayesian Decomposition retrieved the known bacteria phylogenic relationships on the basis of the proteins necessary for survival. In addition, a set of genes required by all bacteria was identified, as well as components and enzymes specific to subsets of bacteria. CONCLUSION: The use of phylogenomic profiles and Bayesian Decomposition provide important insights for the design of new antibacterial therapeutics.     

Variables Affecting Pharmacy Students’ Patient Care Interventions during Advanced Pharmacy Practice Experiences

Objective. To identify the temporal effect and factors associated with student pharmacist self-initiation of interventions during acute patient care advanced pharmacy practice experiences (APPE).Methods. During the APPE, student pharmacists at an academic medical center recorded their therapeutic interventions and who initiated the intervention throughout clinical rotations. At the end of the APPE student pharmacists completed a demographic survey.Results. Sixty-two student pharmacists were included. Factors associated with lower rates of self-initiated interventions were infectious diseases and pediatrics APPEs and an intention to pursue a postgraduate residency. Timing of the APPE, previous specialty elective course completion, and previous hospital experience did not result in any significant difference in self-initiated recommendations.Conclusion. Preceptors should not base practice experience expectations for self-initiated interventions on previous student experience or future intentions. Additionally, factors leading to lower rates of self-initiated interventions on infectious diseases or pediatrics APPEs should be explored.     

Genome study of kidney disease in the age of post genome-sequencing

The genome-based study of human disease has been developing rapidly with the completion of the human genome project and the remarkable progress of technology. The genetic variation information associated with disease will certainly enable us to discover potential drug targets and to develop personalized medicine. Chronic kidney disease (CKD) is now recognized as a public health problem because its prevalence is increasing all over the world. No treatment can reverse the progression of CKD to end-stage renal disease (ESRD), which requires enormous medical resources. Moreover, CKD is known to be a strong risk factor for cardiovascular disease. In this review, we summarize the genetic studies that have reported a number of disease susceptibility genes and loci for CKD and ESRD. Earlier investigations, mostly by linkage analysis and association analysis with candidate gene approaches, have demonstrated that genetic factors play a crucial role in CKD and ESRD. However, the findings have contributed little great impacts related to drug discovery and diagnostic tool development in kidney diseases: further investigations are necessary to confirm the previously identified susceptibility genes. Recent technological advances will enable us to perform genome-wide association analysis, discover new disease susceptibility genes, and establish novel treatment strategies based on genomic information related to kidney disease.     

Finding genes influencing susceptibility to complex diseases in the post-genome era

During the last decade, hundreds of genes that harbor mutations causing simple Mendelian disorders have been identified using a combination of linkage analysis and positional cloning techniques. Traditional approaches to gene mapping have been largely unsuccessful in mapping genes influencing so-called 'complex' genetic diseases, however, because of low power and other factors. Complex genetic diseases do not display simple Mendelian patterns of inheritance, although genes do have an influence and close relatives of probands consequently have an increased risk. These disorders are thought to be due to the combined effects of variation at multiple interacting genes and the environment. Complex diseases have a significant impact on human health because of their high population incidence (unlike simple Mendelian disorders, which tend to be rare). New techniques are being developed aimed specifically at mapping genes conferring susceptibility to complex diseases. A project aimed at mapping genes influencing susceptibility to a complex disease may be undertaken in several stages: establishing a genetic basis for the disease in one or more populations; measuring the distribution of gene effects; studying statistical power using models; carrying out marker-based mapping studies using linkage or association. Quantitative genetic models can be used to estimate the heritability of a complex (polygenic) disease, as well as to predict the distribution of gene effects and to test whether one or more quantitative trait loci (QTLs) exist. Such models can be used to predict the power of different mapping approaches, but are often unrealistic and therefore provide only approximate predictions. Linkage analyses, association studies and family-based association tests are all hindered by low power and other specific problems. Association studies tend to be more powerful but can generate spurious associations due to population admixture. Alternative strategies for association mapping include the use of recent founder populations or unique isolated populations that are genetically homogeneous, and the use of unlinked markers (so-called genomic controls) to assign different regions of the genome of an admixed individual to particular source populations. Linkage disequilibrium observed in a sample of unrelated affected and normal individuals can also be used to fine-map a disease susceptibility locus in a candidate region. New Bayesian strategies make use of an annotated human genome sequence to further refine the position of a candidate disease susceptibility locus.     

Genomics: the implications for ethics and education

Over the past 10 years, the identification of disease genes has been expanding rapidly. Those identified in the earlier part of the decade were largely achieved through positional cloning and the majority are for relatively rare disorders which involve single genes. As the Human Genome Mapping Project has progressed, the rate of gene discovery has increased substantially through the development of new DNA sequencing techniques and in silico approaches. The human genome will have been largely sequenced by ther Spring 2000. We can expect the identification of large numbers of susceptibility genes for common multifactorial polygenic diseases as well as genes which are associated with human behavioural traits. Some of these advances hold out the prospects of real progress in the diagnosis and treatment of a wide range of disorders. However, for many individuals, increased knowledge about their genes will present ethical dilemmas which are difficult to resolve. There are also wider ethical issues which concern the use of genetic information by insurers and employers and yet others which concern ownership and access. In this chapter, the main ethical issues raised by the impact of genomics on healthcare are discussed. The role of education in enabling individuals and health professionals to meet these challenges is also considered.