Current Pharmacogenomics - Volume 1, Issue 4, 2003

The monogenetic cause of familial cardiovascular disease is being unraveled at a rapid pace. Gradually, the scope is moving from mono- to multigenetic analysis of diseases, like atherosclerosis and hypertension. The multigenic approach brings unexpected genes to the spotlight not only as relevant etiologic factors, but also as potential therapeutic targets. To understand the sensitivity of an individual for medical treatment, it is important to study gene expression in relation to treatment. The importance of this approach has been demonstrated for statin treatment as these compounds have beneficial effects on endothelial nitric oxide synthase transcription, in addition to lowering of cholesterol. However, the impact of the statin treatment can be modified by genetic variation in, for instance, the nitric oxide gene, and also in genes involved in cholesterol metabolism. These genes have a direct link to cardiovascular disease. Response to drugs however, is also dependent on general enzyme activity, which determines the rate of drug metabolism. Our knowledge on these subjects is very limited, but some of the more interesting observations are discussed here. Any review is incomplete without considering the relation between genetic variation and environment, or more specifically the cardiovascular risk factors. These topics are briefly addressed for the different cardiovascular entities including; atherosclerosis, hypertension, cardiac failure and arrhythmias.

Chronic Obstructive Pulmonary Disease (COPD) is a complex genetic disease in which multiple susceptibility genes and environmental factors interact to contribute to its development. Although there are two major approaches that can be used to identify susceptibility genes i.e. association studies and genomic scans, most of our knowledge of COPD genetics is derived from association studies. We review association studies of COPD that have examined genes involved in protease-antiprotease and oxidant-antioxidant balance, inflammation and airway defense. Currently, there are four major therapeutic approaches available: 1) Smoking cessation is the most important intervention to alter the clinical course, but only small proportion of smokers are able to quit successfully. Knowledge of genetic susceptibility may increase the rate of smoking cessation; 2) Therapy with bronchodilators; 3) Therapy with corticosteroids. The latter two approaches are the mainstay of current therapy. It has been shown that β2-adrenergic receptor (β2AR) gene polymorphisms affect β2-agonist therapy. However, no polymorphisms have been discovered that affect treatment with anticholinergics, theophylline or corticosteroids; 4) α1-antitrypsin (α1AT) replacement therapy is moderately effective in patients with α1-AT deficiency. New therapeutic methods based on knowledge of COPD genetics are urgently needed since current therapy has not been shown to prevent progression of COPD. Such methods may include protease inhibitors, mediator inhibitors and new anti-inflammatory agents. Thus, knowledge of COPD pharmacogenomics may help to tailor the most appropriate treatment for an individual patient.

It has been suggested that genetic polymorphisms in drug transporters as well as drug-metabolizing enzymes are associated with interindividual differences in drug disposition, efficacy, and toxicity and in disease. Organic anion and cation transporters are expressed in the selective or multiple tissues such as small intestine, liver and kidney, and mediate the transport of many clinically useful drugs. Polymorphisms of drug transporter genes have recently been identified and demonstrated to have functional significance for transporter activity and expression. For example, genetic variants in the OATP-C (SLC21A6) gene are associated with alterations in pravastatin and rifampin uptake into liver. In addition, homozygotes for OCTN2 (SLC22A5) mutant alleles cause systemic carnitine deficiency because of a disruption of carnitine reabsorption in the kidney. Since a growing number of preclinical and clinical studies have demonstrated that the polymorphisms of various drug transporter genes may be responsible for overall outcomes of pharmacokinetics and pharmacotherapy of certain drugs, further understanding of the physiology and biochemistry of drug transporters with respect to genetic variations will be important to establish individualized pharmacotherapy with clinically used drugs.

Thymoma is one of the most common solid tumors in the mediastinum. The histological classification of thymic epithelial tumor includes non-invasive thymoma, invasive thymoma and rare thymic carcinomas. Although several clinico-pathological and immunological studies of thymoma have been reported, little is known of the genetic alterations that occur in the tumorigenesis of thymoma. In this review, we would mention about several gene expression abnormalities in thymoma, including (1) p53, which is mutationally inactivated in many tumors; (2) matrixmetalloproteinases (MMPs), that may play important roles in tumor invasion and metastasis; (3) Epidermal growth factor receptor (EGFR), which is important in normal and neoplastic epithelial cell growth and is an attractive therapeutic target, as reviewed recently; and (4) genes at chromosome 6, which suffers frequent and multiple aberrations in thymoma. Finally, using oligonucleotide arrays to monitor in vivo gene expression levels in the early and late stage thymoma tissues, two candidate genes were identified that were more highly expressed in the advanced stage thymomas. One was a wellknown gene, c-JUN and another was an unknown gene, AL050002.

Bipolar disorder (BD), or manic-depressive illness, is a psychiatric disorder characterized by episodes of major depression and mania. The importance of genes in the etiology of BD has been substantiated through family, twin and adoption studies. BD is treated at both the prophylactic and episodic levels with lithium being one of the most common forms of prophylactic treatment. Recently, pharmacogenetics has come to play an active role in the elucidation of genetic factors that may play a role in modulating drug response. This strategy has provided hope for advancements in understanding the genetics of BD. This review encompasses several studies that either have used populations of lithium responders, responders to selective serotonin re-uptake inhibitors or responders to antidepressants in general to carry out linkage or association studies. There have been positive results found associating a polymorphism in the phospholipase C gamma 1 gene with BD and several variants of the serotonin transporter gene have been related either to worse response or nonresponse, as well as, linkage studies providing evidence for new loci to explore. Although data examining the pharmacogenetics of BD remain scarce, it is clear that this is a promising avenue of investigation. Whether used to define genetically more homogeneous populations or to search for genetic predictors of drug response, pharmacogenetic strategies in BD have produced interesting results thus far and further investigation is warranted.

One major driver of the uptake of pharmacogenomics will be its economic impact on overall health care costs. Given rising health care expenditures and limited health care budgets, pharmacogenomic strategies will be subject to the same scrutiny on their economic impact as other health care technologies. This review examines the economic factors relevant to key U.S. stakeholders applying pharmacogenomic strategies to clinical practice. The primary objective of this review is to examine the potential impact of pharmacogenomic strategies on health care delivery, costs, and policies. A secondary objective of this review is to highlight the economic differences between genetic testing for drug therapy versus disease risk prediction. We address these issues by examining key factors and stakeholders that will shape the economic impact of pharmacogenomics. These stakeholders include patients, providers, the pharmaceutical industry, insurers, and governmental institutions. We conclude that, it is critical that we merge our understanding of the key economic issues with current pharmacogenomic research such that evaluations take place before new technologies are widely adopted in health care systems.