Pharmacogenomics is of particular importance in oncology, a medical subspecialty characterized by rapidly lethal diseases and drugs with narrow therapeutic indices and significant toxicities. Identification of individuals likely to respond to or experience toxicity from a given chemotherapeutic agent, will have significant impact on outcomes, particularly in the field of oncology. Several models currently exist for discovery of pharmacogenomic markers in oncology. Phenotypic variations may range from variability in response as measured by survival or time to progression, to variability in toxicity in individuals treated with a particular agent. Measurements of toxicity can be a challenge to quantify in individuals because of interobserver variability. Lymphoblastoid cell lines (LCLs) and the NCI60 bank of tumor cell lines have been used as models for clinical phenotypes. To date, there are several examples of germline polymorphisms and somatic mutations that predict likelihood of response and/or toxicity from chemotherapeutic agents. A pattern of interethnic variability in response and toxicity has been observed for some chemotherapeutic agents, and the associated field of pharmacoethnicity is likely to contribute to our understanding of pharmacogenomics.

Pharmacogenomics has found extensive application in the field of oncology and is likely to remain an important tool in the race toward personalized medicine. Individualization of therapies is of particular importance in oncology because of several unique features of cancer treatment. First, most oncologic therapies have potential for organ toxicity and typically give rise to an array of potential life-threatening side effects. For example, taxanes are highly efficacious against malignancies of the lung, breast, ovary, and head and neck, but are also associated with significant toxicities such as myelosuppression and peripheral neuropathy. Identification of individuals unlikely to respond to taxane therapy a priori will be tremendously important in therapeutic decision making, because alternative therapies can be considered, thereby reducing the likelihood of unnecessary toxicity. Second, many oncologic diseases progress rapidly and are generally lethal in the absence of effective therapy. Consequently, prompt diagnosis and early institution of efficacious therapies is of paramount importance. In the absence of knowledge about predictors of response, individuals could be subjected to therapies to which their tumors might not respond, resulting in further disease progression. With more advanced disease and organ dysfunction, some therapies may no longer be given safely and may only serve a palliative rather than a curative role. For example, a five-year period of adjuvant tamoxifen therapy following successful treatment of early-stage estrogen receptor (ER)-positive breast cancer in a premenopausal woman is associated with a reduction in the rate of disease recurrence and mortality. A poor metabolizer phenotype results in insufficient conversion of tamoxifen to endoxifen and an increased risk of disease relapse and progression (1). Affected individuals may be better served by alternative antiestrogen maneuvers such as the combination of ovarian ablation and aromatase inhibitor therapy. Third, most chemotherapeutic agents have a fairly narrow therapeutic index (see Figure 10.1). The therapeutic index of a drug compares the dose that produces toxicity with the dose that produces the desired effect and, as such, provides a measure of the drug's safety. Given the significant likelihood of an adverse effect even within the therapeutic window, treatment with a particular agent is best reserved for individuals likely to respond, with the careful weighing of risks and benefits and informed decision making on the part of the patient. Finally, the expenses associated with oncologic therapies necessitate avoidance of therapy-related morbidity that further increases the likelihood of hospitalization and overall cost of care. For example, trastuzumab is an agent used in the treatment of HER2neu-positive breast cancer, is typically infused on a three-weekly schedule for at least one year, and may cost as much as $70,000 for a full course of therapy (2). Given all the aforementioned, it is not surprising that current pharmacogenomic research is dominated by investigation of variability in response to, and toxicity from, oncologic therapies (3).

The Human Genome Project has fueled rapid progress in pharmacogenomics over the past decade. Genetic variability of drug response was suspected in the mid-twentieth century, but scientists only now are gaining the ability to explain this variability and harness it to improve health outcomes. These advances are forcing health care professionals and regulators to reevaluate the duties they owe to the people they serve and protect. Patients with identical symptoms may have genetic differences that carry important implications for the best choice of therapy and for the physician's standard of care. Clinical trial subjects who seem comparable under traditional trial selection criteria like age, gender, or severity of underlying disease may not be comparable at all when genetic differences are taken into account. Studies that gloss over these differences may mislead the public about the safety and effectiveness of the drugs they consume, yet regulators routinely rely on such studies when approving new drugs. Additional steps are needed to protect the public. The very notion of “the public” is evolving as pharmacogenomics divides the population into multiple subgroups. Regulators who once needed only to protect a single, homogeneous “public” now face a situation where their decisions visit disparate impacts on various subgroups within the broader public they are seeking to protect. This shift in perspective already is reshaping the legal and commercial environment for medical products and health care.

This chapter explores trends that are emerging as law adapts to the era of personalized genomic medicine. The focus is on how the broad contours of regulations affecting drugs and medical devices are changing and how these changes may affect clinicians, patients, medical researchers, and people who participate in biomedical research. Important reforms already are in progress, and more can be expected in coming years. One concrete example is the Food and Drug Administration Amendments Act of 2007 (FDAAA), which instituted a major program to modernize medical product regulation by the U.S. Food and Drug Administration (FDA). Related reforms are on the drawing board or already are being implemented in various nations around the world.

Rheumatoid arthritis (RA) is the most common inflammatory rheumatic disease, with a population prevalence of 2 percent to 3 percent and an annual incidence rate of 0.5 percent to 1.0 percent. Like many autoimmune conditions, it affects women more commonly than men (4:1). The prevalence of RA increases from the third decade through the eighth. Because it is the most common inflammatory rheumatic disease, most pharmacogenetic studies in adult rheumatology have concentrated on treatments for RA, and this will be the focus of the chapter.

Clinically, RA is a painful condition associated with significant disability. It primarily affects the joints, resulting in pain, swelling, and loss of musculoskeletal function. Because of its chronic nature, small changes accumulate and many patients experience substantial disability over the decades that they live with the condition. Although classical extraarticular manifestations (e.g., vasculitis, Felty's syndrome, spine disease) have diminished in frequency, there is an increasing awareness that the inflammation of RA places patients at increased risk for common conditions, such as cardiovascular disease, osteoporosis, and insulin resistance. These chronic comorbidities also contribute to the disability associated with RA.

Introduction: The Burden of Respiratory Disease

Respiratory disease refers to the broad category of illnesses affecting the upper and lower airways, the lung parenchyma, and the pulmonary vasculature. To date, however, studies focusing on the pharmacogenetics of respiratory disease have been largely concentrated in the areas of lung cancer and obstructive lung disease. This is primarily due to the relative rarity of many pulmonary diseases, providing insufficient sample size for pharmacogenetic studies. In addition, for many respiratory diseases, there is a relative paucity of available therapies, providing no current alternatives even if a priori prediction of poor response to therapies was available. For many of these diseases (e.g., interstitial pulmonary fibrosis, chronic hypersensitivity pneumonitis, and primary pulmonary hypertension), multicenter studies and/or industry collaborations are warranted. This chapter focuses on the genetics of drug treatment response in obstructive lung disease, with an emphasis on the pharmacogenetics of asthma. Although lung cancer is the leading cause of cancer deaths in both males and females in America and clearly of great importance, the pharmacogenetics of oncologic disorders has been covered separately in Chapter 10. We will review how the respiratory pharmacogenetics fits within the context of the four major categories of pharmacogenetic response and detail approaches to defining respiratory pharmacogenetic phenotypes. The chapter continues with a review of the literature on the pharmacogenetic associations that have been characterized in relation to asthma and chronic obstructive pulmonary disease (COPD). We conclude with some thoughts on the future of pharmacogenetics in these two diseases. However, we first provide an overview of the burden of obstructive respiratory disease.

Chronic obstructive respiratory disease, including COPD and asthma, is currently the fourth leading cause of death in the United States and is projected to move into third place nationwide by 2020 (1). Although mortality rates for the top two leading causes of death in the United States, heart disease and cancer, respectively, are decreasing, deaths from chronic lung disease continue to rise. According to the National Center for Health Statistics, more than 16 million people in the United States have been diagnosed with COPD, and it is estimated that another 16 million cases are undiagnosed (2). COPD cost the nation more than $30 billion in 2000, $14.7 billion in direct health care costs and $15.7 billion in indirect costs. In 2007, there were 22.9 million Americans with asthma, with an estimated annual cost of $19.7 billion ($14 billion in direct costs, of which the largest component was medication costs). Whereas COPD is a leading cause of morbidity and mortality in the elderly, asthma remains the leading cause of hospitalizations and school absences in children.

No area within the field of pharmacogenomics generates greater excitement and potential for altering the way we practice medicine than fetal and neonatal pharmacogenomics. Though only in its infancy (no pun intended), this area that lies at the crossroads of perinatology, neonatology, pharmacology, and genetics will undoubtedly not only shape the way we diagnose and treat diseases of expectant mothers and their infants, but also improve our overall understanding of fetal and neonatal development. By focusing our attention on variations in genetic code and gene expression between the pre- and postnatal life, pharmacogenomics will likely contribute greatly to our understanding of cellular, tissue, and organ differentiation, physiologic and pathologic fetal development, and important variation in fetal and neonatal drug metabolism.

Fetal exposure to maternal medications may occur as a result of deliberate maternal drug therapy or inadvertent drug exposure. Since the discovery linking thalidomide with birth defects, obstetricians and their expectant patients have had to weigh the balance between maternal drug therapy and potential fetal exposure. As we gain insight into specific medications and their adverse fetal effects, it is clear that not all fetuses exposed to a given medication are at risk for developing its associated malformation. Moreover, if we can identify which fetuses may be at risk during the course of pregnancy, it would greatly benefit expectant mothers taking medications, especially in cases where exposure cannot be avoided as with antiepileptic and antithrombotic medications (1).

Scope of Cardiovascular Therapeutics

An estimated 81 million American adults (37.1 percent) have cardiovascular disease (CVD), including coronary artery disease, hypertension, congestive heart failure, and stroke (1). CVD accounts for 36.3 percent of all deaths in the United States (2,400 deaths daily) and is the most common cause of death in developed countries. These chronic diseases usually require lifelong drug treatment, and medications for their treatment or prevention are among the most commonly prescribed drugs worldwide.

Hypertension, congestive heart failure, and other CVDs are often considered as discrete entities, but are, in fact, complex and heterogeneous syndromes mediated by many different pathophysiological mechanisms that eventually result in a similar clinical picture. As a result, clear and reproducible identification of environmental and genetic factors that contribute to these multifactorial diseases is challenging. Adding to the challenges, there is large variability, only a portion of which is genetically determined, among patients in their responses to a drug for a particular disease.

Pain is a fundamental biological response to noxious stimuli, comprising both unpleasant physical perceptions and negative emotions. It signals actual or potential tissue damage, and elicits protective responses needed for survival, such as withdrawal (1). There is profound interindividual variability in the response to noxious stimuli, susceptibility to pain, and the response to analgesics. This chapter will review the genetic factors that influence pain and sensitivity, and the response to drugs for acute and chronic pain therapy. Issues associated with analgesics, such as tolerance, dependence, and withdrawal, will not be addressed. Significant advances in understanding the neurobiology of pain have been made using genetic models (1). This chapter will focus on human pain and analgesia.

General anesthesia, whose goal is to render a patient insensitive to pain and control physiologic responses in the perioperative period, has as its two most basic elements analgesia and hypnosis (“sleep”). Nevertheless, a typical anesthetic comprises drugs from numerous classes, including benzodiazepine anxiolytics, sedative-hypnotics, inhalation anesthetics, opioids, muscle relaxants and their antagonists, and cardiovascular/vasoactive drugs (so-called balanced anesthesia). This chapter will also review the genetic factors that influence the response to anesthetics, with a focus on drug classes not covered in other chapters. Because opioids are central to both anesthesia and pain therapy, these will be a central focus. It is instructive to note that the field of pharmacogenetics had its birth in anesthesiology, with the discovery by Werner Kalow of heritable responses to the muscle relaxant succinylcholine (2, 3).

The primary objective of this chapter is to provide an overview of the clinical applications of psychiatric pharmacogenomic testing. Essentially, two current primary objectives of testing exist. The first is to identify medications for which a patient is at increased risk for developing side effects or adverse events. The second is to identify medications that are less likely to be effective. Ultimately, the objective of psychiatric pharmacogenomics will be to identify psychotropic medications that have a high probability of achieving a therapeutic response for an individual patient based on the identification of specific genetic variations (1).

Although clinical psychiatric pharmacogenomic testing was being provided at some academic centers before 2004, the introduction of the AmpliChip and its approval by the Food and Drug Administration in 2004 was an important milestone in the clinical adoption of genetic testing that was designed to provide guidance in the selection and dosing of psychiatric medications. Over the next 5 years, many academic medical centers introduced clinical pharmacogenomic testing of drug-metabolizing enzyme genes as a component of the clinical evaluation of patients with atypical responses to medication. As the cost of psychiatric pharmacogenomic testing decreases, there is a growing expectation that genotyping patients before initiating treatment with psychotropic medication will be a cost-effective clinical strategy to minimize adverse events.