Pharmacogenetics and pharmacogenomics deal with the genetic basis underlying variable drug response in individual patients. The traditional pharmacogenetic approach relies on studying sequence variations in candidate genes suspected of affecting drug response. On the other hand, pharmacogenomic studies encompass the sum of all genes, i.e., the genome. Numerous genes may play a role in drug response and toxicity, introducing a daunting level of complexity into the search for candidate genes. The high speed and specificity associated with newly emerging genomic technologies enable the search for relevant genes and their variants to include the entire genome. These new technologies have essentially spawned a new discipline, termed pharmacogenomics, which seeks to identify the variant genes affecting the response to drugs in individual patients. Moreover, pharmacogenomic analysis can identify disease susceptibility genes representing potential new drug targets. All of this will lead to novel approaches in drug discovery, an individualized application of drug therapy, and new insights into disease prevention. Current concepts in drug therapy often attempt treatment of large patient populations as groups, irrespective of the potential for individual, genetically-based differences in drug response. In contrast, pharmacogenomics may help focus effective therapy on smaller patient subpopulations which although demonstrating the same disease phenotype are characterized by distinct genetic profiles. Whether and to what extent this individual, genetics-based approach to medicine results in improved, economically feasible therapy remain to be seen.
To exploit these opportunities in genetic medicine, novel technologies will be needed, legal and ethical questions must be clarified, health care professionals must be educated, and the public must be informed about the implications of genetic testing in drug therapy and disease management.
Neurosteroids play an important role in the development of the cerebellum. In particular, estradiol and progesterone appear capable of inducing increases in dendritic spine density during development, and there is evidence that both are synthesized de novo in the cerebellum during critical developmental periods. In normal neonates and adults, there are few differences in the cerebellum between the sexes and most studies indicate that hormone and receptor levels also do not differ significantly during development. However, the sexes do differ significantly in risk of neuropsychological diseases associated with cerebellar pathology, and in animal models there are noticeable sex differences in the response to insult and genetic mutation. In both humans and animals, males tend to fare worse. Boys are more at risk for autism and Attention Deficit Hyperactivity Disorder than girls, and schizophrenia manifests at an earlier age in men. In rats males fare worse than females after perinatal exposure to polychlorinated biphenyls, and male mice heterozygous for the staggerer and reeler mutation show a more severe phenotype. Although very recent evidence suggests that differences in neurosteroid levels between the sexes in diseased animals may play a role in generating different disease phenotypes, the reason this hormonal difference occurs in diseased but not normal animals is currently unknown.
Neurosteroids; cerebellum; neuropsychological diseases; gender
Numerous studies in humans and experimental animals have identified considerable sex differences in respiratory physiology and in the response of the lung to environmental agents. These differences appear to be mediated, at least in part, by sex hormones and their nuclear receptors. Moreover, animal models are increasingly used to study pathogenic mechanisms and test potential therapies for a variety of human lung diseases, many of which appear to be influenced by sex and sex hormones. In this article, data are summarized from studies of lung function and disease in which sex differences have been observed. Specific attention is paid to animal models of acute lung injury, nonallergic and allergic lung inflammation, and lung fibrosis. It is anticipated that continued investigation of the role of sex and sex hormones in animal models will provide valuable insight into the pathogenesis and potential treatments for a variety of acute and chronic human lung diseases.
sex; sex hormones; respiratory mechanics; inflammation; airway
Sex differences occur in most non-communicable diseases, including metabolic diseases, hypertension, cardiovascular disease, psychiatric and neurological disorders and cancer. In many cases, the susceptibility to these diseases begins early in development. The observed differences between the sexes may result from genetic and hormonal differences and from differences in responses to and interactions with environmental factors, including infection, diet, drugs and stress. The placenta plays a key role in fetal growth and development and, as such, affects the fetal programming underlying subsequent adult health and accounts, in part for the developmental origin of health and disease (DOHaD). There is accumulating evidence to demonstrate the sex-specific relationships between diverse environmental influences on placental functions and the risk of disease later in life. As one of the few tissues easily collectable in humans, this organ may therefore be seen as an ideal system for studying how male and female placenta sense nutritional and other stresses, such as endocrine disruptors. Sex-specific regulatory pathways controlling sexually dimorphic characteristics in the various organs and the consequences of lifelong differences in sex hormone expression largely account for such responses. However, sex-specific changes in epigenetic marks are generated early after fertilization, thus before adrenal and gonad differentiation in the absence of sex hormones and in response to environmental conditions. Given the abundance of X-linked genes involved in placentogenesis, and the early unequal gene expression by the sex chromosomes between males and females, the role of X- and Y-chromosome-linked genes, and especially those involved in the peculiar placenta-specific epigenetics processes, giving rise to the unusual placenta epigenetic landscapes deserve particular attention. However, even with recent developments in this field, we still know little about the mechanisms underlying the early sex-specific epigenetic marks resulting in sex-biased gene expression of pathways and networks. As a critical messenger between the maternal environment and the fetus, the placenta may play a key role not only in buffering environmental effects transmitted by the mother but also in expressing and modulating effects due to preconceptional exposure of both the mother and the father to stressful conditions.
Epigenetics; Histone modifications; DNA methylation; Nutrition; DOHaD; Environment; Fetal programming; Sexual dimorphism
Children and young adults of reproductive age have emerged as groups that are highly vulnerable to the current 2009 H1N1 pandemic. The sex of an individual is a fundamental factor that can influence exposure, susceptibility and immune responses to influenza. Worldwide, the incidence, disease burden, morbidity and mortality rates following exposure to the 2009 H1N1 influenza virus differ between males and females and are often age-dependent. Pregnancy and differences in the presentation of various risk factors contribute to the worse outcome of infection in women. Vaccination and antiviral treatment efficacy also vary in a sex-dependent manner. Finally, sex-specific genetic and hormonal differences may contribute to the severity of influenza and the clearance of viral infection. The contribution of sex and gender to influenza can only be determined by a greater consideration of these factors in clinical and epidemiological studies and increased research into the biological basis underlying these differences.
Large interindividual variation is observed in both the response and toxicity associated with anticancer therapy. The etiology of this variation is multifactorial, but is due in part to host genetic variations. Pharmacogenetic and pharmacogenomic studies have successfully identified genetic variants that contribute to this variation in susceptibility to chemotherapy. This review provides an overview of the progress made in the field of pharmacogenetics and pharmacogenomics using a five-stage architecture, which includes 1) determining the role of genetics in drug response; 2) screening and identifying genetic markers; 3) validating genetic markers; 4) clinical utility assessment; and 5) pharmacoeconomic impact. Examples are provided to illustrate the identification, validation, utility, and challenges of these pharmacogenetic and pharmacogenomic markers, with the focus on the current application of this knowledge in cancer therapy. With the advance of technology, it becomes feasible to evaluate the human genome in a relatively inexpensive and efficient manner; however, extensive pharmacogenetic research and education are urgently needed to improve the translation of pharmacogenetic concepts from bench to bedside.
Current pharmacogenomic studies have begun to integrate genetics, gene expression and pharmacologic phenotypes. MicroRNAs (miRNAs), small RNAs (21–25 nucleotides) found in almost all metazoan genomes, have been discovered to be a novel class of gene regulators that generally down-regulate gene expression at the post-transcriptional level. Experimental evidence for the roles of miRNAs in regulating pharmacology-related genes and drug response is now accumulating. Given the universal roles of miRNAs in various diseases such as human cancer, their potential effects on therapeutic treatments (e.g., chemotherapy) for these diseases could be expected. The on-going efforts of pharmacogenomics to incorporate miRNAs could provide more insights into the complex phenotype of drug response, though more studies may be necessary to evaluate their effects in patients since most of the current findings are indirect or in vitro.
microRNA; gene expression; gene regulation; drug response; pharmacogene; pharmacogenomics
Many clinical trials of oncology drugs now include at least a consideration of pharmacogenomics, the study of germline or acquired genetic factors governing a drug's response and toxicity. Besides the potential benefit to patients from the consideration of personalized pharmacogenomic information when making treatment decisions, there is a clear incentive for oncology drug developers to incorporate pharmacogenomic factors in the drug development process since pharmacogenomic biomarkers may allow predictive characterization of sub-populations within a disease that may particularly respond, or may allow preidentification of patients at highest risk for adverse events. There is, however, a lack of agreement in actual practice as to where in the oncology clinical drug development process pharmacogenomic studies should be incorporated. In this article, we examine the recent growth of pharmacogenomics in oncology clinical trials, especially in early phase studies, and examine several critical questions facing the incorporation of pharmacogenomics in early oncologic drug development. We show that phase II clinical trials in particular have a favorable track record for demonstrating positive pharmacogenomic signals, worthy of additional follow-up and validation, and that the phase II setting holds significant promise for potentially accelerating and informing future phase III trials. We conclude that phase II trials offer an ideal “sweet spot” for routine incorporation of pharmacogenomic questions in oncology drug development.
phase II; oncology; clinical trials; pharmacogenomics; biomarker development
This review examines sex differences in health and survival, with a focus on the Nordic countries. There is a remarkable discrepancy between the health and survival of the sexes: men are physically stronger and have fewer disabilities, but have substantially higher mortality at all ages compared with women: the so-called male-female health-survival paradox. A number of proposed explanations for this paradox are rooted in biological, social, and psychological interpretations. It is likely to be due to multiple causes that include fundamental biological differences between the sexes such as genetic factors, immune system responses, hormones, and disease patterns. Behavioral differences such as risk-taking and reluctance to seek and comply with medical treatment may also play a role. Another consideration is that part of the difference may be due to methodological challenges, such as selective non-participation and under-reporting of health problems, and delayed seeking of treatment by men. The Nordic countries provide a unique opportunity for such studies, as theyhave good-quality data in their national health registers, which cover the whole population, and a long tradition of high participation rates in surveys.
Health; mortality; Nordic countries; review; sex differences
Sex steroid hormones play important physiological roles in reproductive and nonreproductive tissues, including immune cells. These hormones exert their functions by binding to either specific intracellular receptors that act as ligand-dependent transcription factors or membrane receptors that stimulate several signal transduction pathways. The elevated susceptibility of males to bacterial infections can be related to the usually lower immune responses presented in males as compared to females. This dimorphic sex difference is mainly due to the differential modulation of the immune system by sex steroid hormones through the control of proinflammatory and anti-inflammatory cytokines expression, as well as Toll-like receptors (TLRs) expression and antibody production. Besides, sex hormones can also affect the metabolism, growth, or virulence of pathogenic bacteria. In turn, pathogenic, microbiota, and environmental bacteria are able to metabolize and degrade steroid hormones and their related compounds. All these data suggest that sex steroid hormones play a key role in the modulation of bacterial-host interactions.
Females and males differ in physiology and in the incidence and progression of diseases. The sex-biased proximate factors causing sex differences in phenotype include direct effects of gonadal hormones and of genes represented unequally in the genome because of their X- or Y-linkage. Novel systems approaches have begun to assess the magnitude and character of sex differences in organization of gene networks on a genome-wide scale. These studies identify functionally related modules of genes that are co-expressed differently in males and females, and sites in the genome that regulate gene networks in a sex-specific manner. The measurement of the aggregate behavior of genes uncovers novel sex differences that can be related more effectively to susceptibility to disease.
XX and XY cells have a different number of X and Y genes. These differences in their genomes cause sex differences in the functions of cells, both in the gonads and in non-gonadal tissues. This review discusses mouse models that have shed light on these direct genetic effects of sex chromosomes that cause sex differences in physiology. Because many sex differences in tissues are caused by different effects of male and female gonadal hormones, it is important to attempt to discriminate between direct genetic and hormonal effects. Numerous mouse models exist in which the number of X or Y genes is manipulated, to observe the effects on phenotype. In two models, the Afour core genotypes@ model and SF1 knockout gonadless mice, it has been possible to detect sex chromosome effects that are not explained by group differences in gonadal hormones. Moreover, mouse models are available to determine whether the sex chromosome effects are caused by X or Y genes.
Under physiological conditions, the response of Xenopus laevis laryngeal muscle fibers to nerve stimulation is sexually differentiated; subthreshold potentials are common in males and rare in females. This sex difference in muscle fiber response is correlated with sex differences in vocal behavior. Quantal analyses at male and female laryngeal synapses were performed to determine if there is a sex difference in synaptic strength. Quantal content at laryngeal synapses is significantly higher in females than in males. Values for quantal content in males can be increased by raising extracellular calcium concentration. There is no sex difference in miniature endplate potential amplitude suggesting that ACh receptor number or properties are not different in the sexes. Sex differences in synaptic strength thus appear presynaptic in origin; transmitter release is less in males. Ultrastructural analyses of the laryngeal motor terminal indicate that there is no sex difference in the length of active zones or in the number of channels per length of active zone. Thus, ultrastructural characteristics of the laryngeal motor terminal do not account for the pronounced sex difference in quantal content.
active zones; frog; miniature endplate potentials; quantal content; synaptic strength; vocal behavior
In this review we propose that there are sex differences in how men and women enter onto the path that can lead to addiction. Males are more likely than females to engage in risky behaviors that include experimenting with drugs of abuse, and in susceptible individuals, they are drawn into the spiral that can eventually lead to addiction. Women and girls are more likely to begin taking drugs as self-medication to reduce stress or alleviate depression. For this reason women enter into the downward spiral further along the path to addiction, and so transition to addiction more rapidly. We propose that this sex difference is due, at least in part, to sex differences in the organization of the neural systems responsible for motivation and addiction. Additionally, we suggest that sex differences in these systems and their functioning are accentuated with addiction. In the current review we discuss historical, cultural, social and biological bases for sex differences in addiction with an emphasis on sex differences in the neurotransmitter systems that are implicated.
Addiction; Dopamine; Acetylcholine; Norepinephrine; Dynorphin; Cocaine; Heroin
Telomere dynamics are intensively studied in human ageing research and epidemiology, with many correlations reported between telomere length and age-related diseases, cancer and death. While telomere length is influenced by environmental factors there is also good evidence for a strong heritable component. In human, the mode of telomere length inheritance appears to be paternal and telomere length differs between sexes, with females having longer telomeres than males. Genetic factors, e.g. sex chromosomal inactivation, and non-genetic factors, e.g. antioxidant properties of oestrogen, have been suggested as possible explanations for these sex-specific telomere inheritance and telomere length differences. To test the influence of sex chromosomes on telomere length, we investigated inheritance and sex-specificity of telomere length in a bird species, the kakapo (Strigops habroptilus), in which females are the heterogametic sex (ZW) and males are the homogametic (ZZ) sex. We found that, contrary to findings in humans, telomere length was maternally inherited and also longer in males. These results argue against an effect of sex hormones on telomere length and suggest that factors associated with heterogamy may play a role in telomere inheritance and sex-specific differences in telomere length.
A consistent observation in drug abuse research is that males and females show differences in their response to drugs of abuse. In order to understand the neurobiology underlying cocaine abuse and effective treatments, it is important to consider the role of sex differences. Sex hormones have been investigated in both behavioral and molecular studies, but further evidence addressing drug abuse and dependence in both sexes would expand our knowledge of sex-differences in response to drugs of abuse. Neuroimaging is a powerful tool that can offer insight into the biological bases of these differences and meet the challenges of directly examining drug-induced changes in brain function. As such, neuroimaging has drawn much interest in recent years. Specifically, positron emission tomography (PET), single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) technology have emerged as effective non-invasive approaches for human and animal models. Studies have revealed sex-specific changes in patterns of brain activity in response to acute cocaine injection and following prolonged cocaine use. SPECT and PET studies have demonstrated changes in the dopamine transporter but are less clear on other components of the dopaminergic system. This review highlights contributions of neuroimaging toward understanding the role of sex differences in the drug abuse field, specifically regarding cocaine, and identifies relevant questions that neuroimaging can effectively address.
drug abuse; neuroimaging; sex differences; cocaine; MRI; PET; SPECT
Until about 50 years ago, the altering of a normal drug effect by a genetic deficiency was only rarely observed. Here, my discovery of the genetic variant of butyrylcholinesterase affecting succinylcholine action is described in some detail. Such discoveries led to the combination of the two older sciences, genetics and pharmacology, thereby forming pharmacogenetics. After the discovery of similar examples in the years that followed, pharmacogenetics expanded on the basis of two discoveries. First, the common occurrence of interethnic differences in drug response and, secondly, the fact that most pharmacological differences were multigenic. New methodologies brought a transition to pharmacogenomics; this included detection of clinically important genetic variants and has uncovered potentially new drug targets. The arrival of personalised medicine -- where a patient's genes determine the choice of drug to be administered -- can be hoped to gradually improve drug safety and efficacy. Efforts to reach this level of perfection are, however, dogged by uncertainties.
pharmacogenetics; butyrylcholinesterase; interethnic pharmocogenomics; personalised medicine; multigenic variation; history
The roles of sex hormones as modulators of lung function and disease have received significant attention as differential sex responses to various lung insults have been recently reported. The present study used a bleomycin-induced pulmonary fibrosis model in C57BL/6 mice to examine potential sex differences in physiological and pathological outcomes. Endpoints measured included invasive lung function assessment, immunological response, lung collagen deposition, and a quantitative histological analysis of pulmonary fibrosis. Male mice had significantly higher basal static lung compliance than female mice (P < 0.05) and a more pronounced decline in static compliance after bleomycin administration when expressed as overall change or percentage of baseline change (P < 0.05). In contrast, there were no significant differences between the sexes in immune cell infiltration into the lung or in total lung collagen content after bleomycin. Total lung histopathology scores measured using the Ashcroft method did not differ between the sexes, while a quantitative histopathology scoring system designed to determine where within the lung the fibrosis occurred indicated a tendency toward more fibrosis immediately adjacent to airways in bleomycin-treated male versus female mice. Furthermore, castrated male mice exhibited a female-like response to bleomycin while female mice given exogenous androgen exhibited a male-like response. These data indicate that androgens play an exacerbating role in decreased lung function after bleomycin administration, and traditional measures of fibrosis may miss critical differences in lung function between the sexes. Sex differences should be carefully considered when designing and interpreting experimental models of pulmonary fibrosis in mice.
fibrosis; bleomycin; sex; respiratory mechanics
We have used a simple and efficient method to identify condition-specific transcriptional regulatory sites in vivo to help elucidate the molecular basis of sex-related differences in transcription, which are widespread in mammalian tissues and affect normal physiology, drug response, inflammation, and disease. To systematically uncover transcriptional regulators responsible for these differences, we used DNase hypersensitivity analysis coupled with high-throughput sequencing to produce condition-specific maps of regulatory sites in male and female mouse livers and in livers of male mice feminized by continuous infusion of growth hormone (GH). We identified 71,264 hypersensitive sites, with 1,284 showing robust sex-related differences. Continuous GH infusion suppressed the vast majority of male-specific sites and induced a subset of female-specific sites in male livers. We also identified broad genomic regions (up to ∼100 kb) showing sex-dependent hypersensitivity and similar patterns of GH responses. We found a strong association of sex-specific sites with sex-specific transcription; however, a majority of sex-specific sites were >100 kb from sex-specific genes. By analyzing sequence motifs within regulatory regions, we identified two known regulators of liver sexual dimorphism and several new candidates for further investigation. This approach can readily be applied to mapping condition-specific regulatory sites in mammalian tissues under a wide variety of physiological conditions.
Sexual dimorphism in anatomical, physiological, and behavioural traits characterize many vertebrate species. In humans, sexual dimorphism is also observed in the prevalence, course, and severity of many common diseases, including cardiovascular diseases, autoimmune diseases, and asthma. Although sex differences in the endocrine and immune systems probably contribute to these observations, recent studies suggest that sex-specific genetic architecture also influences human phenotypes, including reproductive, physiological, and disease traits. It is likely that an underlying mechanism is differential gene regulation in males and females, particularly in sex steroid responsive genes. Genetic studies that ignore sex-specific effects in their design and interpretation could fail to identify a significant proportion of the genes that contribute to risk for complex diseases.
The past decade has seen substantial advances in cardiovascular pharmacogenomics. Genetic determinants of response to clopidogrel and warfarin have been defined, resulting in changes to the product labels for these drugs that suggest the use of genetic information as a guide for therapy. Genetic tests are available, as are guidelines for incorporation of genetic information into patient-care decisions. These guidelines and the literature supporting them are reviewed herein. Significant advances have also been made in the pharmacogenomics of statin-induced myopathy and the response to β-blockers in heart failure, although the clinical applications of these findings are less clear. Other areas hold promise, including the pharmacogenomics of antihypertensive drugs, aspirin, and drug-induced long-QT syndrome (diLQTS). The potential value of pharmacogenomics in the discovery and development of new drugs is also described. In summary, pharmacogenomics has current applications in the management of cardiovascular disease, with clinically relevant data continuing to mount.
Stronger selection on males has the potential to lower the deleterious mutation load of females, reducing the cost of sex. However, few studies have directly quantified the strength of selection for both sexes. As the magnitude of inbreeding depression (ID) is related to the strength of selection, we measured the cost of inbreeding for both males and females in a laboratory population of Drosophila melanogaster. Using a novel technique for inbreeding, we found significant ID for both juvenile viability and adult fitness in both sexes. The genetic variation responsible for this depression in fitness appeared to be recessive for adult fitness (h=0.11) and partially additive for juvenile viability (h=0.29). ID was identical across the sexes in terms of juvenile viability but was significantly more deleterious for males than females as adults, even though female X-chromosome homogamety should predispose them to a higher inbreeding load. We estimated the strength of selection on adult males to be 1.24 greater than on adult females, and this appears to be a consequence of selection arising from competition for mates. Combined with the generally positive intersexual genetic correlation for inbred lines, our results suggest that the mutation load of sexual females could be meaningfully reduced by stronger selection acting on males.
sexual selection; mutation load; adult fitness; viability; inbreeding; intersexual genetic correlation
The existence of a sex difference in Parkinson’s disease (PD) is observed as related to several variables, including susceptibility of the disease, age at onset, and symptoms. These differences between men and women represent a significant characteristic of PD, which suggest that estrogens may exert beneficial effects against the development and the progression of the disease. This paper reviews the neuroprotective and neuromodulator effects of 17β-estradiol and progesterone as compared to androgens in the nigrostriatal dopaminergic (NSDA) system of both female and male rodents. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice model of PD and methamphetamine toxicity faithfully reproduce the sex differences of PD in that endogenous estrogen levels appear to influence the vulnerability to toxins targeting the NSDA system. Exogenous 17β-estradiol and/or progesterone treatments show neuroprotective properties against NSDA toxins while androgens fail to induce any beneficial effect. Sex steroid treatments show male and female differences in their neuroprotective action against methamphetamine toxicity. NSDA structure and function, as well as the distribution of estrogen receptors, show sex differences and may influence the susceptibility to the toxins and the response to sex steroids. Genomic and non-genomic actions of 17β-estradiol converge to promote survival factors and the presence of both estrogen receptors α and β are critical to 17β-estradiol neuroprotective action against MPTP toxicity.
17β-estradiol; androgens; dopamine; neuroprotection; neuromodulation; sex difference; MPTP; methamphetamine
The approval of new medicines has slowed significantly over the past years. In order to accelerate the development of new compounds, novel approaches in drug development are required. Translational medicine or research, an emerging discipline on the frontier of basic science and medical practice, has the potential to enhance the speed and efficiency of the drug development process through the utilization of pharmacogenetics and pharmacogenomics. Pharmacogenetics is the study of genetic causes of individual variations in drug response whereas pharmacogenomics deals with the simultaneous impact of multiple mutations in the genome that may determine the patient’s response to drug therapy. The utilization of these methods in the drug development process may therefore identify patient sub-populations that exhibit more effective responses and/or an improved benefit/risk profile upon treatment. The authors provide examples of the use of pharmacogenetics and pharmacogenomics in the fields of cardiovascular, pulmonary, oncological, and bone diseases and also highlight the potential economic value of their development.
benefit/risk profile, metabolism, pharmacodynamics, pharmacogenetics, pharmacogenomics, translational medicine
The ability to predict how an individual patient will respond to a particular treatment is the ambitious goal of personalized medicine. The genetic make up of an individual has been shown to play a role in drug response. For pharmacogenomic studies, human lymphoblastoid cell lines (LCLs) comprise a useful model system for identifying genetic variants associated with pharmacologic phenotypes. The availability of extensive genotype data for many panels of LCLs derived from individuals of diverse ancestry allows for the study of genetic variants contributing to interethnic and interindividual variation in susceptibility to drugs. Many genome-wide association studies for drug-induced phenotypes have been performed in LCLs, often incorporating gene-expression data. LCLs are also being used in follow-up studies to clinical findings to determine how an associated variant functions to affect phenotype. This review describes the most recent pharmacogenomic findings made in LCLs, including the translation of some findings to clinical cohorts.
β-blockers; acetaminophen; chemotherapy; cytotoxicity; gene expression; genome-wide association studies; HapMap; immunosuppressants; lymphoblastoid cell lines; pharmacogenomics; radiation; selective serotonin reuptake inhibitors; statins