Abstract
The sequencing of the first human genome in 2001 highlighted remarkable complexity and heterogeneity [1] and brought great anticipation in advancing our understanding of disease. The therapeutic promise implicit in research ventures like the Human Genome Project (HGP) and other advancements in genetic-genomic DNA technology lies within the concept of personalized medicine. A key element of personalized medicine is to develop medical treatment that is tailored to the specific disease process of each patient. Pharmacogenetics and pharmacogenomics (often used together or interchangeably) refer to the study of genetic differences and their effect on drug metabolism, therapeutic response, and adverse reactions (i.e., pharmacokinetics and pharmacodynamics). The genetic information can be used to guide clinical decision-making and optimize patient care. Highlighted in this review series are examples by which the use of pharmacogenetics and pharmacogenomics has promoted the advancement of molecular medicine, and started to bridge the gap between science and medicine through a shared progression across a variety of disciplines. This collection of reviews introduces the field of data science, along with the latest experimental approaches and statistical methods being used to analyze the vast amounts of large-scale, genome-based data from pharmacogenetic-pharmacogenomic studies (Penrod and Moore). Furthermore, genome-wide association studies (GWAS) are outlined as a powerful and effective tool to identify susceptibility loci and targeted pharmacotherapies for complex diseases, such as age-related macular degeneration (AMD) (Rosen, Kaushal, and SanGiovanni). Similarly, the utility of lymphoblastoid cell lines (LCLs) is reviewed as an efficient model system for performing human pharmacogenomic studies in vitro (Jack, Rotroff, and Motsinger-Reif). In terms of clinical studies, the latest pharmacogenetic-pharmacogenomic applications relating to neurological disorders, including Parkinson’s and Alzheimer’s disease, as well as common mental illnesses, such as schizophrenia (SCZ), autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD) are outlined (Gilman and Mao). The growing field of anti-obesity medications, together with the genes and gene variants thought to impact their effectiveness is also presented (Guzman and Martin). Among a wide array of cardiovascularrelated topics, the timely issue of "aspirin resistance", along with the cardiovascular risks associated with nonsteroidal anti-inflammatory drugs is explored, as are the underlying genetic factors affecting antithrombotic agents in coronary artery disease and ischemic stroke (Stitham and Hwa). Furthermore, there is a focused review examining the latest U.S. and European clinical trials regarding pharmacogenetic-guided warfarin dosing (Baranova and Maitland-van der Zee), as well as a detailed look into genetic variability and its relation to antihypertensive and lipidlowering medications (Vanichakarn and Stitham). Some of the major obstacles facing pharmacogenetic and pharmacogenomic research, as well as its implementation to mainstream clinical practice are also discussed. In particular, a common hindrance revealed in the series is the lack of consistency and reproducibility across studies. While differences in study design, small sample size, and heterogeneity among patient populations have been noted, the complexity within the genetic basis of disease and heritability is staggering. Even with monogenic disorders, issues such as pleiotropy, variable or incomplete penetrance, as well as inconsistent expressivity, can make genotype-phenotype associations quite difficult [2]. Moreover, these same issues are compounded by the multifaceted nature of polygenic diseases, and coupled with a myriad of potential environmental influences adding to the complexity [3]. As outlined in this review series, tremendous progress has been made to address these limitations however further cross-disciplinary collaborations are needed. The exponential expansion of information (tens of thousands of publications being added annually) makes incorporation of genetic markers into everyday clinical practice both needed and inevitable. Billions of dollars are being invested by both the government and private industry, and the rewards are expected to pay off in the near future [4]. More than a decade has passed since the mapping of the first human genome. Pharmacogenetic and genomic research has revealed thousands of genetic variants that contribute to disease susceptibility, progression, and/or treatment outcomes. Moreover, these advancements have provided tremendous insights into the molecular basis of many diseases, potentially leading to the development of genetic-based therapies and diagnostic tests. But as far as we have come, towards personalized medicine there remains much to be done. We are “so close and yet so far”.
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