Variability is a hallmark of clinical medicine. Why do patients with seemingly similar injuries or severity of acute illness, receiving comparable and appropriate treatment, often follow different trajectories? For example, one patient recovers uneventfully from massive transfusion for hemorrhagic shock while another follows a prolonged course complicated by nosocomial pneumonia and organ failure. Consider also, the seemingly more straightforward task of preventing or treating deep venous thromboembolic disease. Despite our understanding of the biology of coagulation and pharmacotherapeutic strategies, therapy sometimes fails with fatal consequences. Numerous clinical (environmental) and genetic factors contribute to this variability. The completion of the Human Genome Project provided the foundation on which to build knowledge of genetic variation in both humans and animal models.1 This in turn has been used to establish genotype–phenotype associations for common polygenic diseases, such as diabetes mellitus (metabolic syndrome), cancer, and hypertension. Using this genetic variability to understand disease biology and to better direct therapy (such as drug selection and dosing) are the goals of the field of “Genomic Medicine.”2 At the cellular level, differences in DNA sequence can alter RNA transcription and protein translation, which alters clinical phenotypes. For instance, drug absorption, metabolism, and excretion are all affected by genetic variation (pharmacogenomics). Recent progress in these fields and the application of this knowledge to critically injured patients is the focus of this chapter.
Since the discovery and publication of the molecular structure of nucleic acids by Watson and Crick in 1954, the genetic basis for many conditions has been determined.3,4 Misconceptions remain, however, regarding the role of genetics and genomics in clinical medicine. Despite the commonly held notion that genetics had little influence on clinical medicine in the past, genetics has, in fact, played an important role in understanding disease for a minority of conditions and patients. As a result of the advances described above, we have entered a period of tremendous growth in our knowledge of genomics that will influence care for all patients.5 In order for clinicians to understand and participate in these advances, we must become “literate” in the language of genetics and genomic medicine. ch53box1 includes some important definitions of genetic concepts for clinicians, some of which will be more completely developed below.
Box 53-1: Definitions |Favorite Table|Download (.pdf)
Box 53-1: Definitions
Allele: One of two or more versions of a genetic sequence at a particular location in the genome.
Base pair (bp): Two nitrogenous bases paired together in double-stranded DNA by weak bonds; specific pairing of these bases (adenine with thymine and guanine with cytosine) facilitates accurate DNA replication; when quantified (e.g., 8 bp), bp refers to the physical length of a sequence of nucleotides.
Complex condition: A condition caused by the interaction of multiple genes and environmental factors. Examples of complex conditions, which are also called multifactorial diseases, are sepsis, cancer, and heart disease.
DNA: Deoxyribonucleic acid, the molecules inside ...