Chapter 53: Genomics and Acute Care Surgery

INTRODUCTION

Outcomes after traumatic injury, perhaps more than in any other surgical disease, have improved through standardization of care. Nevertheless and despite seemingly ideal care, unexpected outcomes occur. Why do patients with similar injuries or severity of acute illness, despite receiving comparable and appropriate treatment, often follow different paths? While one patient recovers uneventfully from massive transfusion for hemorrhagic shock after a motor vehicle collision, 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, venous thromboses and pulmonary emboli still occur, often with fatal consequences.

Numerous clinical, environmental, and genetic factors contribute to variability in the inflammatory response, variable rates of drug metabolism and risk for venous thromboembolic disease. The completion of the Human Genome Project and technological advances in sequencing and small molecule identification have 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, 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 Understanding the information contained in an individual’s genetic fingerprint has the potential for further decreasing the disability and mortality secondary to traumatic injury.

At the molecular level, differences in DNA sequence can alter RNA transcription and protein translation, which thereby alter clinical phenotypes. For instance, drug absorption, metabolism, and excretion are all affected by genetic variation and are the focus of an emerging field of study called pharmacogenomics. The fields of proteomics and metabolomics are additional pieces of systems biology that are promising new discoveries and improvements in patient care. Taken together these form the foundation of personalized medicine. This chapter focuses on select aspects of these fields and their potential application to the care of critically ill and injured surgical patients.

STRUCTURE OF THE GENOME

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; however, misconceptions remain regarding the role of genetics and genomics in clinical medicine.³ 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, but only for a small number of conditions and patients. As a result of these, we have entered a period of tremendous growth in our knowledge of genomics that will eventually influence care for all patients.¹ In order for clinicians to understand and participate in these advances, we must become “literate” in the language of genomic medicine. Box 53-1 includes some important ...