Genomics and Acute Care Surgery

Grant E. O’Keefe and J. Perren Cobb

INTRODUCTION

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.

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.^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. Box 53-1 includes some important definitions of genetic concepts for clinicians, some of which will be more completely developed below.

Much is known about the human genome. We know that the minority of the 3 gigabases of DNA sequence codes for proteins. It is estimated that only 2% of our DNA sequences code for approximately 20,000 protein coding genes. The function of the remaining 98% of DNA is perhaps the most fascinating aspect of genomics. Figure 53-1 illustrates the general structure of a typical gene. The 5′ control region, often termed the “promoter,” includes DNA sequences that recognize and bind to proteins called transcription factors, whose function is to modify gene expression by controlling transcription. The “start codon” is a series of nucleotides that are recognized by this transcriptional machinery, which initiates generation of messenger RNA (mRNA) from DNA. Not all of this mRNA sequence encodes for protein. Exons are the regions of DNA that are transcribed into RNA to make amino acids. In most genes, multiple exons are separated by introns, which are removed from mRNA prior to translation into protein. The end of transcription is signaled by a series of nucleotides at the end of the coding sequence, referred to as a “stop codon.” The DNA sequence after this end codon, termed the 3′ control region, can also influence the rate of gene transcription and may affect the stability of the mRNA sequence and its translation into protein.

FIGURE 53-1 The general structure of a typical gene.

THE GENETIC BASIS FOR DISEASE

Despite our limited knowledge of the function of much of the genome, our knowledge of the genetic basis for disease is, in fact, extensive. Basic research and clinical observation have elucidated the inheritance of single-gene, Mendelian disorders (transmitted according to Mendel’s laws of inheritance). Most of these are uncommon, and taken together, the most prevalent such as cystic fibrosis or hemochromatosis affect no more than one in several hundred people; however, when the genetic variant is present, its effect on individual patients is substantial. Furthermore, understanding the mechanisms underlying many monogenic disorders has provided pathophysiological information about related and more common disorders. For instance, we have learned a great deal about the pathophysiology of cardiovascular disease from discoveries related to familial hypercholesterolemia, a rare genetic disorder leading to premature atherosclerosis.

The most common type of DNA sequence variation is single base substitutions termed single nucleotide polymorphisms or single-nucleotide polymorphisms (SNPs). SNPs have emerged as powerful genetic markers for studying multifactorial diseases.⁶ Polymorphisms occur in all individuals and, by strict definition, SNPs exist with a frequency of >1%.⁷ Therefore, the term SNP does not include numerous other single base substitutions in which the least common allele is present at a frequency of ≤1% (such as “personal mutations” that may be limited to one family), nor does the term encompass other variations such as insertion/deletion polymorphisms. Importantly, SNPs should be distinguished from disease “causing” mutations, which are generally much less common, but have higher penetrance (e.g., sickle cell anemia). Therefore, SNPs typically do not cause disease but in aggregate may influence the risk for developing a disease (e.g., diabetes mellitus, asthma) or the outcome from a disease or condition (e.g., death from sepsis, rate of atherosclerosis in recipients of cardiac transplants).^8,9 SNPs that exist in mRNA-coding regions (exons) of DNA can lead to amino acid substitutions, and therefore, may change the structure of the resultant protein. This type of variant potentially has the most profound impact on protein function; however, this type of SNP is the least common.⁵ SNPs in the regulatory (promoter) region of a gene may influence (increase or, more often, decrease) transcription of that gene, and therefore, may influence the amount of protein available.¹⁰ Yet, other SNPs may not directly alter protein abundance or function, but may be important markers for other (unidentified) functional variants—a concept known as linkage.¹¹ The analysis of SNPs has been facilitated by two recent and related developments as follows: (1) the establishment of large data repositories of SNPs; and (2) the availability of relatively affordable “high-throughput” methods for genotyping. Recent techniques have identified at least 10 million SNPs interspersed throughout the human genome, at a frequency of one SNP per ˜300 base-pairs.¹²

Stay updated, free articles. Join our Telegram channel

Join