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KEY POINTS
Variability in clinical phenotypes results from the following: differences in DNA sequence (genomics), RNA transcription (transcriptomics), and protein translation and structure (posttranscriptional regulation and posttranslational modification).
It is estimated that only 2% of total DNA includes the code for the approximately 20,000 protein-coding genes of the human genome.
Exons are the regions of DNA that are transcribed to mRNA and then translated into the amino acid structure of proteins.
Histone proteins play a key role in the functional regulation of the genome.
The most common type of DNA sequence variations are single base substitutions termed single nucleotide polymorphisms (SNPs).
SNPs relevant to acute care surgery are found within the promotor regions of genes for Toll-like receptor 1 and tumor necrosis factor-α, both associated with increased mortality after trauma and sepsis.
MicroRNAs are short single-stranded RNA fragments that downregulate gene expression when bound to messenger RNA.
Postinjury systemic inflammatory response syndrome–induced early multiple organ failure is related to a “genomic storm” at the level of circulating leukocyte gene transcription and occurs simultaneously with a compensatory anti-inflammatory and immunosuppressive response.
Chronic critical illness is characterized by an underlying pathophysiology of persistent inflammation, immunosuppression, and catabolism.
A 63-gene transcriptomic metric score within 24 hours after injury has been shown to be associated with subsequent adverse outcomes including multiple organ dysfunction, length of mechanical ventilation and hospital stay, and infection rates.
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Perhaps more than in any other surgical disease, outcomes after traumatic injury have improved through evidenced-based standardization of care.1 Nevertheless, despite seemingly optimized care, unexpected and complicated outcomes continue to occur in critically ill surgical patients. The question then becomes: Why do patients with similar injuries or severity of acute illness, despite receiving comparable and appropriate treatment, often follow different clinical trajectories? Although one patient recovers uneventfully from hemorrhagic shock after a motor vehicle collision, another follows a prolonged intensive care unit course complicated by nosocomial infections and persistent organ dysfunction. Similarly, despite our understanding of the biology of coagulation and the widespread implementation of prophylactic pharmacologic strategies, venous thromboses and pulmonary emboli still occur, often with fatal consequences.
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Numerous clinical, environmental, and genetic factors contribute to variability in the innate inflammatory response, variable rates of drug metabolism, and risk for venous thromboembolic disease. The completion of the Human Genome Project and technologic advances in nucleic acid sequencing and small-molecule identification have provided the foundation on which to build knowledge regarding genetic variation in both humans and animal models.2 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, predict risk of disease onset, and calculate an individual’s response to a given therapy (eg, drug selection and dosing) are the goals of the field of genomic medicine.3
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At the molecular level, differences in DNA ...