Genetic Variability and Critical Care Outcomes
Special Feature
Genetic Variability and Critical Care Outcomes
By Grant E. O’Keefe, MD
The clinical course charted by critical illness is a variable and often unexpected path. After what could be considered similar insults, patients have markedly different responses. Some patients tolerate the stress of severe hemorrhagic shock without any consequences, while others, after successful resuscitation, develop remote organ failure and sepsis and may ultimately die. Moreover, expected responses to standard and usual treatments often do not occur. Subtherapeutic and conversely toxic circulating concentrations of drugs often occur, frequently with detrimental consequences. Idiosyncratic drug reactions occur and are likely underreported. As we face these considerations daily in our clinical practices, we are left with the question: What is the basis for the individual-to-individual variation in responses to trauma, shock, sepsis, and drug therapies?
In addition to the usual contributors to the risk for sepsis, organ dysfunction, and mortality (such as severity of the initial insult, age, and pre-existing medical conditions), it is becoming apparent that there are innate factors that contribute to the inflammatory and immune responses and their consequences. With recent technological advances, the ability to analyze large volumes of genetic material has led to a number of studies examining the relationship between genetic variability and clinical outcomes. Certainly these advances will lead to a better understanding of the pathophysiology of critical illness and may assist in developing more accurate prognostic indices. However, it is presently unknown how knowledge of genetic differences can be used to direct care in the ICU. Given this background, the purpose of this review is to summarize the recent studies of the relationship between genetic variability and outcomes of critical illness, to discuss potential roles for genetic analyses in the care of critically ill patients, and to outline some important cautions in their application.
Genetic Determinants of the Severity of the Inflammatory Response
In an article that has recently been reviewed in Critical Care Alert, Mira and colleagues found that a rare allelic variant in the promoter region of the tumor necrosis factor-a (TNF-a) gene was associated with susceptibility to septic shock and also with death due to septic shock.1 These findings are particularly compelling given that the presence of this allele increases TNF-a secretion by lippopolysaccharide-stimulated cells and the known role played by TNF-a in the pathogenesis of sepsis.2,3 Other studies have contradicted the findings reported by Mira et al. Majetschak and colleagues4 determined that this same TNF-a polymorphism was not associated with TNF-a secretion or with the outcome from sepsis. However, Majetschak et al has found that another single nucleotide polymorphism (SNP), located in the intron of the TNF-beta gene, is associated with survival following severe sepsis.5
Similar relationships have been sought between the susceptibility to and severity of sepsis and polymorphisms in the interleukin (IL)-1 receptor antagonist gene and the heat shock protein 70 genes.6,7 Polymorphisms in the genes for the plasminogen-activation-inhibitor-1, IL-6, IL-10, and other inflammatory-related mediators have been characterized and studied.8-10 The potential number of genes that are candidates for markers or determinants of the severity and, therefore, of the consequences of the inflammatory response is clearly astounding. These include cytokines, adhesion molecules, enzymes, and other molecules involved in inflammation and immunity. Expanding individual gene analyses into directed screening of large regions of the genome may bring the opportunity to characterize the important components of the inflammatory response, but also carries many difficulties that are related to the analysis of multiple potential risk factors on the occurrence and severity of disease.
Genetic Determinants of the Responses to Drugs and Other Agents
Of possibly greater importance than factors that determine the variability in response to severe injury or critical illness are genetic determinants of responses to medications. Individuals respond to medications in a heterogeneous way, in terms of both drug toxicity and efficacy of treatment. It is this area where knowing individual gene polymorphisms for individual patients may be of considerable assistance in the treatment of critically ill patients.11
Adverse drug reactions are estimated to be the fourth leading cause of in-hospital deaths in this country and a substantial proportion of these are not the result of clerical error or otherwise related to the actual administration of the drug.12 Idiosyncratic drug reactions are likely due, at least in part, to the coincident occurrence of multiple genetic defects in drug-metabolizing enzymes and receptors, and the potential clinical impact of this concept is great. Conceivably, protocols for the management of such adverse reactions, involving large-scale but directed gene screening, could ultimately reduce these all-too-often fatal events to uncommon occurrences.
Complicated drug interactions are common in the ICU and may be related to genetic differences in enzymes and receptors that determine rates of drug absorption, extent of availability, and rates of elimination. The newly coined field of "pharmacogenomics," in which genetic determinants of drug effects are identified, may be where genetics has its greatest beneficial effect upon the practice of critical care medicine.
Ethical, Legal, Social, and Methodological Issues
Any potential benefits of genetic diagnosis and, ultimately, genetic-based therapy must be considered in the context of important ethical, legal, and social issues, in addition to critical methodological considerations. Presently, most clinical reports of the effect of genetic differences and outcomes in critical care are epidemiological in nature and therefore suffer from the potential difficulties and limitations of studies of association.
First, when interpreting this literature, it is important to remember that causation cannot be inferred solely from any identified associations. Second, it is critical to consider the reliability and reproducibility of the molecular genetic techniques that were used by the investigators. Most of the techniques used to measure genotypes are subjective and involve visual interpretation of an electrophoretically generated DNA "ladder." Surprisingly few studies have included discussions regarding the reliability of the performance or the reading of these tests.13 As more of these studies appear in the literature, it will be important for us to be critical of the methods used and also to ensure that we do not accept claims that specific genes are causative.
Implications for Daily Practice in Critical Care
The field of molecular genetics has grown rapidly and has already found its way into many areas of clinical practice. In the critical care arena, literature examining the relationships between genetic differences and outcomes is becoming common. At the present time, our practices have not been altered, but they may be in the near future. We may soon be able to identify patients at highest risk for the complications of sepsis and multiple organ failure, with potential therapeutic implications. More important, through large-scale and rapid genetic screening of individuals, we may be able to optimize drug management and minimize adverse drug reactions.
This summary was intended to introduce critical care practitioners to the rapidly developing field of molecular genetics and its present but, more important, future effect upon clinical practice. We will need to have basic familiarity with the methods and terminology in order to determine their ultimate use.
References
1. Mira JP, et al. Association of TNF2, a TNF-a promoter polymorphism, with septic shock susceptibility and mortality. JAMA 1999;282(6):561-568.
2. Wilson AG, et al. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci USA 1997; 94(7):3195-3199.
3. Dinarello CA. Proinflammatory and anti-inflammatory cytokines as mediators in the pathogenesis of septic shock. Chest 1997;112(6):321S-329S.
4. Majetschak M, et al. Relation of a TNF gene polymorphism to severe sepsis in trauma patients. Ann Surg 1999;230(2):207-214.
5. Stuber F, et al. A genomic polymorphism within the tumor necrosis factor locus influences plasma tumor necrosis factor-a concentrations and outcome of patients with severe sepsis. Crit Care Med 1996; 24(3):381-384.
6. Fang XM, et al. Comparison of two polymorphisms of the interleukin-1 gene family: Interleukin-1 receptor antagonist polymorphism contributes to susceptibility to severe sepsis. Crit Care Med 1999;27(7): 1330-1334.
7. Schroeder S, et al. Clinical investigations: Analysis of two human leukocyte antigen-linked polymorphic heat shock protein 70 genes in patients with severe sepsis. Crit Care Med 1999;27(7):1265-1270.
8. Westendorp RGJ, et al. Variation in plasminogen-activator-inhibitor-1 gene and risk of meningococcal septic shock. Lancet 1999;354(9178):561-563.
9. Helminen M, et al. Polymorphism of the interleukin-10 gene is associated with susceptibility to Epstein-Barr virus infection. J Infect Dis 1999;180:496-499.
10. Foster CB, et al. Host defense molecule polymorphisms influence the risk for immune-mediated complications in chronic granulomatous disease. J Clin Invest 1998; 102:2146-2155.
11. Evans WE, Relling MV. Pharmacogenomics: Translating functional genomics into rational therapeutics. Science 1999;286:487-491.
12. White TJ, et al. Counting the costs of drug-related adverse events. Pharmacoeconomics 1999;15(5): 445-458.
13. Bogardus ST, et al. Clinical epidemiological quality in molecular genetic research: The need for methodological standards. JAMA 1999;281(20):1919-1926.
Which of the following is correct regarding present genotyping methods?
a. Polymerize chain reaction (PCR) and fragment restriction is an objective method.
b. Simultaneously testing for polymorphisms in multiple genes using microchip arrays has had fairly widespread application in clinical medicine.
c. Gene sequencing is widely available for clinical use.
d. Results from PCR and restriction can be available within 12-24 hours of obtaining a tissue sample.
e. Because of the objective nature of the newly developed technologies, ethical concerns can be minimized and genetic testing will become routine.
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