Editorial Views  |   July 2003
Perioperative Genomics: Venturing into Uncharted Seas
Author Affiliations & Notes
  • Jeffrey R. Balser, M.D., Ph.D.
  • Vanderbilt University School of Medicine, Nashville, Tennessee.
  • *
Article Information
Editorial Views
Editorial Views   |   July 2003
Perioperative Genomics: Venturing into Uncharted Seas
Anesthesiology 7 2003, Vol.99, 7-8. doi:
Anesthesiology 7 2003, Vol.99, 7-8. doi:
Since its inception, the science and art of anesthesiology have been challenged and stimulated by the extraordinary variability in patient response. Patients exhibit untoward, and often unpredictable, responses to surgical procedures and to the pharmacopoeia employed in the perioperative period. As our technology and scientific understanding have become more refined, so has our ability to identify patients at risk for specific postoperative complications related to these interventions. Yet, our predictive capacity remains far from omniscient.
In this issue of Anesthesiology, Ziegeler et al.  1 examine some of the recent developments in our quest to use the information unleashed by advances in human genetics to identify patients at risk. The findings highlighted catalog some of the initial efforts of those wrestling with a new and challenging field (coined functional genomics  ). 2,3 This field has the potential to establish a firm rationale behind many unexplained risks related to anesthesia and surgery that the field has long dismissed as “idiopathic,” or even as “acts of God.” The review summarizes a number of statistical correlations between DNA sequence variations common in the population (single nucleotide polymorphisms, or SNPs), and important clinical outcomes in perioperative medicine. The challenge will be to move from these intriguing statistical correlations to an operational understanding of how genetic variability can be used in a practical manner to guide therapy, predict outcome, and improve patient care.
Studies and reviews in this field herald a new age of preoperative risk factor identification, 2,3 as molecular medicine broadly focuses on generating predictions regarding clinical outcome on the basis of each individual's unique DNA sequence. Ziegeler et al.  ably define for us the essential genetic parlance, and then review the recent literature associating genetic variation to clinical outcomes with relevance to perioperative medicine. Given the extraordinary rate at which the information on genetic associations is expanding, concurrent with the increasing Web-based availability of healthcare data to physicians and their patients, clinicians may soon find it necessary to navigate this literature on a routine basis. Moreover, just as we routinely judge when a particular (new) drug therapy should become part of our own practice, as industry moves to make genetic screens available and relatively inexpensive, we will soon be called to judge when identification of particular genetic variants should be integrated into our routine preoperative evaluation practices.
In view of these emerging trends, guidelines are being developed to assist clinicians and scientists in evaluating the impact of genetic association studies. 3 A guiding principle is that results obtained in a single population require confirmation and validation in distinct, unrelated populations. In perioperative medicine, a statistical linkage between a genetic variant and a clinical outcome in a cohort of patients, particularly when operated on by a specific surgical team, requires validation in another population who have undergone surgery in a different center, by a different surgical team. This provides assurance that the genetic association is not spurious; that is, not related to an (unidentified) environmental variable that happens to correlate with the outcome of interest. Recent work from our own center 4 exemplifies this caution, where linkage between the factor V Leiden polymorphism and a nearly 30% reduction in blood loss following cardiac surgery was demonstrated. This result was obtained in more than 500 patients operated on by our clinical team; hence, validation in other centers and patient populations will be required before prospective screening of patients can be recommended. 4 At the same time, the risks conferred by genetic variants must be dovetailed into our existing knowledge of nongenetic clinical risk factors. Given the vast number and complexity of clinical variables that influence a clinically apparent surgical outcome (i.e.  , neurologic injury following heart surgery), assignment of a genetic variant as a truly independent risk factor requires rigorous, prospective clinical trials involving exceedingly large numbers of patients (usually thousands). Moreover, demonstrating that a statistically significant outcome risk associated with a genetic variation is truly a causative  risk requires accompanying basic science investigations aimed at correlating the impact of the DNA sequence change on protein function, and thus human physiology, in a manner that correlates in a meaningful way with the clinical outcome in question.
Most genetic association studies focus on DNA polymorphisms, genetic variants that are relatively common in the population, occurring at an incidence of greater than 1%. As such, these variants are often clinically silent and are manifest only during adverse circumstances (i.e.  , surgery, exposure to a new drug, etc.). This contrasts with rare, disease-associated sequence variants, denoted mutations  , that may occur only within a single family and often provoke pathophysiology (i.e.  , Marfan syndrome). As such, the usually silent phenotype of a polymorphism suggests that these variants, when present, usually do not cause adverse outcome in 100% of patients exposed to an intervention; rather, the presence of the genetic variant contributes a small but statistically significant increase in risk within a large population. Hence, the predictive value of most polymorphisms for guiding therapy toward improved outcome, or even as a basis for counseling patients on their perioperative risk, requires rigorous assessment relative to standard practice in prospective trials. A contemporary example of this deficiency lies in the undefined risk for untoward, life-threatening arrhythmias (Torsades de Pointes) during drug therapy with agents that prolong the electrocardiographic Q-T interval. This concern is highlighted in the ongoing debate over the safety of droperidol administration for postoperative nausea and vomiting. 5 Recent studies make it clear that clinically silent polymorphisms in cardiac potassium channels, not detectable on a screening electrocardiograph, can sometimes mediate exceptional (and unpredictable) Q-T prolongation and Torsades on drug administration, even at low doses. 6,7 Conversely, only a small minority of patients carrying these sequence variants demonstrate adverse responses, and the studies to demonstrate the predictive value of prospective identification of these “risk” polymorphisms have not been performed. Without trials firmly establishing the value  of prospective identification, it is difficult to justify routine patient screening for particular DNA variants.
With this scientific rigor in mind, it is understandable that career geneticists have limited enthusiasm for the initial wave of genetic association studies, because of concerns that spurious associations may pervade the literature, only to be found invalid on subsequent attempts at validation. 8,9 The design and publication of genetic association studies, particularly as they relate to studies of perioperative risk, must take into account rational selection of candidate genes, corrections for population ethnicity, sufficiently large sample sizes, publication of negative as well as positive results, statistically sound methods for dealing with issues of multiple testing, use of intermediate endpoints and surrogate markers, and validation in independent populations. 8,9 
Historically, our efforts to refine the identification of perioperative risk factors have resulted directly in important advances in patient management. One of the best examples of this progress is the clinical identification of patients at risk for perioperative myocardial injury. Important clinical predictors of myocardial events were first described in the 1970s. 10 As our diagnostic and informatics technology became more advanced, additional risk factors and their interactions were described. 11 These culminated in the creation of practice guidelines, published initially by the American College of Cardiology and American Heart Association Task Force in 1996 12 and revised last year. 13 As our confidence in genetic associations increases, and the number of variant alleles with predictive value for guiding rational therapy expands, we can foresee an analogous need to develop consensus-based genetic risk factor practice guidelines. Anesthesiology as a specialty is called to provide leadership in these efforts, and is even now supporting the training of young investigators through the Foundation for Anesthesia Education and Research and other major research organizations. At the same time, as our specialty embraces the excitement and “glitz” of genetic medicine, it must be ever cognizant of the profound economic and social consequences genetic associations may have on individuals and on populations. These ethical issues demand ardent adherence to the most rigorous standards of evidence-based practice, as well a strong dose of healthy skepticism, as we journey into the uncharted sea of perioperative genomics.
Ziegeler S, Tsusaki BE, Collard CD: Influence of genotype on perioperative risk and outcome. A nesthesiology 2003; 99: 212–9Ziegeler, S Tsusaki, BE Collard, CD
Schwinn DA, Booth JV: Genetics infuses new life into human physiology: Implications of the human genome project for anesthesiology and perioperative medicine. A nesthesiology 2002; 96: 261–3Schwinn, DA Booth, JV
Cooper DN, Nussbaum RL, Krawczak M: Proposed guidelines for papers describing DNA polymorphism-disease associations. Hum Genet 2002; 110: 207–8Cooper, DN Nussbaum, RL Krawczak, M
Donahue BS, Gailani D, Higgins MS, Drinkwater DC, George AL Jr: Factor V Leiden protects against blood loss and transfusion after cardiac surgery. Circulation 2003; 107: 1003–8Donahue, BS Gailani, D Higgins, MS Drinkwater, DC George, AL
Prielipp RC, Balser J: Providers need to take warning seriously. Anesthesia Patient Safety Foundation Newsletter, Spring Edition, 2002
Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, Keating MT, Goldstein SA: MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 1999; 97: 175–87Abbott, GW Sesti, F Splawski, I Buck, ME Lehmann, MH Timothy, KW Keating, MT Goldstein, SA
Sesti F, Abbott GW, Wei J, Murray KT, Saksena S, Schwartz PJ, Priori SG, Roden DM, George AL Jr, Goldstein SA: A common polymorphism associated with antibiotic-induced cardiac arrhythmia. Proc Natl Acad Sci USA 2000; 97: 10613–8Sesti, F Abbott, GW Wei, J Murray, KT Saksena, S Schwartz, PJ Priori, SG Roden, DM George, AL Goldstein, SA
Hegele RA: SNP judgments and freedom of association. Arterioscler Thromb Vasc Biol 2002; 22: 1058–61Hegele, RA
Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG: Replication validity of genetic association studies. Nat Genet 2001; 29: 306–9Ioannidis, JP Ntzani, EE Trikalinos, TA Contopoulos-Ioannidis, DG
Tarhan S, Moffitt EA, Taylor WF, Giuliani ER: Myocardial infarction after general anesthesia. JAMA 1972; 220: 1451–4Tarhan, S Moffitt, EA Taylor, WF Giuliani, ER
Mangano DT: Perioperative cardiac morbidity. A nesthesiology 1990; 72: 153–84Mangano, DT
Eagle KA, Brundage BH, Chaitman BR, Ewy GA, Fleisher LA, Hertzer NR, Leppo JA, Ryan T, Schlant RC, Spencer WH III, Spittell JA Jr, Twiss RD, Ritchie JL, Cheitlin MD, Gardner TJ, Garson A Jr, Lewis RP, Gibbons RJ, O'Rourke RA, Ryan TJ: Guidelines for perioperative cardiovascular evaluation for noncardiac surgery: Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Circulation 1996; 93: 1278–317Eagle, KA Brundage, BH Chaitman, BR Ewy, GA Fleisher, LA Hertzer, NR Leppo, JA Ryan, T Schlant, RC Spencer, WH Spittell, JA Twiss, RD Ritchie, JL Cheitlin, MD Gardner, TJ Garson, A Lewis, RP Gibbons, RJ O'Rourke, RA Ryan, TJ
Eagle KA, Berger PB, Calkins H, Chaitman BR, Ewy GA, Fleischmann KE, Fleisher LA, Froehlich JB, Gusberg RJ, Leppo JA, Ryan T, Schlant RC, Winters WL Jr, Gibbons RJ, Antman EM, Alpert JS, Faxon DP, Fuster V, Gregoratos G, Jacobs AK, Hiratzka LF, Russell RO, Smith SC Jr: ACC/AHA Guideline update for perioperative cardiovascular evaluation for noncardiac surgery: Executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Anesth Analg 2002; 94: 1052–64Eagle, KA Berger, PB Calkins, H Chaitman, BR Ewy, GA Fleischmann, KE Fleisher, LA Froehlich, JB Gusberg, RJ Leppo, JA Ryan, T Schlant, RC Winters, WL Gibbons, RJ Antman, EM Alpert, JS Faxon, DP Fuster, V Gregoratos, G Jacobs, AK Hiratzka, LF Russell, RO Smith, SC