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Critical Care Nurse. 2004;24: 34-45
Copyright © 2004 by the American Association of Critical-Care Nurses.
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Clinical Article
CE Online

Genomics

What Every Critical Care Nurse Needs to Know About the Genetic Contribution to Critical Illness

Chris Winkelman, RN, PhD, CCRN

Chris Winkelman is an assistant professor of nursing at Case Western Reserve University, Cleveland, Ohio, and a staff nurse in the trauma and critical care float pool at Metro-Health Medical Center in Cleveland. She was a fellow at the summer genetics institute at the National Institutes of Health in 2001.

To purchase reprints, contact The InnoVision Group, 101 Columbia, Aliso Viejo, CA 92656. Phone, (800) 809-2273 or (949) 362-2050 (ext 532); fax, (949) 362-2049; e-mail, reprints{at}aacn.org.

To receive CE credit for this article, visit the American Association of Critical-Care Nurses’ (AACN) Web site at http://www.aacn.org, click on "Education" and select "Continuing Education," or call AACN’s Fax On Demand at (800) 222–6329 and request item No. 1178.

Information from the Human Genome Project has the potential to transform the care of patients in the next decade. Pathological changes can now be analyzed at the molecular level, linking specific DNA sequences to complex diseases. Genomic science offers the potential to diagnose, prevent, and treat disease, including identifying individual factors that respond favorably to pharmacological intervention. Genomics will alter assessment and intervention strategies across health-care systems. Awareness of genetic concepts and advances in genomic information will enable critical care nurses to deliver optimal care.

In this article, I provide an overview of genomics and a review of genetic concepts, integrating current information about the molecular etiology of selected critical illnesses. I also describe the usefulness of obtaining a family history in the form of a pedigree to detect genetic anomalies, and I introduce some of the issues related to genetic testing.


   Genetics, Genomics, and Disease
Top
 Genetics, Genomics, and Disease
Genetic Variation Within the...
 Genomics and Cardiovascular...
 Implications for Critical Care...
 Conclusion
 References
 
Genetics is the study of heredity and how traits are passed along from parents to offspring.1 Commonly, genetics refers to the study of single genes and their traits. Genetics explains how physical characteristics, susceptibility to disease, and even personality and behavior "run" in families.

A genome is all the DNA contained in an organism or a cell.1 Thus, the human genome consists of the approximately 30000 genes found in human beings.2 Genomics is the study of how all the genes function, interact, and influence the biology and physical characteristics of living things. Genomic science is used to examine common but complex diseases such as chronic obstructive pulmonary disease, acute coronary syndromes, sepsis, infection, and the conditions that contribute to these and other complex illnesses. With genomic resources, technology, and education, the interaction of multiple genes and environmental factors can be investigated, and individualized treatment can be developed.3

Genetic inheritance has a variable impact on well-being. A person’s genetic inheritance may have no real consequence to the person’s health (eg, male-pattern baldness), be of minor consequence (eg, lower extremity varicosities), or have important adverse effects on the quality or length of life (eg, hypertension). The observable characteristics of a person are the phenotype; the genetic constitution of a person is the genotype.1 Thus, a person’s genotype may have a range of effect on his or her phenotypical health.

Some experts4,5 suggest that all disease has a genetic component. Genetic disease can be classified as chromosomal disorders, defects in a single gene, or complex genetic disease. In chromosomal disorders, the defect is due to an excess or deficiency of the genes contained in a whole chromosome or a chromosomal segment (see aneuploid in Table 1Go). The most common chromosomal disorder associated with a viable neonate is Down syndrome, which is due to an extra copy of chromosome 21. This trisomy of genes causes mild-to-moderate mental retardation and numerous physical changes such as atrial septal defect and an increased risk for leukemia.1


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  		Table 1 Glossary

 
A defect in a single gene is characterized by an anomaly—a mutation—at a specific area on one or both members of a chromosome pair. About 6000 single-gene defects are known. Single-gene defects are rare, occurring in fewer than 1 in 200 births,1 and are typically associated with mendelian inheritance (Table 2Go). Some diseases formerly thought to follow mendelian patterns are much more complicated, including diabetes, asthma, and even fragile X syndrome.7


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  		Table 2 Classic mendelian inheritance commonly associated with single-gene variants and disorders

 
Complex genetic diseases are caused by more than a single genetic variation and are characterized by interaction between the environment and the genome. In addition to mendelian patterns, these diseases have unique inheritance characteristics (Table 3Go). Genetic diseases common to critically ill adults are more likely to be complex rather than chromosomal disorders or single gene defects.


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  		Table 3 Other patterns of inheritance

 
Human Chromosomes, DNA, and Genes
The following review of genetics, central to understanding the role of genomics in critical illness, includes examples from critical care practice.

Chromosomes
The human genome consists of 23 paired chromosomes in the nucleus of most cells and in mitochondrial DNA. Among most normal body cells, each cell contains the entire genome. A few cell types have different multiples of chromosomes. Two exceptions are reproductive cells, specifically oocytes and sperm, which contain half of the paired chromosomes, and some liver cells, which have 4 times (ie, 92 chromosomes) the basic number. In nucleated cells, 22 pairs of chromosomes are matched; each chromosome in a pair has the same genes in the same position and order as does the other chromosome in the pair. The members of the 23rd pair are the sex chromosomes X and Y. A male has both an X and a Y chromosome; a female has 2 X chromosomes. Each parent contributes half of the parent’s chromosome/gene pairs to offspring; only males contribute Y chromosomes.

DNA
Each chromosome is a single long molecule of DNA. DNA is composed of a linear array of a nitrogen base, a sugar (deoxyribose), and a phosphate paired to adjacent bases on the same strand (Figure 1Go). The human genome contains about 3.2 billion nitrogen base pairs divided among the 46 chromosomes. The order of these paired bases codes the genetic information contained within DNA. The sequence of nitrogen bases in each gene is quite robust (ie, quite resistant to change). Scientists estimate that variation of the DNA sequence among the human genome of people unrelated to one another is 1%.4



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  		Figure 1 From chromosomes to genes.

 
Genes
Along each chromosome are genes (Figure 1Go). Genes code for proteins (Figure 2Go). Proteins serve as the building blocks for the developing organism and also have functional and structural roles. Structural proteins include those found in cell walls, transport pores, and filaments that provide cell shape. Functional proteins include enzymes, hormones, and molecules for transporting substances; these proteins provide for activity in a cell so that metabolism, growth, and development can occur.



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  		Figure 2 Gene expression: genes code for proteins.

 
Genes, as a result of inherited or acquired mutations (Figure 3Go), may code for an ineffective protein or an abnormal amount of protein. Many anomalies are caused by a change of a single base in the sequence of DNA (Figure 3Go), leading to a substitution of an amino acid along the chain of protein that provides cell structure or function.3 A substituted amino acid may result in misshaped cells, nonfunctional transport pores, missing enzymes and neurotransmitters, or inability to provide necessary energy for cellular maintenance and replacement.



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  		Figure 3 Types of mutations. Most of the mutations that have been identified and studied by geneticists are rare, recessive, and deleterious. For recessive diseases, if a single abnormal gene is inherited, the offspring will not have clinical disease. In a dominant disease, a single defective gene will result in disease in the offspring. Many more mutations are neutral, having no effect on the phenotype.

 
DNA has regions that contain genes that code for proteins (Figure 4Go) and other regions that are not genes, or noncoding regions. Some of these noncoding regions near the gene regulate protein synthesis. All genes are not necessarily "on" at all times, producing quantities of protein continuously. Noncoding operator and promoter regions interact with small effector molecules that may either induce (ie, turn on) or repress (ie, turn off ) gene expression. Effector molecules are usually small amino acids, sugars, and similar products of metabolism. The process by which proteins are made from instructions encoded in DNA is called expression.



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  		Figure 4 Illustration of a gene. Exons are coding regions; introns are noncoding regions. Along both noncoding and coding regions can be small variations, such as changes in a single nucleotide pair, that result in polymorphisms.

 
Genes with related functions occur in coordinately regulated units known as operons. Such coordination is essential for inducing the biosynthesis of enzymes involved in cellular activities such as glucose utilization, proteolytic cascades, and inflammation.

Some persons have enhanced promoter function along genes associated with oxidative stress and inflammation.9–12 Enhanced expression of these oxidants and inflammatory proteins is associated with an increased severity of illness in patients with adult respiratory distress syndrome, sepsis, and myocardial infarction and may even be predictive of mortality in patients with these conditions.


   Genetic Variation Within the Human Genome
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 Genetics, Genomics, and Disease
 Genetic Variation Within the...
Genomics and Cardiovascular...
 Implications for Critical Care...
 Conclusion
 References
 
Each gene has a specific location on a specific chromosome. Genes occur in pairs; each person inherits 2 copies of a gene, 1 copy from each parent. Alternative forms of paired genes are called alleles. Table 4Go gives an example of different allelic combinations that code for apolipoprotein E, which is important to both the central nervous and metabolic systems. Certain apolipoprotein E allelic combinations have been implicated in early-onset Alzheimer disease, recovery from traumatic brain injury, and hyper cholesterolemia.


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  		Table 4 Alleles and genetic variation

 
Variations in genes are known as polymorphisms; a gene is polymorphic if at least 2 mutations of the gene are present in the population. Critical care nurses are well aware of the polymorphic genes that code for tissue type; these genes produce the protein antigens that make donor-recipient matching challenging in organ transplantation. The genes for histocompatibility or HLA antigens are highly polymorphic, with more than 100 different alleles. Many of the proteins (ie, the HLA antigens) encoded by these alleles are deposited on cell surfaces, potentially causing antigen-antibody reactions. As a result, finding tissue donors with an exact HLA match is often difficult, and so a subset, the major histocompatibility complex of only 6 antigens, is more commonly used to determine tissue matches between organ donors and recipients.

Polymorphisms are often described as mutations in genes. Perhaps variations in genes is a more accurate description, because mutation implies an aberration with adverse consequences. Instead, many of the variations simply contribute to individualization. A mutation may occur in any cell. If a mutation or variation occurs in a gamete, or germ-line cell, then all progeny of that gamete inherit the altered genetic code. If a mutation occurs in a somatic cell (a non–germ-line cell), the resultant variation will occur only in descendants of that cell and will not be passed on to the next generation of the organism.

Polymorphisms have no health consequence. The most common polymorphism is a variation of a single base pair in a genetic sequence. Most single nucleotide polymorphisms are silent; they occur in non-coding regions or they do not alter the protein produced by the gene. Additionally, because each person inherits 2 copies of a gene, the inherited combination may mean that a single genetic polymorphism coding for a defective protein does not affect the person’s health or characteristics, because the second gene does not code for a defective protein. Some polymorphisms can be used in forensic science to identify a specific person by examining DNA to locate unique alleles. Typically, forensic DNA analysis identifies 8 to 13 different polymorphisms to confirm either identity or inheritance.18 Because of human variation within a population or geographic location, the chances that 2 persons share exactly the 8 to 13 alleles examined by a forensic genetic scientist would be greater than 1 in many hundred million (eg, greater than 1 in 300 million or more).

Polymorphisms are a result of mutations or physical changes in the genetic material that ultimately cause a change in protein composition or conformation. When this protein alteration occurs, the phenotype is likely to change; a new physical characteristic occurs that is associated with the new genetic sequence or genotype. Mutations can occur in ova and sperm; offspring then inherit these germ-line variations. Mutations can also occur after birth in somatic cells; these changes are not passed on to offspring and can be associated with neoplasms. Mutations can be the result of physical or chemical damage to chromosomal material, especially if the harm occurs during chromosomal replication. Some materials that cause mutation are x-rays, ultraviolet light, antineoplastic agents, and hair dye. Mutations also occur spontaneously during cellular replication.

Polymorphisms can be pathological, causing disease. In complex diseases, the pathological change can result in variations in the age of onset, signs and symptoms, and severity of a disease, resulting in different phenotypes despite similar genetic inheritance. An example of variable pathological polymorphism is familial hypertrophic cardiomyopathy (FHC).

FHC is an autosomal dominant disease characterized by left ventricular hypertrophy and sudden cardiac death at a young age. FHC is related to defects in at least 8 genes that code for the contractile proteins of the heart; these 8 genes have more than 100 known polymorphisms. Mutations of actin, tropomyosin, and troponin have all been implicated in the development and progression of the disease, although not everyone with FHC has every genetic anomaly.19–21 Dysfunctional properties in these contractile proteins include altered calcium sensitivity, changes in adenosine triphosphate activity, changes in the force and velocity of contraction, and destabilization of the contractile complex.

Wide phenotypical variation is well documented even in families with the same genotype. This variation is attributed to the interaction of the environment with genomic aberration and to the possible presence of other, nondefined genes that provide a protection against or a substitution for the defective genes of FHC. Despite the complexity of FHC, the specific genetic etiology of this devastating disease (ie, which combination of genetic anomalies is causing signs and symptoms) can be used to predict the risk of sudden cardiac death and the average life span of patients with FHC.20,21

Polymorphisms can be detected in a number of ways. One of the more tangible successes of the Human Genome Project is the development of microarray technology (Figure 5Go). A small amount of blood or tissue can be used to determine whether a specific polymorphism is present and whether the polymorphism is active. This process is a promising method to individualize drug prescriptions. For example, microarray technology can be used to determine whether a person’s genome codes for liver enzymes that enhance or slow metabolism of a medication. In the presence of either extreme, dosage can be adjusted with the initial prescription rather than through trial and error, reducing adverse effects. In fact, the results of microarray technology are already used to adjust the dosage of chemotherapeutic agents for children with lymphoblastic leukemia.3



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  		Figure 5 Microarray technology: how a single drop of blood can be used to determine genetic variation. A robot is used to precisely apply tiny droplets containing functional DNA to glass slides. Fluorescent labels are then attached to DNA from the cells under study. The labeled probes are allowed to bind to complementary DNA strands on the slides. The slides are put into a scanning microscope that can measure the brightness of each fluorescent dot; brightness reveals how much of a specific DNA fragment is present, an indicator of how active the fragment is.

 
With microarray analysis, medications that may not help all patients with a specific condition can be targeted to those patients whose genetic makeup makes them responsive to the medications. For example, several long QT syndromes have been linked to specific genetic polymorphisms.22–24 Mutations in the genes for potassium channels and in the gene for the sodium channel are the most common causes of the syndrome.23–25 Any alteration in the structure of transport channels in cardiac cells caused by the genetic mutation(s) results in changes in depolarization and repolarization during the cardiac cycle. These changes can be especially problematic when catecholamines enhance transport of sodium and potassium during stress or adrenal stimulation. As a result, in selected long QT syndromes, catecholaminergic polymorphic ventricular tachycardia occurs (eg, torsades de pointes).

Pharmacological agents that block catecholamines (ie, ß-blockers) can be effective therapy along with implantable cardioverter defibrillators in treatment of inherited long QT syndrome. Gene-specific pharmacotherapy of long QT syndrome that targets either sodium or potassium channels to prevent life-threatening dysrhythmias is under investigation. To date, data are insufficient to allow recommendations.23


   Genomics and Cardiovascular Illness
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 Genetic Variation Within the...
 Genomics and Cardiovascular...
Implications for Critical Care...
 Conclusion
 References
 
Cardiovascular disease is an example of a complex genetic disease characterized by the presence of more than a single genetic anomaly, interaction between genetic variations and the environment, and complex inheritance patterns.26,27 Studies on the genomic contributions to lipoprotein abnormalities and hypertension illustrate many of the concepts in this article, and several findings are reviewed in the following sections.

Risk factors for cardiovascular disease include a diet high in fat and cholesterol, yet many persons whose diets are high in these nutrients have no signs and symptoms of atherosclerosis, whereas other persons with low intake of fat and cholesterol have significant plaque and signs and symptoms of disease. Some of these differences can be explained by the genetically driven ability to process cholesterol.

Mutations in the receptors for low-density lipoprotein (LDL) on the endovascular surface can result in elevated levels of LDL cholesterol. A defect in a single allele for the LDL receptor can result in double the normal serum levels of LDL; having defects in both alleles (ie, homozygosity) for the receptor is associated with a 4- to 6-fold increase in LDL levels and very early onset of coronary syndromes.28 A second genetic anomaly associated with cholesterol processing is a gene that codes for defective apolipoprotein B100 (which coats LDL). Serum levels of LDL in persons with this defective gene are 50% to 100% higher than normal levels.28

A third anomaly associated with hypercholesterolemia is the gene that codes for apolipoprotein E, which is used in the vascular system to transport cholesterol. When all variations in the alleles for apolipoprotein E are compared, LDL cholesterol levels are 0.26 to 0.52 mmol/L (10–20 mg/dL) higher than normal in persons with the E3, E4 allelic combination and 10% to 20% lower in persons with the E2, E3 combination.28

Each of the monogenic disorders accounts for about 5% of the population variance in LDL cholesterol levels.28 A fourth polymorphism occurs in the promoter region for CYP7, a cytochrome P-450 enzyme in the liver that metabolizes cholesterol.29 A mutation in the noncoding region near the CYP7 gene can result in increased serum levels of LDL, accounting for another 15% of the variation in LDL levels in the population.

A person who has all 4 genetic anomalies for processing cholesterol is at great risk for hypercholesterolemia and associated coronary events. Unraveling the genetic defects that result in atherosclerosis can lead to effective treatment such as specific dietary interventions and individualized drug therapy that affects LDL metabolism, LDL distribution and, ultimately, acute coronary syndromes.

Inheritance of a deletion allele on chromosome 17 results in high serum levels of angiotensin-converting enzyme that may lead to hypertension.30,31 Detecting patients with the genetic potential for elevated levels of angiotensin-converting enzyme could lead to early prevention strategies. More pertinent to critical care, an allele combination (ie, DD) associated with primary hypertension is also associated with hypertensive crisis in men.32 Establishing the genetic risk for severe hypertension might lead to treatment to minimize or prevent the devastating consequences of blood pressure sustained at greater than 200/120 mm Hg. Other factors that contribute to the development of hypertension include additional variations in the genes for angiotensin-converting enzyme and variations in the genes for (1) ß-adrenergic receptors, (2) proteins such as nitric oxide that regulate endothelial function, and (3) neurotransmitters in the automatic nervous system and the vascular system.33

Importantly, genotype is not always predictive of phenotype, especially in complex disease.4,6,34 Just as some combinations of genes increase risk for disease, other genes and combinations of genes reduce risk or provide protection against disease. Further, the interaction of the genome with a person’s internal and external environments significantly influences the manifestation of disease. Understanding the genetic contribution to complex disease requires sophisticated analysis and interpretation of data. Nurses are in a unique position to bridge information between genetic experts, specialized clinicians, and patients.


   Implications for Critical Care Nursing
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 Genetics, Genomics, and Disease
 Genetic Variation Within the...
 Genomics and Cardiovascular...
 Implications for Critical Care...
Conclusion
 References
 
Critical care nurses have several opportunities to use information from genomics in their practice. Increasingly, the literature includes genomic terms and concepts. Informed patients will ask questions about the need for and implications of genetic testing. By obtaining astute histories from patients, critical care nurses can help screen the patients for genetic anomalies. Public policy questions can be shaped by informed nurses.

Genetic Testing
Assessing a person’s genome is increasingly affordable. An online catalog35 funded by the National Institutes of Health, Human Resources and Services Administration, and the Department of Energy now lists more than 950 diseases that can be evaluated through genetic testing. DNA and messenger RNA microarrays can be used to detect multiple genomic factors in less than 2 mL of plasma or in the tissue from a cheek swab (Figure 5Go). Several commercial ventures have "genetic kits" to evaluate common diseases. Francis Collins, director of the Human Genome Project, predicts that microarrays will be used diagnostically and prescriptively in the clinical arena in less than 5 years.2 Nonetheless, individual genomic analysis is in its infancy. Roughly two thirds of the 30000 genes that make up the human genome are of unknown function.36,37

Analyzing a person’s genome has practice implications for critical care nurses. One of the most promising fields of research is pharmacogenomics. Experienced nurses know that the efficacy and safety of medications differ markedly among individual patients. Most of these differences can be explained in terms of differences in the absorption, metabolism, excretion, and targets of the drugs.38,39 Patients respond differently to some medications as a result of a specific genotype. For example, some patients with asthma have a decreased response to ß-agonists used for rescue breathing during an exacerbation of the disease. One genetic polymorphism results in ß-agonist–promoted downregulation of ß-adrenergic receptors.40 As a result, repeated exposure to doses of a ß-agonist during respiratory distress leads to a genetically controlled reduction in the number of pulmonary receptors for the rescue medication. Fewer receptors lead to a decreased response during treatment that is manifested by continuing bronchoconstriction despite high doses of ß-agonist inhalants. Recognizing patients who do not respond to ß-agonists in the presence of asthma exacerbation is an important nursing action. Pharmacogenomics offers the hope of individualizing medications on the basis of the results of microarray analysis. The profile created by such an analysis could result in the elimination of the trial-and-error approaches now used by clinicians to identify agents effective for common and deadly illnesses such as hyperlipidemia and sepsis and to avoid allergic responses.

Value of a Pedigree in Identifying Genetic Anomalies
Critical care nurses have a role to play in identifying genes associated with critical illness. For example, gene expression of inflammatory factors in patients with sepsis is the focus of several investigations.41 Identification of coagulation defects such as protein C deficiency could be used to detect patients at risk for cerebrovascular and cardiovascular diseases.42 Critical care nurses might participate in genome testing of patients with prevalent, complex diseases in the next decade.4 A key skill that all nurses need that is related to genetic testing is obtaining family histories from patients and constructing a 3-generation pedigree.43,44 In fact, obtaining an accurate pedigree is the initial step in screening for genetic disease.

A pedigree has a greater visual impact than does a narrative history. The following examples highlight the value of a timely pedigree.

Extending a class on pedigrees into the clinical setting, an undergraduate nursing student returned with a 3-generation diagram that indicated the risk of a 38-year-old man admitted because of syncope. The results of the cardiac evaluation were normal, and his vital signs were stable. He was planning to be discharged after a 23-hour stay in the telemetry unit. The student’s pedigree drawing indicated that the patient had a grandparent, an uncle, and a cousin who had all died before age 40; in apparent good health, "they just dropped dead." Recognizing the familial pattern of sudden cardiac death, the student shared the pedigree with the patient’s physician. As a result, the patient received additional diagnostic testing and an implantable defibrillator. The defibrillator fired the very next week, no doubt saving this young man’s life.

In another instance, an advanced practice nursing student obtained the pedigree of a woman who was pregnant for the first time. The patient was the recipient of a liver transplant. The pedigree provided additional relevant information about a possible genetic basis for the hepatic vein thrombosis syndrome that had led to liver failure in this patient; 3 first-degree relatives had a history of cancer with probable hyper-coaguability and a fourth relative died of liver failure. This information had important implications for not only the patient but also for her child, who might be at higher risk than the general population for coagulopathy and liver disease.

Acquiring the skills to draw and interpret a pedigree is valuable for both bedside nurses and advanced nurse practitioners for understanding the link between genes and disease.

Contributions to Public Policy
Critical care nurses need to be involved in the societal and ethical debate about the use of genetic testing. How do persons perceive genetic risk, and what do they do about it? What role does genetic susceptibility play in individual decision making for health maintenance? How does a previously diagnosed genetic disease affect choice of treatment for new diseases? What is the best way to understand probability in terms of genetic testing? Who should have access to genetic testing and the test results?

Uncertainty about the clinical validity and effectiveness of prevention surrounds genetic testing at this early stage of knowledge.45 Having equity in access and developing diverse and effective models of care delivery will become important to the quality of knowledge and care as genomic care expands. Obtaining information about genetic testing, genetic databases, and advances in genetic practice will allow critical care nurses to provide the holistic care that is a hallmark of the nursing profession.43,46


   Conclusion
Top
 Genetics, Genomics, and Disease
 Genetic Variation Within the...
 Genomics and Cardiovascular...
 Implications for Critical Care...
 Conclusion
References
 
All disease may have a genetic component, either inherited or acquired. The Human Genome Project is changing how we define, prevent, and manage health problems42 (Table 5Go). Controversy will exist among critical care nurses about their role in caregiving as genomic science becomes part of patients’ care in the intensive care unit. However, the need for a basic foundation in genetics is beyond dispute.46,50 Understanding and interpreting the assessment of genetic risk can help vulnerable patients and their families negotiate overwhelming, new information.51 "Thinking genetically" will be important to optimal care in most healthcare settings.3,5 Critical care nurses should embrace this new knowledge as part of holistic care.


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  		Table 5 The Human Genome Project

 
A wonderful, serendipitous byproduct of the cooperative and computer-intensive methods used to develop genomic science is the accessibility of genomic information for persons with many levels of expertise. Some of the best Web sites that most critical care nurses can appreciate are highlighted in Table 6Go. Now is the time to prepare for an era of genomic care in the intensive care unit.


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  		Table 6 Sources to advance your genomic knowledge from novice level to expert level

 


   Acknowledgments
 
I am particularly grateful for the pedigree stories shared by colleagues John Clochesy and Elizabeth Damato and students Anne Fleager Kunos and Mistie Winkfield, BSN. I gratefully recognize the insight and assistance of Linda Workman and Sara Douglas, who reviewed the manuscript while it was in development.


   References
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 Genetic Variation Within the...
 Genomics and Cardiovascular...
 Implications for Critical Care...
 Conclusion
 References
 

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