Jennifer E. Axilbund
Constance A. Griffin
Numerous genes present in normal-appearing individuals can affect an individual's susceptibility to disease or contribute to the way an individual metabolizes particular drugs. Generalist clinicians need to be able to recognize genetic syndromes that may have a significant impact on their patients’ future health. This chapter provides an overview of basic genetics, summarizes currently recognized genetic syndromes important in the practice of adult medicine, and describes the role of genetic testing and counseling in today's medical practice.
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Primer of Basic Genetics and Inheritance
Genetic Code
The genetic code is spelled out in our deoxyribonucleic acid (DNA). DNA is built of a combination of nucleotides, including purines (adenine [A], guanine [G]), and pyrimidines (cytosine [C], thymine [T]). DNA is further arranged in a double helix, held together by hydrogen bonds between the complementary bases (A pairs with T, C pairs with G). The 20 amino acids found in the proteins of humans are spelled out using the four nucleotide bases. A sequence of three bases is called a codon; each codon codes for a specific amino acid. Because 64 combinations of bases are possible (4 × 4 × 4), the code is redundant, meaning that some amino acids are coded for by several different combinations of bases. The gene specified by the DNA is transcribed into messenger ribonucleic acid (RNA) and then translated into specific proteins. Not all DNA codes for proteins. Some DNA codes for “worker” RNA. Other DNA has structural functions at parts of the chromosomes called centromeres. The function of much of the DNA remains unknown. The process of translating the code from our DNA to the specified gene product (i.e., protein) is complex and requires editing functions that are specified in the code itself.
DNA is packaged into chromosomes, which are physical structures in the cell nucleus consisting of DNA and associated proteins. Humans have 46 chromosomes, arranged in 23 pairs. Twenty-two of these pairs are autosomes, meaning they are found in both males and females. The 23rd pair, consisting of XX or XY, specifies the individual's sex. During production of germline cells, namely eggs or sperm, the chromosomes undergo a reduction to haploidy, or a single set of chromosomes. When fertilization occurs, diploidy (two sets) is restored by the combination of one set of chromosomes from the mother and one set from the father.
In the process of duplicating our DNA, copy changes can occur. Polymorphisms are alterations that occur in the genetic code for a protein but that do not result in loss of function of the protein. The term mutation is generally reserved for changes in DNA sequence that alter the coded protein significantly. Types of mutations observed range from single base-pair substitutions, such as insertions or deletions of one or a few bases, to mutations that cause a shift in the DNA reading frame, resulting in a premature stop of protein translation.
Types of Inheritance
Gregor Mendel described the basic types of inheritance, and from his name comes the term “mendelian inheritance.” This term describes single-gene inheritance. Individuals have two copies (alleles) of each gene and receive one copy of each gene from the germ cells of each parent. Autosomal dominant disease requires only a single abnormal copy of the gene to manifest disease. Examples of autosomal dominant diseases include Huntington disease and many of the recognized cancer predisposition syndromes. Autosomal recessive diseases require the inheritance of an abnormal copy of the gene from both the mother and the father. Cystic fibrosis is a well-known example in which phenotypically normal parents are only recognized to be carriers of a mutant allele when they have a child who has inherited the dysfunctional forms of the gene from both parents. Sex-linked disease means that the disease gene is located on a sex chromosome. Most sex-linked diseases are linked to the X chromosome. With X-linked inheritance, women typically do not manifest disease even when they inherit a mutant gene because the normal copy of the gene on their other X chromosome compensates. Men, with only a single copy of the X chromosome, are not protected by a normal gene copy and therefore manifest disease. Duchenne muscular dystrophy and hemophilia A are examples of sex-linked diseases.
Other disorders, including common diseases such as diabetes mellitus and hypertension, may involve the interactive effects of multiple genes. This is referred to as polygenic or multifactorial inheritance, and simple rules of mendelian inheritance seem not to apply.Mitochondrial inheritance describes yet another form of inheritance, because mitochondria, and, therefore, the genome of the mitochondria, are inherited only from the egg of the mother. Mitochondrial diseases include oxidative phosphorylation disorders, and widely varying manifestations can include specific types of cardiomyopathy, deafness, skeletal myopathy, and renal tubular acidoses, to name just a few.
The term genotype describes the genetic composition of an individual, whereas the term phenotype refers to the physical manifestations of a given genetic blueprint. Similar phenotypes can result from mutations in different genes presumably in related pathways; the specific molecular alteration in a gene may also relate to the phenotype observed. Penetrance of a gene refers to the likelihood that an abnormal form of a gene will be observed to cause an abnormal phenotype during an individual's lifetime. Some genes are high penetrance, such as those causing the hereditary forms of breast and ovarian cancer. Such individuals have a lifetime risk of developing breast cancer that is as high as 85%. Other genes are of relatively low penetrance, such as the I1307K mutation in the APC gene. This mutation is found in approximately 6% of the Ashkenazi Jewish population and is correlated with a lifetime colon cancer risk estimated to be between 10% and 30%. The interaction of environmental exposure, mutation repair, and the presence of other modifier genes presumably combine to affect the expression of disease.
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Core Competencies in Genetics
Health care professionals ordering genetic testing must be adequately trained to provide genetic counseling, obtain informed consent, and correctly interpret test results. Because availability of specialized genetics services is still limited, the generalist may be called upon to provide genetic counseling as part of routine care. The Core Competency Working Group of the National Coalition for Health Professional Education in Genetics has proposed a set of core competencies in genetics, of which the major components are listed here. The original publication describes the competencies in their entirety (1).
All health professionals should understand the following:
All health professionals should be able to:
The need for these competencies is illustrated in a study by Giardiello et al. (2), who examined physicians’ ordering and interpretation of genetic testing for familial adenomatous polyposis (FAP). Eighty-three percent of tests were ordered for valid indications, but only 18.6% of patients received genetic counseling, only 16.9% of patients provided written consent, and 31.6% of test results were misinterpreted by the ordering physician.
Mendelian Genetic Disorders
In contrast to genetic diseases recognized in childhood such as cystic fibrosis or Duchenne muscular dystrophy, a number of other genetic disorders, in addition to hereditary cancer, may not be recognized until the person is an adult. Some, such as Marfan syndrome, have major clinical phenotypic manifestations and very specific diagnostic criteria (see General References, Useful Websites, Online Mendelian Inheritance in Man). Genetic testing is available for many of these disorders, a subset of which is illustrated in Table 17.1. In contrast, a number of inherited diseases lack specific phenotypic features but may present with abnormal laboratory values or with common clinical events such as venous thrombosis (see examples in Table 17.2).
Profile of a Common Inherited Disease: Hemochromatosis
Hereditary hemochromatosis is a genetic disease with significant implications for the generalist. It is an autosomally recessively inherited disease, in which early diagnosis and treatment can lead to a normal to near-normal life span; the phenotypic manifestations are not usually apparent before significant iron overload has occurred. The causative gene is HFE, and mutations can result in inappropriately high absorption of iron by the gastrointestinal tract. Excess iron stores in the liver, pancreas, heart, skin, and other organs first produce only nonspecific symptoms, but left untreated, ultimately patients develop hepatic fibrosis or cirrhosis, diabetes mellitus, congestive heart failure, and other problems. Symptoms usually develop between ages 40 and 60 years in males, and somewhat later in females, after menopause.
Diagnosis in patients with symptoms is usually based on a serum transferrin iron saturation of greater than 60% for men and greater than 50% for women on at least two different determinations, in the absence of other causes of primary and secondary iron overload disorders.Heterozygotes (individuals carrying one copy of normal allele and one copy of mutant allele) do tend to have serum iron and
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ferritin and transferrin saturation levels that exceed normal but do not develop clinical iron overload. Confirmatory tests after the elevated transferrin iron saturation include liver biopsy or genetic testing for the two mutations that have been observed. Between 60% and 90% of patients with hereditary hemochromatosis (varies with the population) are homozygotes (individuals in whom both alleles of a gene are mutant) for the missense mutation C282Y. Approximately 3% are compound heterozygotes: they have one copy of the C282Y mutation and their second copy of the HFE gene contains a different missense mutation (H63D). The remainder of individuals with clinical manifestations of hereditary hemochromatosis have other mutations in the HFE gene or no identifiable mutation in the HFE gene. Molecular identification of the type(s) of mutations present in an affected individual is important, because C282Y homozygotes have greater degrees of iron overload than do compound heterozygotes. Identification of mutation in affected individuals allows predictive testing in their at-risk siblings and children. Treatment of hereditary hemochromatosis is by phlebotomy at regular intervals.
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TABLE 17.1 Examples of Genetic Diseases with Specific Phenotypic Features for Which Genetic Testing Is Available |
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TABLE 17.2 Examples of Genetic Diseases without Specific Phenotypic Features for Which Genetic Testing Is Available |
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One in nine individuals in the population carries a mutant HFE allele, and the prevalence of individuals with two disease-causing mutations is estimated at approximately 1 in 400. Although the biochemical penetrance of disease (i.e., elevated serum transferrin) is particularly high in C282Y homozygotes, it is not 100%. Precise risk estimates are unknown, but clinical manifestation of iron overload, such as diabetes and cirrhosis, is low. Overall disease penetrance is higher in men than in women, attributed in large part to the regular blood loss associated with menstruation.
Identifying Patients at Risk for Hereditary Cancer
Most cancers are sporadic or nonhereditary in origin. However, approximately 5% to 10% of all cancers are believed to be caused by inherited mutations in cancer-related genes. The characteristics of hereditary cancer include one or more of the following:
Table 17.3 contains information about selected neoplasias for which genetic testing is available. Several excellent reviews describe the currently recognized cancer predisposition syndromes (3,4). Those identified thus far are those that are strongly influenced by a single gene. The role of additional genes, each of which might contribute a more moderate risk for cancer development, will undoubtedly be elucidated in the future.
Complex Genetic Disorders
Unlike mendelian genetic disorders where the pattern of inheritance is clear, risk assessment is usually more difficult with complex disorders. They are often multifactorial, and phenotypic manifestation is dependent upon numerous variables. The causative genes are more elusive, and genetic testing is seldom available. Thus, family history is the best way to recognize individuals at increased risk for complex genetic disorders. Documentation of family history is made easier through the development of tools, such as those by the American Medical Association and the Surgeon General of the United States (see General References, Useful Websites).
Diabetes Mellitus
Diabetes mellitus is widespread in the United States, and includes type 1, type 2, and gestational diabetes (5). With the exception of maturity-onset diabetes of the young (MODY), which is an autosomal dominant form of non–insulin-dependent diabetes diagnosed prior to age 25 years, diabetes is predominantly thought to be polygenic and multifactorial. Thus, it is caused by the interaction of many genetic and environmental factors, each contributing modestly to the eventual disease presentation. This makes it difficult to identify predisposing genetic factors in the majority of cases.
Almost half of type 1 diabetes is believed to be associated with the major histocompatibility complex human leukocyte antigens (HLAs), but even individuals who possess the highest risk genotype only develop disease 8% of the time (5). Prevention trials are underway, and are focusing on identifying environmental triggers of disease, as well as ways to suppress immunity and slow disease progression. Predictive genetic testing for type 1 diabetes is currently limited to research studies, including the potential for newborn screening.
Type 2 diabetes is strongly associated with obesity; 70% of type 2 diabetics are overweight. However, only 30% of obese Americans have the disease (5). Relatives of nonobese type 2 diabetics are at particularly increased risk. This provides evidence that obesity is an environmental trigger of the underlying genetic predisposition, although the responsible genes remain elusive. As a result, family
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history remains the best way to identify at-risk individuals so that lifestyle changes and medication may be introduced to prevent disease, or at least slow its progression.
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TABLE 17.3 Examples of Hereditary Neoplasias for Which Genetic Testing Is Available |
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One current public health initiative is to develop an adequate tool to identify individuals at high risk to develop diabetes. Family history intake should include (a) relatives who have diabetes; (b) age of onset; (c) associated conditions, such as obesity or hypertension; and (d) specific disease complications. The latter area is of particular importance, as diabetic complications, such as nephropathy and retinopathy, tend to cluster in families. Ultimately, pharmacogenomics (for a definition, see Future Roles of Genetics in Patient Care) may play a vital role in management of this disease.
Heart Disease
As the leading cause of death in industrialized countries, understanding the genetic risks for coronary artery disease could have significant impact on preventive measures. However, this complex disorder is affected by many risk factors, both genetic and nongenetic, and is thought to result from a combination of several factors. More than 30 single-gene disorders include significant risk for coronary artery disease or myocardial infarction at a young age (6). The mode of inheritance varies with each specific disorder and includes autosomal dominant, autosomal recessive, and polygenic inheritance. Ultimately, most heart disease is multifactorial, and caused by the combination of multiple genetic and environmental factors. The personal and family histories are the most important clues to identifying individuals at risk. The greatest benefit of preventive measures may be for those with a strong genetic predisposition to coronary artery disease.
Hypertrophic cardiomyopathy is the most frequent cause of sudden death from cardiac causes in children and adolescents (7). The incidence is estimated to be 1/500 young adults based on population studies. Inheritance is autosomal dominant, with mutations identified in at least ten different sarcomeric proteins. The clinical course and degree of cardiac dysfunction is highly variable. Genes that predispose to arrhythmia have also been identified; these affect cardiac ion channels (7) and include long QT syndrome, idiopathic ventricular fibrillation, and cardiac conduction disease. Clinical genetic testing is not generally available for the diagnosis of monogenic cardiac disease and diagnosis currently relies on physical examination and clinical testing.
Genetic Counseling and Testing FOR HEREDITARY CANCER
The impact of genetic testing on the health of patients has not yet been subjected to extensive clinical trials. In the coming decade, it is likely that much will be learned about
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this evolving area of preventive medicine. The approach to testing for genetic susceptibility to disease begins with genetic counseling. The flow diagram in Figure 17.1 illustrates the decisions in this process, beginning with the generalist clinician's recognition of a possible genetic disorder and the decision to offer referral for genetic counseling. Because much of the currently available genetic testing and counseling in adults is cancer related, Fig. 17.1 and the following sections describe the approach to an individual or family in which there may be a hereditary predisposition to cancer. The same approach would pertain to evaluation of other inherited diseases, infertility, and in prenatal diagnostics.
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FIGURE 17.1. Recommended approach for a patient contemplating genetic testing for hereditary cancer. |
Overview of Counseling and Testing
To ensure that genetic tests are ordered appropriately and interpreted accurately, it is important, whenever possible, to enlist the help of a practitioner trained in cancer genetics. Genetic counselors are health care professionals who typically hold a masters-level graduate degree in the field of genetics, and most are certified by the American Board of Genetic Counseling. The National Society of Genetic Counselors maintains a directory of genetic counselors and their affiliated institutions. The cost of a genetic counseling visit usually ranges from $150 to $350. Depending on the problem, patients may need to return for one or more followup visits.
Genetic counseling is generally undertaken in a nondirective fashion (8). Because the decision to undergo genetic testing has family, societal, and insurance implications, it must be an informed decision made by the person who will be tested. Except for the few hereditary cancer syndromes that have onset in childhood and for which treatment is available, testing is not performed on children. The exceptions currently include familial adenomatous polyposis, which requires colon screening beginning at puberty, and multiple endocrine neoplasia type 2, which necessitates thyroidectomy in childhood (Table 17.3).
When a patient schedules a genetic counseling session, a detailed medical and family history is obtained. Relevant information includes type and location of the cancer, age at diagnosis, how the cancer was diagnosed, stage at diagnosis, whether or not the cancer was bilateral, history of other cancers, history of other chronic medical conditions, and history of exposures to carcinogens. Pathology reports are extremely useful when obtaining personal or family history, because patients often have difficulty distinguishing specific cancer types, or primary cancers versus recurrences or metastases.
The proband is the individual who comes for consultation. The consultant is the parent(s) who comes for consultation when the proband is a minor. The family history is the key to identifying a hereditary pattern of cancer within a family. Information about the proband and his or her parents, grandparents, aunts, uncles, first cousins, siblings, and children is obtained and diagrammed into a three-generation pedigree(9) (Fig. 17.2). This diagram makes traits inherited in a mendelian manner easier to recognize. Included is information about unaffected and affected relatives. For each family member, detailed medical history is necessary. It is important to recognize that in some diseases, such as FAP, the rate of new germline mutations is high (approximately 30%), and there may be no family history of disease. However, an individual with a new germline mutation can still pass on the disease to his or her children.
If the medical and family history is suspicious for inherited cancer susceptibility, the patient is educated on specific disease characteristics, basic genetic information, and the pattern of inheritance. If applicable, the risks, benefits, and limitations of genetic testing are reviewed, and the most informative approach to testing is determined. In addition, the patient is told about possible genetic discrimination and about the most current legal decisions regarding genetic testing.
Peripheral blood is usually the specimen of choice for genetic testing. Although some specific testing can be performed on paraffin-embedded formalin-fixed pathology specimens, the preservation of DNA in the specimen may be inadequate for the technical requirements of many of the analytical processes currently in use. The specific type of laboratory test that is performed is related to the type of alteration being sought. Some disease-causing mutations tend to occur in one area or a small number of areas of a gene, and testing can be confidently limited to those regions. An example is multiple endocrine neoplasia type 2b in which more than 90% of cases have the same
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mutation. For other genetic disorders, such as hereditary nonpolyposis colon cancer (HNPCC) and BRCA-linked breast cancer, mutations in the relevant genes can occur over many thousands of base pairs. For these disorders, more comprehensive testing, such as DNA sequencing, is necessary. Recent advances also show that large rearrangements account for a significant proportion of genetic abnormalities. Such mutations are typically only detectable using techniques like Southern blot analysis. For these reasons, genetic testing ideally begins with an affected individual, so that one can define the mutation in the family.
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FIGURE 17.2. A: Example of a patient's family history diagrammed as a pedigree. B: Common pedigree symbols. |
If genetic testing detects a specific disease-causing mutation in an affected individual, this is termed positive. Other family members can then be tested for that specific mutation and receive definitive (positive or true negative) results. The test is deemed inconclusive if an affected individual is tested but no mutation is found. It is also inconclusive if the affected individual is not available for testing and testing of the at-risk unaffected individual does not identify a known disease-causing mutation. In the latter case, the at-risk person might not have a detectable mutation because he or she did not inherit it; alternatively, the cause of disease in the family may be an undiscovered gene or one for which testing has not been performed. Consequently, to prove that a person has not inherited a specific mutation, it is necessary that such a mutation be detectable using current technology and that it actually exists in the family. Finally, test results are also considered inconclusive if the laboratory detects an alteration in the DNA but is unable to classify it as clearly disease-causing or as a benign polymorphism. This is termed a “variant of uncertain significance.” Typically, at-risk relatives are not tested for these variants as their impact on risk is unknown.
Genetic testing for cancer syndromes costs from $250 to more than $3,000, depending on how many laboratories perform a particular test and the technology employed. Many insurance companies cover some or all of the cost if the individual's personal or family history is suggestive of an inherited predisposition and medical necessity can be demonstrated. Very often, test availability is a function of patents or licenses on particular genetic tests. Some testing techniques are more sensitive than others, again based primarily on the type(s) of genetic abnormalities being sought. Depending on test complexity, days to months may elapse before a genetic test result is reported. A genetic test, in general, is classified as a high-complexity test under current Public Health Service Clinical Laboratory Improvement Act of 1988 guidelines. Quality control programs for genetic testing are under development, but at this time, these tests are not specifically regulated. Therefore, choice of a testing laboratory is best left to professionals with experience with specific laboratories.
Management of cancer risk is discussed by the genetic counselor, both with patients interested in genetic testing and those who prefer not to pursue such an analysis. Because genetic test results can drastically alter management, patients are often asked to return after the results are known for final recommendations. Management options include increased surveillance, chemoprevention, prophylactic surgery, and lifestyle alterations. For some disorders, consideration of prophylactic surgery may be indicated, whereas for others, a specific surveillance regimen is more appropriate. This usually depends on the lifetime
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cancer risk and the efficacy of available screening methods. There is virtually no evidence-based data regarding the impact of preventive behaviors, such as low-fat diet, exercise, and so forth, on the development of cancer in mutation-positive individuals. Because the disorders most often discussed are hereditary, some patients also seek information regarding various reproductive options or genetic testing recommendations for other family members.
Psychosocial Issues
Genetic testing not only impacts the individual patient but other family members as well. Consequently, patients may experience emotions different from those regularly encountered in the clinical setting (10). Positive results can evoke fear, anxiety, or uncertainty. Some patients experience guilt at having potentially passed a mutation to a child or anger for having inherited the mutation from a parent in the first place. Negative results can lead to relief and happiness, but also to survivor's guilt over having been “spared” from the disease that affected family members. Thus, genetic testing may lead to strained familial relationships. Still, some patients report a feeling of relief, regardless of whether the result is positive or negative, because cancer risk to themselves and their family members is better defined and better able to be managed.
It should be noted that each individual has a different perception of high risk versus low risk. To some patients, a 45% risk is still “less than half,” whereas others view a 5% to 10% risk as frighteningly high. Therefore, before embarking on genetic testing, it is important to explore the patient's viewpoints. Particular attention should be paid to risk perception, ability to handle a positive or negative result, and patient communication with family members. It is also advantageous to discuss which management options the patient may prefer, knowing that decisions may ultimately be shaped by the results of the genetic testing.
Ethical and Legal Concerns
When involved in genetic testing, it is important to be familiar with ethical, social, and legal issues. As previously addressed, genetic testing provides information about other family members in addition to the individual seeking testing. This raises the ethical dilemma of “duty to warn.” In short, is a health care professional required to notify relatives of a patient if a genetic disorder is detected in the family? Thus far, legal decisions on this matter are in conflict, because disclosure of information may violate confidentiality, whereas failure to disclose may be viewed as endangerment. Consequently, the impact of genetic information on family members must be clearly explained to patients.
Another issue is potential discrimination by insurance companies or employers. Currently, the concern is that genetic information will be viewed as evidence for a pre-existing condition that insurers will refuse to cover or that will render an individual unemployable. Federal laws, such as the Health Insurance Portability and Accountability Act, provide some protection for individuals who are covered under a group health insurance plan. Many states have enacted protective laws as well. As of now, however, there is no federal legislation regarding patients who have individual health insurance coverage. There is also no protection from discrimination relating to life insurance or disability insurance.
Informed Consent
Because the implications of genetic testing are far-reaching, informed consent is vital. Proper informed consent includes a thorough discussion of the risks, benefits, and limitations of testing. Among other details, the patient should be made aware of what information can and cannot be obtained by the particular test in question. The sensitivity of the test must be clearly explained as well, and the patient should understand that the test may not be informative, meaning that it may not provide information that is useful for risk modification. The patient should also be aware that genetic testing is a personal decision and the patient should not be pressured into obtaining such testing.
In practice, genetic counseling should occur before testing for mutations in cancer-predisposition genes, as discussed above. In contrast, informed consent and extensive counseling before ordering tests for alterations in coagulation predisposition genes, such as factor V Leiden, are uncommon. This may reflect a decreased perception of risk for discrimination or the fact that the mutation in factor V is a simpler, less expensive, more widely available test.
Future Roles of Genetics in Patient Care
Testing for genetically determined responses to drugs and screening for a broad array of genetic susceptibility to disease may soon be available for use in clinical decision making. As is true of all tests used in clinical preventive medicine, expanded genetic testing and counseling will require critical assessment of their impact on patients’ health before they become standards of care.
Pharmacogenomics describes the concept of individualized choice of drug therapy based on knowledge of the differences in drug absorption, metabolism, and excretion as determined by variation in the relevant genes (11). For example, a polymorphism in the gene NAT2 (N-acetyltransferase 2) determines whether an individual is a rapid or slow acetylator of many drugs such as
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hydralazine and isoniazid. Adverse drug reactions, such as the increased risk for peripheral neuropathy caused by isoniazid, occur more frequently in individuals who are slow acetylators. Identification of increasing numbers of polymorphisms in genes that affect drug metabolism will allow health care practitioners to prescribe some drugs on the basis of the genetic profile of individual patients. This will only occur if testing for such genetic alterations can be performed quickly and inexpensively.
Technologic advances, such as the development of microarray technology, offer a way to screen for multiple genetic changes quickly and cheaply. Commonly known as “chips,” these are high-density assemblies of oligonucleotides or complementary DNAs on a membrane or glass substrate. Specific DNA sequences can be sought by annealing with fluorescent dye-labeled RNA or DNA in solution and read with the assistance of computer programs. The Human Genome Project, which completed the sequencing of the human genome in 2001, is providing the information needed to develop such diagnostic technology. The day may not be far off when an individual with high blood pressure can be rapidly screened for specific genetic changes that affect blood pressure and the drugs that could be used to treat it, resulting in prescription of individualized rational drug therapy.
Prior to the widespread use of genetic information for clinical decision making, it will be necessary not only to develop efficient and affordable technologies, but also to assess the impact of the introduction of such technologies on clinical outcomes while simultaneously addressing the concerns discussed above regarding privacy and potential discrimination.
Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.