- Email: [email protected]
Integration of genetics into medical practice
Growth Hormone & IGF Research 14 (2004) S146–S149 www.elsevier.com/locate/ghir
Integration of genetics into medical practice Bruce R. Korf
*
Department of Genetics, University of Alabama at Birmingham, 1530 3rd Avenue South, Hugh Kaul Human Genetics Bldg. 230, Birmingham, AL 35294-0024, USA
Abstract It has been a century since the first human genetic disorders were recognized, but only recently have there been any prospects that the genetic approach would become integral to medical practice. Throughout most of the 20th century, medical genetics has focused on rare monogenic and chromosomal disorders. There were major successes, including chromosomal analysis, prenatal diagnosis and newborn screening for inborn errors of metabolism, but the impact was confined to a relatively narrow corner of medicine. The situation has changed, however, with advances in genetics and especially with the sequencing of the human genome. The tools are now at hand to begin to understand the genetic basis of common as well as rare disorders. It is expected that this will lead to major advances in both diagnosis and treatment, so that physicians in all areas of medicine will be using the tools of genetics in their daily practice. Ó 2004 Elsevier Ltd. All rights reserved. Keywords: Genetics; Traits; Disorders; Diagnosis; Treatment
1. Genetic mechanisms in health and disease Patterns of single-gene transmission disorders have been known in humans since Garrod described inborn errors of metabolism during the first decade of the 20th century [1]. Thousands of single-gene disorders are now known, inherited as dominant or recessive traits. Individuals who have mutations in a gene for such a disorder in a heterozygous state (dominant trait) or homozygous state (recessive trait) are highly likely to manifest signs and symptoms of the disorder at some point in their lives. Often these disorders exhibit incomplete or agedependent penetrance, so having the gene mutation is not absolutely deterministic of disease, though the probability may be high for disease expression. Frequently, these disorders affect multiple members of a family, passing from generation to generation in the case of a dominant trait or affecting multiple siblings in the case of a recessive trait. Although many single-gene disorders are rare, in some cases carrier frequency is high, especially in specific populations where the gene frequency is high due to a founder effect, such as with *
Tel.: +1-205-934-9411; fax: +1-205-934-9488. E-mail address: [email protected] (B.R. Korf).
1096-6374/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.ghir.2004.03.032
Tay-Sachs disease in individuals of Ashkenzi Jewish decent, where the carrier frequency is 1:30. This has led to introduction of carrier screening programs in some cases where a couple at risk might be interested in prenatal testing. It has long been recognized that genetic factors contribute to common disorders, but most are determined by combinations of multiple genes interacting with one another and with the environment. This is referred to as ‘‘multifactorial inheritance’’. For the most part, the specific genetic or environmental factors involved are unknown. Furthermore, the particular combination of factors may differ in different individuals with the same disorder, especially in individuals from different populations. Examination of genetic factors that contribute to common disorders is a major focus of current research in genetics. Two major approaches are used. First, in some rare instances, studies are conducted on families with single-gene causes of ‘‘common’’ disorders, such as hypertension [2] or cardiovascular disease [3]. Of course, these are rare families who have rare disorders, but in some cases the genes involved reveal mechanisms that might also apply to the more common versions of these conditions. The second approach is to do large
B.R. Korf / Growth Hormone & IGF Research 14 (2004) S146–S149
population studies, searching for a genetic variation that is associated with the disease. A large number of such variations are now known in the genome, making it easier to conduct association studies [4]. Still, this approach is laborious and requires access to DNA specimens from large numbers of individuals with wellcharacterized clinical disorders. Techniques for scanning the genome for variations that are associated with particular diseases are continually being developed so that this approach will be more powerful in the coming years. The identification of a genetic contribution to a common disorder can lead to major clinical advances, which are outlined below. Although individual genes may add only slightly to the risk of disease, recognition of these genes may illuminate biological pathways that are involved in the disorder, suggesting new targets for diagnostic testing and treatment. It is likely that the genetic approach will add greatly to our understanding of mechanisms of both health and disease.
2. Genetic testing and treatment Genetic testing for monogenic or chromosomal disorders has been available for almost 50 years. It is used either to establish a diagnosis in an individual with signs or symptoms of a genetic disorder or to determine whether a disorder has been passed on to an individual at risk. In the latter case, it has been used for prenatal diagnosis as well as for diagnosis of adult-onset disorders. In the past, much of the activity in genetic testing took place within the realms of obstetrics and gynecology (for prenatal testing) or pediatrics (for diagnosis of congenital anomalies or severe genetic disorders). Most physicians who took care of adult patients assumed that major genetic disorders in their patients would have been diagnosed in childhood. There were some notable exceptions (e.g., Huntington’s disease), but most of these occurred within specialty disciplines such as neurology. The general internist or family practitioner had come to ignore genetics in his or her daily practice [5]. Identification of genetic causes of relatively common adult-onset disorders, such as breast, colon and ovarian cancer, and hemochromatosis, changed this perception. Even if less than 10% of breast cancer is due to mutations in individual genes such as BRCA1 or BRCA2, breast cancer is common and therefore it is not rare for a physician in general practice to encounter a woman at risk for the disease [6]. Hemochromatosis is most often a recessive trait due to mutation in the HFE gene; 1 in 10 individuals of northern European descent carries a hemochromatosis mutation [7]. Although there is an appreciable rate of non-penetrance, the disorder should not be overlooked since initiation of treatment early in the course can prevent life-threatening complications.
S147
How will physicians recognize those patients for whom testing for these genetic traits is appropriate? Most patients do not have obvious signs and symptoms, at least not until they have developed disease. Perhaps the best clue is found in family history. Woman at risk of breast cancer due to genetic causes are likely to have firstor second-degree relatives with a history of breast and/or ovarian cancer. There may be multiple primary tumors in individuals who carry a cancer-predisposing gene mutation, or cancer may develop at an anomalously early age. The other clue is ethnic background. In addition to the example of the association between the HFE mutation with individuals of northern European descent, women of Ashkenazi Jewish descent have an increased risk of a BRCA1 mutation [8], as previously noted. The major pitfalls in interpretation of genetic tests involve false-negative and false-positive results and nonpenetrance. False-negative results occur when the entire gene cannot be thoroughly searched for mutations, or when multiple genes—perhaps some still undiscovered— account for a single disorder. In such cases, not finding a mutation does not mean that the patient does not carry a pathogenic mutation. False-positive results occur when a benign genetic variant is mistaken for a pathogenic one. Genetic variation is common and most of it does not cause or contribute to disease. In some cases, there will be substantial experience with a specific mutation indicating pathogenicity, but in others, a mutation may be found that has never been seen before. Such ‘‘private mutations’’ should be interpreted with special care. Evidence of pathogenicity might include: segregation of the mutation with disease within a family; the mutation does not occur in controls; a mutation that has a major impact on protein function; or a mutation that can reproduce a disease when introduced into a model system. Non-penetrance means that the presence of a mutation does not necessarily predict the occurrence of a phenotype. Some individuals with a mutation may never develop disease; whereas, others may not develop symptoms for many years after testing. Pre-symptomatic testing may be appropriate only in instances where some specific intervention is possible. Such intervention may include family planning, for example, for a dominant disorder that can be transmitted to offspring. It might also include changes in lifestyle or taking medication to prevent or forestall onset of disease. However, it is important to recognize the psychological implications of pre-symptomatic testing since individuals determined to be at risk of disease based on genetic testing may experience anxiety and stigmatization; those found not to be at risk may experience guilt. Genetic testing is likely to play a different role in the care of individuals with common disorders. In some cases, predictive testing may be offered. In addition to the psychological concerns mentioned, it must be recognized that individual genes may make very small
S148
B.R. Korf / Growth Hormone & IGF Research 14 (2004) S146–S149
contributions to risk [9]. Therefore, a specific genetic test is unlikely to be highly predictive, but rather will make a small change in relative risk. It is unclear whether individuals would change lifestyles or take medication on the basis a small increment of risk. It is more likely that genetic testing for common disorders will be used to guide treatment decisions. The basis for this is the hope that understanding the genetics of common disorders will reveal new pathophysiological mechanisms that will lead to the development of new types of drugs that target these mechanisms. If this approach is successful, it may be discovered that different individuals with the same disorder, such as hypertension, have the disorder for different reasons and would be best treated with different medications. In such a situation, genetic testing could be used to establish a precise diagnosis and direct the choice of drug to be used for treatment. It is also likely that genetic testing will be used to better match a medication to the physiological needs of an individual patient. Polymorphisms in genes that encode enzymes involved in drug metabolism can result in unusually rapid or slow metabolism of specific drugs [10]. An individual with slow metabolism will accumulate the drug and face an increased risk of side effects; whereas, a person with rapid metabolism will be undermedicated using standard dosing. Determination of genotype at loci encoding proteins involved in drug metabolism can allow the dose to be titrated to the patient’s physiology without a lengthy period of trial and error. Also, some severe idiosyncratic drug reactions are likely to be due to individuals who are especially vulnerable because they carry rare polymorphisms. Genetic testing may allow these individuals to be identified, avoiding the use of drugs that are dangerous for them while allowing the drug to be used safely in others.
3. Into the future It has been predicted that genetics will transform medical practice, but the pace of this change is difficult to predict. There are already several major advances, such as breast, ovarian and colon cancer testing. Patterns of gene expression are beginning to be used to diagnose tumors, and at least one new drug has been designed based on understanding of genetic mechanisms [11]. Nevertheless, is it likely to take many years to see the full benefit of genetics in medicine, and advances will come at different rates for different disorders. Moreover, a number of challenges must be overcome in order to achieve implementation. There is a major need for education, both of health professionals and the general public, about genetics. This is an extraordinarily fast-moving field, and most physicians were not taught about modern applications
of genetics in medical school or residency. They need to be knowledgeable about the proper use of genetic testing in their practice to avoid some of the pitfalls of interpretation noted previously. Consumers also need to be better informed as they will increasingly be presented with options for genetic testing, both by their health providers and by direct-to-consumer marketing. There has been much debate about the potential for misuse of genetic information, which has engendered concern about the possibilities of stigmatization and discrimination [12]. Genetic privacy laws have been passed in many states in the US, but such legislation has not yet passed through the US Congress. If genetic testing is to be used for medical decision-making, it will be critical to stimulate public confidence in the privacy of such information so that people are willing to be tested without fear of negative consequences. The promise of genetics in medicine remains to be fully realized. Achieving this potential will keep a generation of physicians and scientists occupied trying to understand the biological mechanisms, developing new approaches to testing and treatment and determining outcomes in clinical trials. There is a great need to educate clinical investigators who will take up this challenge. We have embarked on an era in which many of the mysteries of health and disease are being solved. Translation of this new knowledge to the improvement of human health is a task that will require a partnership of clinicians, investigators, educators and the public that will occupy much of this century.
References [1] A. Garrod, The incidence of alkaptonuria. A study in chemical individuality, Lancet ii (1902) 1616–1620. [2] R.P. Lifton, A.G. Gharavi, D.S. Geller, Molecular mechanisms of human hypertension, Cell 104 (2001) 545–556. [3] H. Watkins, J.G. Seidman, C.E. Seidman, Familial hypertrophic cardiomyopathy: a genetic model of cardiac hypertrophy, Hum. Mol. Genet. 4 (1995) 1721–1727. [4] M. Cargill, D. Altshuler, J. Ireland, P. Sklar, K. Ardlie, N. Patil, C.R. Lane, E.P. Lim, N. Kalyanaraman, J. Nemesh, L. Friedland, A. Rolfe, J. Warrington, R. Lipschutz, G.Q. Daily, E.S. Lander, Characterization of single-nucleotide polymorphisms in coding regions of human genes, Nat. Genet. 22 (1999) 231–238. [5] S.J. Hayflick, M.P. Eiff, L. Carpenter, J. Steinberger, Primary care physicians’ utilization and perceptions of genetics services, Genet. Med. 1 (1998) 13–21. [6] B. Newman, H. Mu, L.M. Butler, R.C. Millikan, P.G. Moorman, M.C. King, Frequency of breast cancer attributable to BRCA1 in a population-based series of American women, JAMA 279 (1998) 915–921. [7] E.H. Hanson, G. Imperatore, W. Burke, HFE gene and hereditary hemochromatosis: a HuGE review. Human Genome Epidemiology, Am. J. Epidemiol. 154 (2001) 193–206. [8] J.P. Struewing, D. Abeliovich, T. Peretz, N. Avishai, M.M. Kaback, F.S. Collins, L.C. Brody, The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals, Nat. Genet. 11 (1995) 198–200.
B.R. Korf / Growth Hormone & IGF Research 14 (2004) S146–S149 [9] N.A. Holtzman, T.M. Marteau, Will genetics revolutionize medicine, N. Engl. J. Med. 343 (2000) 141–144. [10] W.E. Evans, M.V. Relling, Pharmacogenomics: translating functional genomics into rational therapeutics, Science 286 (1999) 487– 491. [11] H. Kantarjian, C. Sawyers, A. Hochhaus, F. Guilhot, C. Schiffer, C. Gambacorti-Passerini, D. Niederwieser, D. Resta, R. Capdev-
S149
illi, U. Zoellner, M. Talpaz, B. Drucker, International STI571 CML Group, Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia, N. Engl. J. Med. 346 (2002) 645–652. [12] K.L. Hudson, K.H. Rothenberg, L.B. Andrews, M.J.E. Kahn, F.S. Collins, Genetic discrimination and health insurance: an urgent need for reform, Science 270 (1995) 391–393.
Integration of genetics into medical practice Bruce R. Korf
*
Department of Genetics, University of Alabama at Birmingham, 1530 3rd Avenue South, Hugh Kaul Human Genetics Bldg. 230, Birmingham, AL 35294-0024, USA
Abstract It has been a century since the first human genetic disorders were recognized, but only recently have there been any prospects that the genetic approach would become integral to medical practice. Throughout most of the 20th century, medical genetics has focused on rare monogenic and chromosomal disorders. There were major successes, including chromosomal analysis, prenatal diagnosis and newborn screening for inborn errors of metabolism, but the impact was confined to a relatively narrow corner of medicine. The situation has changed, however, with advances in genetics and especially with the sequencing of the human genome. The tools are now at hand to begin to understand the genetic basis of common as well as rare disorders. It is expected that this will lead to major advances in both diagnosis and treatment, so that physicians in all areas of medicine will be using the tools of genetics in their daily practice. Ó 2004 Elsevier Ltd. All rights reserved. Keywords: Genetics; Traits; Disorders; Diagnosis; Treatment
1. Genetic mechanisms in health and disease Patterns of single-gene transmission disorders have been known in humans since Garrod described inborn errors of metabolism during the first decade of the 20th century [1]. Thousands of single-gene disorders are now known, inherited as dominant or recessive traits. Individuals who have mutations in a gene for such a disorder in a heterozygous state (dominant trait) or homozygous state (recessive trait) are highly likely to manifest signs and symptoms of the disorder at some point in their lives. Often these disorders exhibit incomplete or agedependent penetrance, so having the gene mutation is not absolutely deterministic of disease, though the probability may be high for disease expression. Frequently, these disorders affect multiple members of a family, passing from generation to generation in the case of a dominant trait or affecting multiple siblings in the case of a recessive trait. Although many single-gene disorders are rare, in some cases carrier frequency is high, especially in specific populations where the gene frequency is high due to a founder effect, such as with *
Tel.: +1-205-934-9411; fax: +1-205-934-9488. E-mail address: [email protected] (B.R. Korf).
1096-6374/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.ghir.2004.03.032
Tay-Sachs disease in individuals of Ashkenzi Jewish decent, where the carrier frequency is 1:30. This has led to introduction of carrier screening programs in some cases where a couple at risk might be interested in prenatal testing. It has long been recognized that genetic factors contribute to common disorders, but most are determined by combinations of multiple genes interacting with one another and with the environment. This is referred to as ‘‘multifactorial inheritance’’. For the most part, the specific genetic or environmental factors involved are unknown. Furthermore, the particular combination of factors may differ in different individuals with the same disorder, especially in individuals from different populations. Examination of genetic factors that contribute to common disorders is a major focus of current research in genetics. Two major approaches are used. First, in some rare instances, studies are conducted on families with single-gene causes of ‘‘common’’ disorders, such as hypertension [2] or cardiovascular disease [3]. Of course, these are rare families who have rare disorders, but in some cases the genes involved reveal mechanisms that might also apply to the more common versions of these conditions. The second approach is to do large
B.R. Korf / Growth Hormone & IGF Research 14 (2004) S146–S149
population studies, searching for a genetic variation that is associated with the disease. A large number of such variations are now known in the genome, making it easier to conduct association studies [4]. Still, this approach is laborious and requires access to DNA specimens from large numbers of individuals with wellcharacterized clinical disorders. Techniques for scanning the genome for variations that are associated with particular diseases are continually being developed so that this approach will be more powerful in the coming years. The identification of a genetic contribution to a common disorder can lead to major clinical advances, which are outlined below. Although individual genes may add only slightly to the risk of disease, recognition of these genes may illuminate biological pathways that are involved in the disorder, suggesting new targets for diagnostic testing and treatment. It is likely that the genetic approach will add greatly to our understanding of mechanisms of both health and disease.
2. Genetic testing and treatment Genetic testing for monogenic or chromosomal disorders has been available for almost 50 years. It is used either to establish a diagnosis in an individual with signs or symptoms of a genetic disorder or to determine whether a disorder has been passed on to an individual at risk. In the latter case, it has been used for prenatal diagnosis as well as for diagnosis of adult-onset disorders. In the past, much of the activity in genetic testing took place within the realms of obstetrics and gynecology (for prenatal testing) or pediatrics (for diagnosis of congenital anomalies or severe genetic disorders). Most physicians who took care of adult patients assumed that major genetic disorders in their patients would have been diagnosed in childhood. There were some notable exceptions (e.g., Huntington’s disease), but most of these occurred within specialty disciplines such as neurology. The general internist or family practitioner had come to ignore genetics in his or her daily practice [5]. Identification of genetic causes of relatively common adult-onset disorders, such as breast, colon and ovarian cancer, and hemochromatosis, changed this perception. Even if less than 10% of breast cancer is due to mutations in individual genes such as BRCA1 or BRCA2, breast cancer is common and therefore it is not rare for a physician in general practice to encounter a woman at risk for the disease [6]. Hemochromatosis is most often a recessive trait due to mutation in the HFE gene; 1 in 10 individuals of northern European descent carries a hemochromatosis mutation [7]. Although there is an appreciable rate of non-penetrance, the disorder should not be overlooked since initiation of treatment early in the course can prevent life-threatening complications.
S147
How will physicians recognize those patients for whom testing for these genetic traits is appropriate? Most patients do not have obvious signs and symptoms, at least not until they have developed disease. Perhaps the best clue is found in family history. Woman at risk of breast cancer due to genetic causes are likely to have firstor second-degree relatives with a history of breast and/or ovarian cancer. There may be multiple primary tumors in individuals who carry a cancer-predisposing gene mutation, or cancer may develop at an anomalously early age. The other clue is ethnic background. In addition to the example of the association between the HFE mutation with individuals of northern European descent, women of Ashkenazi Jewish descent have an increased risk of a BRCA1 mutation [8], as previously noted. The major pitfalls in interpretation of genetic tests involve false-negative and false-positive results and nonpenetrance. False-negative results occur when the entire gene cannot be thoroughly searched for mutations, or when multiple genes—perhaps some still undiscovered— account for a single disorder. In such cases, not finding a mutation does not mean that the patient does not carry a pathogenic mutation. False-positive results occur when a benign genetic variant is mistaken for a pathogenic one. Genetic variation is common and most of it does not cause or contribute to disease. In some cases, there will be substantial experience with a specific mutation indicating pathogenicity, but in others, a mutation may be found that has never been seen before. Such ‘‘private mutations’’ should be interpreted with special care. Evidence of pathogenicity might include: segregation of the mutation with disease within a family; the mutation does not occur in controls; a mutation that has a major impact on protein function; or a mutation that can reproduce a disease when introduced into a model system. Non-penetrance means that the presence of a mutation does not necessarily predict the occurrence of a phenotype. Some individuals with a mutation may never develop disease; whereas, others may not develop symptoms for many years after testing. Pre-symptomatic testing may be appropriate only in instances where some specific intervention is possible. Such intervention may include family planning, for example, for a dominant disorder that can be transmitted to offspring. It might also include changes in lifestyle or taking medication to prevent or forestall onset of disease. However, it is important to recognize the psychological implications of pre-symptomatic testing since individuals determined to be at risk of disease based on genetic testing may experience anxiety and stigmatization; those found not to be at risk may experience guilt. Genetic testing is likely to play a different role in the care of individuals with common disorders. In some cases, predictive testing may be offered. In addition to the psychological concerns mentioned, it must be recognized that individual genes may make very small
S148
B.R. Korf / Growth Hormone & IGF Research 14 (2004) S146–S149
contributions to risk [9]. Therefore, a specific genetic test is unlikely to be highly predictive, but rather will make a small change in relative risk. It is unclear whether individuals would change lifestyles or take medication on the basis a small increment of risk. It is more likely that genetic testing for common disorders will be used to guide treatment decisions. The basis for this is the hope that understanding the genetics of common disorders will reveal new pathophysiological mechanisms that will lead to the development of new types of drugs that target these mechanisms. If this approach is successful, it may be discovered that different individuals with the same disorder, such as hypertension, have the disorder for different reasons and would be best treated with different medications. In such a situation, genetic testing could be used to establish a precise diagnosis and direct the choice of drug to be used for treatment. It is also likely that genetic testing will be used to better match a medication to the physiological needs of an individual patient. Polymorphisms in genes that encode enzymes involved in drug metabolism can result in unusually rapid or slow metabolism of specific drugs [10]. An individual with slow metabolism will accumulate the drug and face an increased risk of side effects; whereas, a person with rapid metabolism will be undermedicated using standard dosing. Determination of genotype at loci encoding proteins involved in drug metabolism can allow the dose to be titrated to the patient’s physiology without a lengthy period of trial and error. Also, some severe idiosyncratic drug reactions are likely to be due to individuals who are especially vulnerable because they carry rare polymorphisms. Genetic testing may allow these individuals to be identified, avoiding the use of drugs that are dangerous for them while allowing the drug to be used safely in others.
3. Into the future It has been predicted that genetics will transform medical practice, but the pace of this change is difficult to predict. There are already several major advances, such as breast, ovarian and colon cancer testing. Patterns of gene expression are beginning to be used to diagnose tumors, and at least one new drug has been designed based on understanding of genetic mechanisms [11]. Nevertheless, is it likely to take many years to see the full benefit of genetics in medicine, and advances will come at different rates for different disorders. Moreover, a number of challenges must be overcome in order to achieve implementation. There is a major need for education, both of health professionals and the general public, about genetics. This is an extraordinarily fast-moving field, and most physicians were not taught about modern applications
of genetics in medical school or residency. They need to be knowledgeable about the proper use of genetic testing in their practice to avoid some of the pitfalls of interpretation noted previously. Consumers also need to be better informed as they will increasingly be presented with options for genetic testing, both by their health providers and by direct-to-consumer marketing. There has been much debate about the potential for misuse of genetic information, which has engendered concern about the possibilities of stigmatization and discrimination [12]. Genetic privacy laws have been passed in many states in the US, but such legislation has not yet passed through the US Congress. If genetic testing is to be used for medical decision-making, it will be critical to stimulate public confidence in the privacy of such information so that people are willing to be tested without fear of negative consequences. The promise of genetics in medicine remains to be fully realized. Achieving this potential will keep a generation of physicians and scientists occupied trying to understand the biological mechanisms, developing new approaches to testing and treatment and determining outcomes in clinical trials. There is a great need to educate clinical investigators who will take up this challenge. We have embarked on an era in which many of the mysteries of health and disease are being solved. Translation of this new knowledge to the improvement of human health is a task that will require a partnership of clinicians, investigators, educators and the public that will occupy much of this century.
References [1] A. Garrod, The incidence of alkaptonuria. A study in chemical individuality, Lancet ii (1902) 1616–1620. [2] R.P. Lifton, A.G. Gharavi, D.S. Geller, Molecular mechanisms of human hypertension, Cell 104 (2001) 545–556. [3] H. Watkins, J.G. Seidman, C.E. Seidman, Familial hypertrophic cardiomyopathy: a genetic model of cardiac hypertrophy, Hum. Mol. Genet. 4 (1995) 1721–1727. [4] M. Cargill, D. Altshuler, J. Ireland, P. Sklar, K. Ardlie, N. Patil, C.R. Lane, E.P. Lim, N. Kalyanaraman, J. Nemesh, L. Friedland, A. Rolfe, J. Warrington, R. Lipschutz, G.Q. Daily, E.S. Lander, Characterization of single-nucleotide polymorphisms in coding regions of human genes, Nat. Genet. 22 (1999) 231–238. [5] S.J. Hayflick, M.P. Eiff, L. Carpenter, J. Steinberger, Primary care physicians’ utilization and perceptions of genetics services, Genet. Med. 1 (1998) 13–21. [6] B. Newman, H. Mu, L.M. Butler, R.C. Millikan, P.G. Moorman, M.C. King, Frequency of breast cancer attributable to BRCA1 in a population-based series of American women, JAMA 279 (1998) 915–921. [7] E.H. Hanson, G. Imperatore, W. Burke, HFE gene and hereditary hemochromatosis: a HuGE review. Human Genome Epidemiology, Am. J. Epidemiol. 154 (2001) 193–206. [8] J.P. Struewing, D. Abeliovich, T. Peretz, N. Avishai, M.M. Kaback, F.S. Collins, L.C. Brody, The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals, Nat. Genet. 11 (1995) 198–200.
B.R. Korf / Growth Hormone & IGF Research 14 (2004) S146–S149 [9] N.A. Holtzman, T.M. Marteau, Will genetics revolutionize medicine, N. Engl. J. Med. 343 (2000) 141–144. [10] W.E. Evans, M.V. Relling, Pharmacogenomics: translating functional genomics into rational therapeutics, Science 286 (1999) 487– 491. [11] H. Kantarjian, C. Sawyers, A. Hochhaus, F. Guilhot, C. Schiffer, C. Gambacorti-Passerini, D. Niederwieser, D. Resta, R. Capdev-
S149
illi, U. Zoellner, M. Talpaz, B. Drucker, International STI571 CML Group, Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia, N. Engl. J. Med. 346 (2002) 645–652. [12] K.L. Hudson, K.H. Rothenberg, L.B. Andrews, M.J.E. Kahn, F.S. Collins, Genetic discrimination and health insurance: an urgent need for reform, Science 270 (1995) 391–393.