Genetic testing: Hope or hype?
2004; Elsevier BV; Volume: 6; Issue: 4 Linguagem: Inglês
10.1097/01.gim.0000132683.24854.44
ISSN1530-0366
Autores Tópico(s)Nutrition, Genetics, and Disease
Resumo“One hundred years ago no one imagined the impact that electrical energy would have on every aspect of daily life. Similarly, it is impossible to predict how the science of genetics will alter opportunities to advance individual, family, and community health.”1.French M.E. Moore J.B. Harnessing genetics to prevent disease and promote health. 2003; (Washington, DC: Partnership for Prevention)Google ScholarCrystal-balling is a very precarious enterprise because, as Yogi Berra said, “It’s tough to make predictions, especially about the future… The future ain’t what it used to be.”2.Famous-Quotes-And-Quotations.com. Available at: http://www.famous-quotesand-quotations.com/yogi-berra-quotes.html. Accessed March 2004.Google Scholar Nevertheless, I believe that it is incumbent upon us as an organization and as a profession to look ahead, if not a hundred years, at least into the next ten or twenty, to get a sense of where genetics and, particularly, medical genetics are likely to be.There appears to be pervasive belief in both scientific and public circles that genetic testing is going to be the cornerstone of much, if not all, of what medicine holds for the future. And, what is generally meant is the wide scale testing for susceptibility to common diseases and for responsiveness to drugs—what has come to be described as genetic profiling. However, there are many who think that there is more hype than hope in what is being predicted, and I think that is important for us as geneticists to decide which it is. We need to do this to be able to define where we fit into the medical and health care system—what might be called our scope of practice—so that we can establish meaningful interactions with other medical specialists and professionals and with the public. And, we need to do this so that we can design our training programs to meet future needs. Therefore, I want to share with you my own personal and unofficial attempt to come to grips with the role that genetic testing will play in the future and with how we as medical geneticists should relate to it.However, before tackling these issues, I need to acknowledge that genetic testing and screening of many types are currently being done and will continue to be done in the future. Some are performed on an individual basis. These include pre- and postnatal diagnostic testing for monogenic and chromosomal disorders by cytogenetic, biochemical, and DNA mutation analysis, presymptomatic diagnosis of Huntington disease and other high penetrance late-onset neurodegenerative disorders, and diagnostic and presymptomatic testing for high penetrance familial cancer mutations. Others are performed on a population basis: maternal serum screening, newborn screening, and heterozygote detection for a variety of conditions.I present this list to make four points. First, the indications and targets for the current forms of testing will expand as technologies change (as, for example, in newborn screening with tandem mass spectrometry)3.Wilcken B. Wiley V. Hammond J. Carpenter K. Screening newborns for inborn errors of metabolism by tandem mass spectrometry.1:CAS:528:DC%2BD3sXkt1KktrY%3D10.1056/NEJMoa025225N Engl J Med. 2003; 348: 2304-2312Google Scholar and as new disease-causing mutations are discovered. Second, medical geneticists and genetic counselors are not the only parties involved with genetic testing, and there are many interactions between them and primary care providers, other medical specialists, and public health programs. Third, virtually all of the current forms of genetic testing have raised a large number of social, legal, and ethical issues. And, fourth, as the program of this meeting reveals, the American College of Medical Genetics is very much concerned with genetic testing in the present.Having acknowledged the present, I now turn to the perception that genetic testing and profiling are the wave of the future. Consider this quotation from Time magazine: “Even more genetic gee-wizardry lies just down the road. Using bio-chips… scientists should be able to identify genetic errors almost as quickly as a supermarket scanner prices a load of groceries… Genetic researchers are already talking about using ‘FISH… and chips’… to look for any number of genetic characteristics, including the more elusive web of genes that may lurk behind familial patterns of heart disease and stroke, cancer, diabetes, Alzheimer’s, various kinds of mental disorders and even gingivitis… ‘We’ll soon be governed by a new paradigm—genomic medicine—with tests and ultimately treatment for every disease linked to the human genome’… With the prestidigitation of gene amplification, only a single drop of blood or snippet of hair or a scraping of skin can reveal the full length of the human genome, including its myriad flaws.”4.Golden F. Good eggs, bad eggs. Time January 11, 1999: 56–59.Google ScholarThe writing is a little florid, but the message is one that the scientific community has itself been promulgating. Here are but a few examples: “…[W]ithin the next 2 decades it will be technically feasible to sequence the genome of every new baby—providing them with a rundown of each and every one of their genes and their associated risk of developing certain diseases. This will enable them to seek preventable measures and adopt healthier lifestyles… There are benefits to having the ability to examine our genetic make up. Genetic technology could lead to an era of personalized medicine and better-tailored preventive treatment.”5.Nurse P. The comments of Sir Paul Nurse, Nobel Laureate and head of Cancer Research UK, at the Royal Society's People's Science Summit on Genetic Testing. Available at: http://www.royalsoc.ac.uk/templates/press/releasedetails.cfm?file=433.txt. Accessed January 2004.Google Scholar “The great potential of the genomic era is the development of interventions to prevent or better manage costly, chronic diseases… Medical interventions could include drugs and preventive measures that are tailored to a person’s genetic profile… Health professionals will increasingly use tests and family histories to assess risk for disease in individual patients, families, and populations. Once clinicians and public health professionals identify increased risk, they can recommend preventive measures…”1.French M.E. Moore J.B. Harnessing genetics to prevent disease and promote health. 2003; (Washington, DC: Partnership for Prevention)Google Scholar “The potential is enormous for pharmacogenomics to yield a powerful set of molecular diagnostic methods that will become routine tools with which clinicians will select medications and drug doses for individual patients. A patient’s genotype needs to be determined only once for any given gene, because except for rare somatic mutations, it does not change. Genotyping methods are improving so rapidly that it will soon be simple to test for thousands of single-nucleotide polymorphisms in one assay.”6.Evans W.E. McLeod H.L. Pharmacogenomics: Drug disposition, drug targets, and side effects.1:CAS:528:DC%2BD3sXovVKlsQ%3D%3D10.1056/NEJMra020526N Engl J Med. 2003; 348: 538-556Google ScholarThe same vision has been put forward others closer to us. For example, Muin Khoury and Linda and Ed McCabe recently wrote that: “Over the next decade or two, it seems likely that we will screen entire populations or specific subgroups for genetic information in order to target interventions to individual patients that will improve their health and prevent disease… In the future, genetic information will increasingly be used to determine individual susceptibility to common disorders such as heart disease, diabetes, and cancer. Such screening will identify groups at risk so that primary-prevention efforts (such as diet an exercise) and secondary-prevention efforts (early detection or pharmacologic intervention) can be initiated. Such information could lead to the modification of screening recommendations, which are currently based on population averages.”7.Khoury M.J. McCabe L.L. McCabe E.R.B. Population screening in the age of genomic medicine.1:CAS:528:DC%2BD3sXhsFSmtg%3D%3D10.1056/NEJMra013182N Engl J Med. 2003; 348: 50-58Google ScholarFrancis Collins, in his frequently quoted 1999 Shattuck lecture,8.Collins F.C. Shattuck lecture: medical and societal consequences of the human genome project.1:STN:280:DyaK1M3psVelug%3D%3D10.1056/NEJM199907013410106N Engl J Med. 1999; 341: 28-37Google Scholar has a figure in which he shows the steps involved in the “genetic revolution.” The pathway goes from “disease with genetic component” through “map” to “clone gene.” From there it is on to “diagnostics,” which bifurcates to “preventive medicine” and “pharmacogenomics.” The same type of thinking is echoed in the “vision for the future of genomics research” recently promulgated by the National Human Genome Research Institute.9.Collins F.S. Green E.D. Guttmacher A.E. Guyer M.S. A vision for the future of genomics research.1:CAS:528:DC%2BD3sXjtFCitbc%3D10.1038/nature01626Nature. 2003; 422: 835-847Google Scholar This vision is cast in terms of 15 Grand Challenges, two of which speak to the issue of genetic testing: Grand Challenge II-3: Develop genome-based approaches to prediction of disease susceptibility and drug response… Grand Challenge II-5: Investigate how genetic risk information is conveyed in clinical settings, how that information influences health strategies and behaviors, and how these affect health outcomes and costs.Several steps are proposed for responding to the first of these challenges. These include the unbiased determination of risks associated with variants, reduction in the cost of genotyping, research on whether information will change health behaviors, oversight for clinical validity, and education.The overall assumption for the goals encompassed by both challenges is that predictive risk information will be used by individuals to “develop an individualized prevention or treatment plan.” Indeed, there are a few terms that recur in many of the statements about genetic testing in the future: “genetic profiling,” “tailoring,” and “personalized” or “individualized.” So, the mantra goes something like the following:Genetic profiling will permit the tailoring of health care, prevention strategies, treatments, and/or interventions and will thereby make personalized or individualized medicine possible.The quotations I have presented are but a brief sampling of the loud and steady drum beat of predictions and assertions that genetic testing for predispositions to common diseases and for the prevention of drug toxicity and promotion of drug efficacy are what genetics holds for the future. However, as I have already noted, there are many who do not accept this vision, and, therefore, the first question that I set out to answer for myself is the following: How credible is the promise of an all-encompassing personalized medicine based on wide-scale genetic testing? I shall consider testing for disease susceptibility first.I have just presented some of the positive views asserting the likelihood of this eventuality, but Holtzman and Marteau see things differently. “Statements like these clothe medicine in a genetics mantle. The result of efforts to identify genes that have a role in common diseases suggests a different picture: the genetic mantle may prove to be like the emperor’s new clothes… Although we do not contend that the genetic mantle is as imperceptible as the emperor’s new clothes were, it is not made of the silks and ermines that some claim it to be. Those who make medical and science policies in the next decade would do well to see beyond the hype.”10.Holtzman N.A. Mateau T.M. Will genetics revolutionize medicineN Engl J.1:STN:280:DC%2BD3czjtFCgsg%3D%3DMed. 2000; 343: 141-144Google ScholarThe arguments behind this statement and others like it fall into two very broad categories: whether genetic testing for complex traits can be done and whether it should be done. Starting with the can it be done, the first thing that has to be said is that complex traits are indeed complex. Arthur Beaudet summarized this very nicely in his 1998 presidential address to the American Society of Human Genetics: “Most genetic traits of interest in populations of humans and other organisms are determined by many factors, including genetic and environmental components, which interact in often unpredictable ways. For such complex traits, the whole is not only greater than the sum of its parts, it may be different from the sum of its parts. Thus complex traits have a genetic architecture that consists of the genetic and environmental factors that contribute to the trait, as well as their magnitude and their interactions.”11.Beaudet A.L. 1998 ASHG Presidential address: Making genomic medicine a reality.1:STN:280:DyaK1M7hsFSktg%3D%3D10.1086/302217Am J Hum Genet. 1999; 64: 1-13Google ScholarGiven this complexity, can testing for susceptibility to common diseases actually be done? The issues here are principally genetic and epidemiological and are concerned with our ability to identify susceptibility alleles and with their frequency in the population, penetrance, absolute and relative risks, and positive and negative predictive values. To date, as Joel Hirschhorn and colleagues have pointed out,12.Hirschhorn J.N. Lohmueller K. Byrne E. Hirschhorn K. A comprehensive review of genetic association studies.1:CAS:528:DC%2BD38XjtFSru7w%3D10.1097/00125817-200203000-00002Genet Med. 2002; 4: 45-61Google Scholar most of the reported associations have not been robust. In their analysis, only 6 of 166 associations that were studied three or more times were consistently replicated. This variability among reports has been attributed to a variety of factors. Some, such as the alleles that are being looked at and the size and selection of the population, are essentially technical in nature and are potentially correctable, although perhaps not easily. However, two factors—weak genetic effects with low relative risks and gene-gene and gene-environment interactions—are inherent in what is being looked at, and they cannot be dismissed. Because of this, Angus Clarke has made the following sweeping assertion: “The scientific rationale for carrying out genetic research into these [complex] diseases has never included the development of tests that will identify the risk for healthy individuals that they will develop the disease. The fact that so many genes and nongenetic factors are involved in the etiology of these common diseases means that the identification of inherited predisposition is of little use at the individual level; it will never be possible to predict those who will be affected nor to know when an individual will develop a disease if he does so at all.”13.Clarke A.J. The genetic dissection of multifactorial disease: The implications of susceptibility screening.Genetics, society, and clinical practice. 1997; (Oxford: BIOS Scientific Publishers): 93-106Google ScholarI would agree, based on what has been accomplished thus far and is likely to be done in the near future, that Clarke is correct about both the who and the when. However, it seems likely to me that, with the passage of time, alleles that confer susceptibility or protection and that affect penetrance, timing, and severity, will be identified at many different loci and for many different conditions. Precedents for this exist in the analysis of modifier genes in the mouse. Furthermore, although we already have reasonably good information about many of the lifestyle and environmental factors that influence the development of common diseases, it likely that more will be recognized. The implication of all of this for me, and others as well,14.Willett W.C. Balancing life-style and genomics research for disease prevention.1:CAS:528:DC%2BD38XjtlOhtbg%3D10.1126/science.1071055Science. 2002; 296: 695-698Google Scholar, 15.Yang Q. Khoury M.J. Botto L. Friedman J.M. Flanders W.D. Improving the prediction of complex diseases by testing for multiple disease-susceptibility genes.1:CAS:528:DC%2BD3sXitFajsr0%3D10.1086/367923Am J Hum Genet. 2003; 72: 636-649Google Scholar, 16.Khoury M.J. Yang Q. Gwinn M. Little J. Flanders W.D. An epidemiologic assessment of genomic profiling for measuring susceptibility to common diseases and targeting interventions.10.1097/01.GIM.0000105751.71430.79Genet Med. 2004; 6: 38-47Google Scholar is that genetic risk assessment will attain sufficient predictive power to be of use only if the analyses of many genetic loci are combined with the evaluations of nongenetic lifestyle and environmental factors. In other words, it will be necessary to multiplex and combine the analyses, and this is what I think will happen. Testing one or a few genes at a time will not be the route to follow.Therefore, although I concur with Hirschhorn and colleagues that “a ‘DNA chip’ that can determine crucial genotypes and accurately predict future health is unlikely to become a widespread and useful screening tool in the near future,”12.Hirschhorn J.N. Lohmueller K. Byrne E. Hirschhorn K. A comprehensive review of genetic association studies.1:CAS:528:DC%2BD38XjtFSru7w%3D10.1097/00125817-200203000-00002Genet Med. 2002; 4: 45-61Google Scholar I can visualize, in the not too distant future, the development of computer-based algorithms that will combine the output of such chips or their equivalents with a broad environmental assessment to produce better estimates of risk for the development of common diseases than would otherwise be possible. Given that the genetic factors remain constant, these estimates will, of course, be highly sensitive to the nongenetic factors acting at the time of the evaluation and could change significantly if these factors were altered.I do not think that any of this is going to be easy to accomplish or expect that it will occur very rapidly, but I do not doubt that it will ultimately happen. What we are likely to see along the way are a series of intermediate stages of multiplexed testing as the numbers of loci being entered into the prediction algorithms are increasing. An interesting theoretical example of this has already been provided by Yang and colleagues15.Yang Q. Khoury M.J. Botto L. Friedman J.M. Flanders W.D. Improving the prediction of complex diseases by testing for multiple disease-susceptibility genes.1:CAS:528:DC%2BD3sXitFajsr0%3D10.1086/367923Am J Hum Genet. 2003; 72: 636-649Google Scholar who have shown that in assessing the risk for venous thrombosis, a combination of three tests—factor V Leiden, prothrombin G20210A, and protein C deficiency—will increase the positive predictive value of testing by 8-fold.When I say that I think that a highly multiplexed form of risk assessment that incorporates genetic testing will eventually become possible and will provide better estimates of risk than we now have, I do not mean to imply that the results will be absolutely definitive. The information will be probabilistic, and we shall always be dealing with estimates of risk, not predictions of certain outcomes. For some, such uncertain information is without value,13.Clarke A.J. The genetic dissection of multifactorial disease: The implications of susceptibility screening.Genetics, society, and clinical practice. 1997; (Oxford: BIOS Scientific Publishers): 93-106Google Scholar whereas for others, it suffers from being too “abstract.”17.McConnell L.M. Koenig B.A. Greely H.T. Raffin T.A. Genetic testing and Alzheimer disease: recommendations of the Stanford Program in Genomics, Ethics, and Society.1:STN:280:DyaK1Mzptlygug%3D%3D10.1089/gte.1999.3.3Genet Test. 1999; 3: 3-12Google Scholar However, life is filled with probabilities and risks rather than certainties. When we cross the street or fly in an airplane, we do not have an absolute certainly that we will survive the experience. In fact, there are definite, albeit low, probabilities that we will not. Probabilistic information is not new to the practice of medicine, and many, if not most, diagnostic and therapeutic decisions are made on the basis of probabilities. What is important is that, even though the results of testing are probabilities and not certainties, they can still form the basis on which people make decisions.However, merely stating the belief that susceptibility testing or profiling can be done does not mean that it actually will or, indeed, should be done. This will ultimately be determined by whether testing really offers more than currently available forms of risk assessment in terms of predictive power and securing compliance; in other words, by whether it will have greater clinical utility. In discussing whether genetic testing for cardiovascular disease will be useful, Humphries and colleagues18.Humphries S.E. Ridker P.M. Talmud P.J. Genetic testing for cardiovascular disease susceptibility: useful clinical management tool or possible misinformation.Arterioscler Thromb Vasc Biol. 2004; 29: 1-9Google Scholar have asked whether the genetic test or tests will have additional predictive power over and above the accepted risk factors that can already be easily, and usually inexpensively, measured with high reproducibility and replicability. These accepted risk factors would include family history, for which Maren Scheuner and others have made a strong case,19.Scheuner M.T. Wang S.-J. Raffel L.J. Larabell L.J. Rotter J.I. Family history: A comprehensive genetic risk assessment method for the chronic conditions of adulthood.1:STN:280:DyaK2svhtF2ruw%3D%3D10.1002/(SICI)1096-8628(19970822)71:3 3.0.CO;2-NAm J Med Genet. 1997; 71: 315-324Google Scholar a number of lifestyle and environmental factors, and relevant markers of disease and disease predisposition, such as blood pressure and serum cholesterol, lipids, and C-reactive protein.18.Humphries S.E. Ridker P.M. Talmud P.J. Genetic testing for cardiovascular disease susceptibility: useful clinical management tool or possible misinformation.Arterioscler Thromb Vasc Biol. 2004; 29: 1-9Google Scholar,20.Scheuner M.T. Genetic evaluation for coronary artery disease.10.1097/01.GIM.0000079364.98247.26Genet Med. 2003; 5: 269-285Google Scholar The short answer to the Humphries et al. question is that in the short run there is no evidence that genetic testing will add significantly to currently available modalities for risk assessment. My personal feeling is that in the future it will, but this remains to be shown.A related matter is whether the results of genetic testing would enhance a person’s motivation to comply with recommendations for therapy and changes in lifestyle. As Marteau and Lerman put it, “Providing people with personalized information is not new. The question is whether responses will be any different if the information is based on DNA.”21.Marteau T.M. Lerman C. Genetic risk and behavioural change.1:STN:280:DC%2BD3MzgvFelsw%3D%3D10.1136/bmj.322.7293.1056BMJ. 2001; 322: 1056-1059Google Scholar Haga and colleagues are not very optimistic: “If all would benefit from a healthy diet, exercise, smoking cessation or prudent alcohol intake, regardless of genotype, the added value of the test is unclear unless it can be shown to motivate compliance in those who test positive without reducing compliance in those who test negative. Unfortunately, current data suggest little reason for optimism concerning the potential for genetic tests to motivate behavioral change.”22.Haga S.B. Khoury M.J. Burke W. Genomic profiling to promote a healthy lifestyle: not ready for prime time.1:CAS:528:DC%2BD3sXmt1Sktbs%3D10.1038/ng0803-347Nat Genet. 2003; 34: 347-350Google ScholarWe already know that changing behavior is difficult, and providing people with genetic information on risk may not increase their motivation to change behavior unless effective therapies are available and beliefs in them are reinforced. In some cases, genetic information could conceivably decrease motivation if it engendered a deterministic belief in some pre-ordained outcome.22.Haga S.B. Khoury M.J. Burke W. Genomic profiling to promote a healthy lifestyle: not ready for prime time.1:CAS:528:DC%2BD3sXmt1Sktbs%3D10.1038/ng0803-347Nat Genet. 2003; 34: 347-350Google Scholar It seems clear, therefore, that enhancing motivation and securing compliance with whatever interventions are indicated by the results of the overall risk assessment will determine whether the testing will be worthwhile, assuming, of course, that effective interventions actually exist. In their absence, or if they result in more harm than good, there is really no justification for the testing.23.Burke W. Genetic testing.1:CAS:528:DC%2BD38Xpt1ensbo%3D10.1056/NEJMoa012113N Engl J Med. 2002; 347: 1867-1874Google Scholar,24.Reich L.M. Bower M. Key N.S. Role of the geneticist in testing and counseling for inherited thrombophilias.10.1097/01.GIM.0000067987.77803.D0Genet Med. 2003; 5: 133-143Google ScholarBecause I have been speaking about the effectiveness of genetic testing to motivate changes in lifestyle and environment, I need to point out that perhaps the most extreme argument used against genetic testing is that it just is not necessary. The basis for this, the argument goes, is that because most, if not all, of the common diseases are products of adverse environmental factors, they are therefore best approached on a population-wide basis by environmental and lifestyle modification and by improvement of economic and social conditions.25.Goodman A.H. Why genes dont count (for racial differences in health).1:STN:280:DC%2BD3M%2FkslCqsg%3D%3D10.2105/AJPH.90.11.1699Am J Public Health. 2000; 90: 1699-1702Google Scholar,26.Hubbard R. Wald E. Exploding the gene myth. 1999; (Boston: Beacon Press): 77Google Scholar The importance of such nongenetic factors is certainly undeniable, and Walter Willett points out that “We have been able to identify modifiable behavioral factors, including specific aspects of diet, overweight, inactivity, and smoking that account for over 70% of stroke and colon cancer, over 80% of coronary heart disease, and over 90% of adult onset diabetes….”14.Willett W.C. Balancing life-style and genomics research for disease prevention.1:CAS:528:DC%2BD38XjtlOhtbg%3D10.1126/science.1071055Science. 2002; 296: 695-698Google ScholarThe importance of nongenetic factors is also substantiated by the fact that when groups migrate from regions of low risk to ones of high risk for common diseases such as cancer, the incidence of the disease rapidly increases to match that of the new location. The same message has been derived from the marked increase in the incidence of asthma over the past several decades, and it has been suggested that “Although the causes are disputed, environmental or lifestyle factors—outdoors or at home—must underlie the increase.”27.Barrett S, Hall H. Dubious genetic testing. Available at: http://www.quackwatch.org/01QuackeryRelatedTopics/Tests/genomics.html. Accessed January 2004.Google ScholarThe real danger, the critics believe, is that attempts to identify genetic risk factors will detract from efforts to eliminate the environmental and lifestyle ones. Therefore, some think that we should forget about testing altogether and get on with modifying the environment for everyone.26.Hubbard R. Wald E. Exploding the gene myth. 1999; (Boston: Beacon Press): 77Google Scholar The risk factors, they say, are “mass phenomena” and therefore require “mass preventive approaches.”28.Blackburn H. Population strategies of cardiovascular disease prevention: scientific base, rationale and public health implications.1:STN:280:DyaL1MzltF2mtg%3D%3D10.3109/07853898909149926Ann Med. 1989; 21: 157-162Google ScholarI certainly do not take exception to the goal of eliminating environmental and lifestyle risk factors, but I do not see it as a the only approach to disease prevention. Population-based programs aimed at smoking cessation and at the detection and treatment of hypertension are considered to be quite effective,29.Brown A.D. Garber A.M. Cost effectiveness of coronary heart disease prevention strategies in adults.1:STN:280:DyaK1czovVGjtw%3D%3D10.2165/00019053-199814010-00004Pharmacoeconomics. 1998; 14: 27-48Google Scholar and it has been estimated that each of these, if universally implemented, could increase the life expectancy of the entire population of 35-year-old males in the United States by about a year.30.Tsevat J. Weinstein M.C. Williams L.W. Tosteson A.N. Goldman Expected gains in life expectancy from various coronary heart disease risk factor modifications.1:STN:280:DyaK3M7ptFOnsg%3D%3D10.1161/01.CIR.83.4.1194Circulation. 1991; 83: 1194-1201Google Scholar However, the results of several population-based multiple risk factor intervention studies for the prevention of coronary heart disease have shown showed only modest benefits, if any.31.Ebrahim S. Smith G.D. Systematic review of randomized controlled trials of multiple risk factor interventions for preventing coronary heart disease.1:STN:280:DyaK2szjs1Gntw%3D%3D10.1136/bmj.314.7095.1666BMJ. 1997; 314: 1666-1674Google Scholar,32.Hoffmeister H. Mensink G.B.M. Stolzenberg H. Hoeltz J. Kreuter H. Laaser U. Reduction of coronary heart disease risk factors in the German cardiovascular prevention study.1:STN:280:DyaK2s%2FhtlCnsA%3D%3D10.1006/pmed.1996.0039Prev Med. 1996; 25: 135-145Google Scholar Less than optimal compliance with the intervention program is undoubtedly one of the major reasons for the poor outcome, and compliance may be difficult unless there is a high degree of motivation. Hopefully, a more comprehensive approach based on a combined genetic and nongenetic risk assessment might provide this.I now want to turn briefly to pharmacogenetic testing, for which the purpose seems to be more straight forward than susceptibility testing—to look for variants that might make a person more or less sensitive to the therapeutic and tox
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