E-Letter responses to:

p-forum: S. H. Katsanis, G. Javitt, and K. Hudson PUBLIC HEALTH: A Case Study of Personalized Medicine Science 2008; 320: 53-54 [Summary] [Full text] [PDF]

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Published E-Letter responses:

Assessing Drug Metabolism

Laura Lowe Furge   (3 October 2008)

Promises, Promises

Neil A. Holtzman   (3 October 2008)

Global Direct-to-Consumer Marketing Strategies Call for Global Oversight

David Gurwitz, Jeantine E. Lunshof, Faculty of Earth and Life Sciences, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands   (3 October 2008)

Assessing Drug Metabolism 3 October 2008
Laura Lowe Furge Department of Chemistry, Kalamazoo College, Kalamazoo, MI 49006, USA Respond to this E-Letter: Re: Assessing Drug Metabolism	I read with interest the short Policy Forum article on personalized medicine ("A case study of personalized medicine," by S. H. Katsanis et al., 4 April 2008, p. 53). I was surprised that while the terms “genotype” and “gene” were mentioned nearly 20 times in the short article, the word “phenotype” never appeared. It is increasingly clear in the area of drug metabolism, it is increasingly clear that genotype does not always predict enzyme activity with regards to metabolism of xenobiotics, i.e. phenotype (1, 2). This is particularly true for the main drug metabolizing enzyme in humans, P450 3A4, which is affected by enzyme inducers and also inhibitors such as grapefruit juice and other drugs (3–6). There is a large body of literature describing the disconnect between genotype and phenotype with P450s and the need to assess phenotype by a non-invasive method [such as monitoring caffeine metabolism by urine sampling (7)] in order to understand an individual’s personal drug metabolizing profile. In fact, the article quotes EGAPP (Evaluation of Genomic Applications in Practice & Prevention) as saying "no evidence was available showing the results of CYP450 testing influenced selective serotonin reuptake inhibitor (SSRI) choice or dose and improved patient outcomes...." This does not seem surprising if genotype—rather than phenotype—was the standard for testing. I wondered if there were any efforts to track SSRIs with non-invasive assays (e.g. P450 2D6 transformations such as dextromethorphan oxidation), as this would seem more appropriate for assessing drug metabolism. Finally, while the prospect of an individualized medicine is exciting, the many confounding factors that can influence drug metabolism (smoking status, diet, polypharmyuse of multiple medications, etc.) make the task much larger and complex than a simple genetic test could solve. Laura Lowe Furge Department of Chemistry, Kalamazoo College, 1200 Academy Street, Kalamazoo, MI 49006, USA. References 1. Z. Jiang et al., Pharmacogenet. Genomics 16, 359 (2006). 2. L. M. Hesse et al., Pharmacogenetics 14, 225 (2004). 3. H. Dally et al., Cancer Lett. 207, 95 (2004). 4. P. He, M. H. Court, D. J. Greenblatt, L. L. Von Moltke, Clin. Pharmacol. Ther. 77, 373 (2005). 5. C. Rodriguez-Antona, J. G. Sayi, L. L. Gustafsson, L. Bertilsson, M. Ingelman-Sundberg, Biochem. Biophys. Res. Commun. 338, 299 (2005). 6. B. Edgar et al., Clin. Pharmacol. Ther. 47, 181 (1990). 7. L. L. Furge, K. J. Fletke, Biochem. Mol. Biol. Ed. 35, 138 (2007).
Promises, Promises 3 October 2008
Neil A. Holtzman Former Director, Genetics and Public Policy Studies, The Johns Hopkins Medical Institutions, USA Respond to this E-Letter: Re: Promises, Promises	S. H. Katsanis, G. Javitt, and K. Hudson begin their otherwise excellent Policy Forum ("A case study of personalized medicine," 4 April 2008, p. 53) with the sentence, "Personalized medicine through pharmacogenetics promises to revolutionize health care…" Use of the word "promises" is an example of genohype (1). In a PubMed search (April 14, 2008) I found the words "promise" or "promises" in 104 of the 1,735 (6 %) articles in PubMed with a major topic descriptor of pharmacogenetics or pharmacogenomics. These articles represent 0.8% of all uses of these words in the English language medical literature in the last ten years, far greater than the proportion of articles devoted to pharmacogenetics or pharmacogenomics. "Revolutionize" appeared 11 times in articles with these descriptors. Forty-five of the 104 articles were published in 2006 or later, so genohype is not abating. In science and medicine, promises are rarely justified. (A finding can be promising but that is different than a promise.) By use of the verb "promises," Katsanis et al. are predicting that personalized medicine will be important in the future. Their purpose, perhaps, is to emphasize that we had better prepare so that when it does become widespread, personalized medicine will cause more good than harm. Although this may be their intent, use of "promise" reifies the belief that personalized medicine will revolutionize health care, a possibility for which, as the authors acknowledge, there is little evidence. Nevertheless, based on the promise, investors are lured into financing companies that promote pharmacogenetic and other genetic tests (often directly to consumers, as Katsanis et al. describe) and consumers are sucked in to having tests from which they are unlikely to derive benefit. Given the proliferation of these testing companies in the face of little or no regulation, a situation that has not changed much in the last ten years (1), we don’t have to appeal to future promise in order to argue for better regulation today. Neil A. Holtzman Former Director, Genetics and Public Policy Studies, The Johns Hopkins Medical Institutions, Baltimore, MD, 21205, USA. Reference 1. N. A. Holtzman, Science 286, 409 (1999).
Global Direct-to-Consumer Marketing Strategies Call for Global Oversight 3 October 2008
David Gurwitz Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978 Israel, Jeantine E. Lunshof, Faculty of Earth and Life Sciences, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands Respond to this E-Letter: Re: Global Direct-to-Consumer Marketing Strategies Call for Global Oversight	We fully agree with the authors' call for enhanced enforcement by Federal Trade Commission (FTC) in oversight of misleading claims made by direct-to-consumer (DTC) genetics testing, as well as for the development of a mandatory registry of such providers (Policy Forum, "A case study of personalized medicine," by S. H. Katsanis et al., 4 April 2008, p. 53). The problem has been recognized in Europe as well. The need for regulation of the use of pharmacogenetics diagnostics in the clinical setting, including among other things the need for a reliable quality control scheme involving making the accreditation of participating laboratories depend upon control by a central service laboratory, were already recommended in a detailed 2006 European Commission Joints Research Centers report on the socio-economic impact of pharmacogenetics in Europe (1). And there are other reasons why such calls for oversight should not be targeted merely at United States policy-makers. Considering that (for the time-being) most such providers are based in the USA but do business through the internet and address customers globally, the quality of these services–in particular the test validity–should also be guaranteed globally. Else, the proliferation of genetic testing would only widen the already large healthcare gap between developed and developing countries (2). Moreover, polymorphic alleles of drug response-related genes often vary among ethnic groups, and tests developed in the USA may, without proper scientific oversight, be useless for Asian or African populations (3). It seems that as a first workable step a directive by the Organization for Economic Co-operation and Development (OECD) would have on a global scale the greatest immediate impact for ensuring the validity and quality of tests offered as a direct-to-consumers commercial product. Such steps are pertinent for ensuring public trust in the potential of improving health through genetic testing and genomic medicine. Options for testing will increasingly be available via DTC marketing, parallel with the services provided by health care professionals. Personalized medicine is becoming a global issue. Pharmacogenetics-guided drug therapy, as one of its first applications, should benefit people globally. The quality of the products and services, therefore, should be overseen as such. David Gurwitz Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978 Israel. Jeantine E. Lunshof Faculty of Earth and Life Sciences, VU University Amsterdam, 1081 HV Amsterdam, The Netherlands. References 1. E. Zika, D. Gurwitz, D. Ibarreta, Pharmacogenetics and Pharmacogenomics: State-of-the-art and Potential Socio-economic Impacts in the EU. EUR 22214 EN. ISBN: 92-79-01901-5. http://esto.jrc.es/detailshort.cfm?ID_report=1387. 2. J. E. Lunshof, M. Pirmohamed, D. Gurwitz, Pharmacogenomics 7(2), 237 (2006). 3. S. Marsh, D. J. Van Booven, H. L. McLeod, Pharmacogenomics 7, 625 (2006).