- Email: [email protected]
Personalised medicine: who is an Asian?
Comment
Personalised medicine: who is an Asian? “The Asian word is abused…I would rather somebody called me ‘Indian’, ‘Hindu’—but to be called Asian is a violation…Half of Russia is Asian but they are never called ‘Asian’. Chinese are Asians and they are never called ‘Asians’. They are called ‘Chinese’. But Indians, somehow, become ‘Asians’ as though they own the whole of the continent of Asia.” “Actually I’m not an Asian, I’m a Hindu.”1 These quotations, from a UK Government report in 2006,1 expresses the views of two Hindus living in the UK about being labelled as Asian. The use of pharmacogenetics to guide prescribing for the individual patient is gradually increasing. For example, Emily Fargher and colleagues recently reported that, to improve the dosing of azathioprine, two-thirds of the responding clinicians assessed thiopurine methyltransferase status.2 However, the technique used was usually measurement of enzyme concentration rather than genotyping or DNA analysis. Paradoxically, despite much progress in pharmacogenetics, there seems to be an increase in use of the imprecise label of ethnicity to predict drug response. The UK Medicines and Healthcare products Regulatory Agency highlighted the recommendation of a lower starting dose of rosuvastatin of 5 mg for Asians.3 The controversial licensing of the combination of isosorbide dinitrate and hydralazine specifically for 700
Geometric mean AUC (ng h per mL)
600
500
400
300
200
100
GG hi te W
W
hi te
AG
AA hi te
CC te hi
W
TC W
W
hi
te
TT hi te W
hi te W
M ala y
In ian As
Ch
in
di
es
e
an
0
Figure: Pharmacokinetics and pharmacogenetics of rosuvastatin10 AUC=area under blood-concentration time-curve after single dose of rosuvastin 40 mg (95% CI, log-transformed data).
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African-Americans has perhaps legitimised ethnicgroup targeting further.4 Practice guidelines on overthe-counter sales of simvastatin identified that being south Asian was a risk factor,5 although in the UK few people assigned to this category see themselves as belonging to this group.6 The Asian category has a wide geographical variability in its interpretation. Even within the same population, different constructions of the term might exist.7 In the UK, Asian usually refers to “brown” Asians. In the USA, Asian is typically used to describe, “yellow” Asians. One trial, led by a UK investigator,8 of gefitinib in chemorefractory non-small-cell lung cancer used the American vernacular definition, and excluded Asian Indians. A clear definition of the term is essential, as shown by subgroup analyses in that study, which suggested that Asians responded better to the tyrosine-kinase inhibitor (Thatcher N, Christie Hospital, Manchester, UK, personal communication). Data from Singh and colleagues9 further show the danger of inferring drug-response phenotype from ethnicity. Although all participants were west Bengali Asians, the frequency of non-tasters of phenylthiocarbamide within the different subcommunities showed wide variability. The pharmacokinetics of rosuvastatin provides further evidence of the complexity of inferring biological response from ethnicity.10 Although systemic exposure to rosuvastatin is usually smaller in whites than in other ethnic groups, this is not necessarily so for all SLCO1B1 T521→C (Val174Ala) genotypes (figure). For the CC genotype, the area under the curve for white and other participants overlaps. Only 16 drug labels in the UK comment on the response to drugs in Asians; only one label defines Asian. The main reason for the continued use of racial categorisation in therapeutics is the inability of molecular pharmacogenetic studies to provide the basis for definitive guidance.11 The use of frequencies of different polymorphisms in different populations to personalise therapy is generally imprecise. In a study12 of seven Mexican Americans who were phenotyped as poor metabolisers for CYP2C9, only two were identified by genotyping. Would a Mexican American be outwardly distinguishable from an Asian? They might be in some milieux but most probably not in others. www.thelancet.com Vol 369 May 26, 2007
Comment
Classifications provide the basis for language and scientific progress. Darwin and Linnaeus used categorisations to help us conceptualise the world. Genetic classifications carry the potential for both great medical progress and, as human history shows, malignant bigotry. When racial labels are used in drug datasheets and health advisories, inferences should be based on robust evidence. Racebased therapy relies on an average response to predict a higher probability of response for individuals. The least we can do is to better define racial labels so that inappropriate generalisations are not made from narrow criteria. Koreans are not necessarily the same as Chinese or Japanese people, nor Indian or Pakistani people, in drug response. Who is an Asian? A diverse person, usually misleadingly and variably defined only in the eyes of the beholder. Alain Li Wan Po National Genetics Education and Development Centre, Birmingham, UK; and Centre for Evidence-Based Pharmacotherapy, Nottingham NG9 3FD, UK [email protected] I have research funding from AstraZeneca for a study investigating ethnicity in drug response, and participated in a meeting with GlaxoSmithKline about over-the-counter availability of statins. I am a former member of the UK Committee on Safety of Medicines.
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Department for Communities and Local Government. Connecting British Hindus, an enquiry into the identity and public policy engagement of British Hindus by the Runnymede Trust. 2006. http://www.hfb.org. uk/FileServer.aspx?oID=307&lID=0 (accessed April 10, 2007). Fargher EA, Tricker K, Newman W, et al. Current use of pharmacogenetic testing: a national survey of thiopurine methyl transferase testing prior to azathioprine prescription. J Clin Pharm Ther 2007; 32: 187–95. Committee on Safety of Medicines and Medicines and Healthcare products Regulatory Agency. Rosuvastatin (Crestor): introduction of 5 mg starting dose. Curr Probl Pharmacovigil 2006; 31: 4. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004; 351: 2049–57. The Royal Pharmaceutical Society of Great Britain. Practice guidance: OTC simvastatin 10 mg. Pharm J 2004; 273: 169–70. Bhopal R. Glossary of terms relating to ethnicity and race: for reflection and debate. J Epidemiol Community Health 2004; 58: 441–45. Rasanathan K, Craig D, Perkins R. The novel use of ‘Asian’ as an ethnic category in the New Zealand health sector. Ethn Health 2006; 11: 211–27. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005; 366: 1527–37. Singh KS, Bhalla V, Kaul V. The biological variation in Indian populations, 1st edn. Delhi: Oxford University Press, 1994. Lee E, Ryan S, Birmingham B, et al. Rosuvastatin pharmacokinetics and pharmacogenetics in white and Asian subjects residing in the same environment. Clin Pharmacol Ther 2005; 78: 330–41. Royal Society. Personalised medicines: hopes and realities. Sept 29, 2004. http://www.royalsoc.ac.uk/displaypagedoc.asp?id=23244 (accessed April 10, 2007). Luo HR, Poland RE, Lin KM, Wan YJ. Genetic polymorphism of cytochrome P450 2C19 in Mexican Americans: a cross-ethnic comparative study. Clin Pharmacol Ther 2006; 80: 33–40.
A strategy for translation The Cooksey report into UK health-research funding,1 which was highlighted in an editorial in The Lancet,2 was accepted in full by the UK Government. The report proposed that funding available from both National Health Service (NHS) Research and Development (via the National Institute for Health Research [NIHR]) and the Medical Research Council should be overseen by the Office for Strategic Coordination of Health Research. This Office will ensure that, although funding for basic biomedical science is constant, any future growth in research spending should drive innovation in translational biomedicine. To deliver this aim, excellence in basic scientific endeavour and clinical care will need to be bridged. Although there is general agreement that it is important to drive translation for the benefit of patients, the definition of translational research is less clear.3 In this context, new diagnostic, prognostic, preventive, and therapeutic strategies that have direct relevance to human disease can be considered as discrete but www.thelancet.com Vol 369 May 26, 2007
overlapping areas of research. This broad-based definition of translational research accords with the UK Department of Health’s strategy document, Best Research for Best Health.4 Through the NIHR, five Comprehensive Biomedical Research Centres were recently established by open competition and international peer review.5 The funding is substantial (£450 million over 5 years) in international terms and several times higher than that available to comparable centres in the USA,6 where translational research is a major focus of the National Institutes of Health.7 The past few months have seen a major shift in the structures that aim to deliver translational research. Thus we need a strong plan to enable these public resources to be of maximum benefit for patients. Successful redeployment of NHS Research and Development funding in this way requires the removal of significant barriers that prevent high-quality translational research.8,9 However, no real consensus about how this could be best achieved has emerged. The UK has 1771
Personalised medicine: who is an Asian? “The Asian word is abused…I would rather somebody called me ‘Indian’, ‘Hindu’—but to be called Asian is a violation…Half of Russia is Asian but they are never called ‘Asian’. Chinese are Asians and they are never called ‘Asians’. They are called ‘Chinese’. But Indians, somehow, become ‘Asians’ as though they own the whole of the continent of Asia.” “Actually I’m not an Asian, I’m a Hindu.”1 These quotations, from a UK Government report in 2006,1 expresses the views of two Hindus living in the UK about being labelled as Asian. The use of pharmacogenetics to guide prescribing for the individual patient is gradually increasing. For example, Emily Fargher and colleagues recently reported that, to improve the dosing of azathioprine, two-thirds of the responding clinicians assessed thiopurine methyltransferase status.2 However, the technique used was usually measurement of enzyme concentration rather than genotyping or DNA analysis. Paradoxically, despite much progress in pharmacogenetics, there seems to be an increase in use of the imprecise label of ethnicity to predict drug response. The UK Medicines and Healthcare products Regulatory Agency highlighted the recommendation of a lower starting dose of rosuvastatin of 5 mg for Asians.3 The controversial licensing of the combination of isosorbide dinitrate and hydralazine specifically for 700
Geometric mean AUC (ng h per mL)
600
500
400
300
200
100
GG hi te W
W
hi te
AG
AA hi te
CC te hi
W
TC W
W
hi
te
TT hi te W
hi te W
M ala y
In ian As
Ch
in
di
es
e
an
0
Figure: Pharmacokinetics and pharmacogenetics of rosuvastatin10 AUC=area under blood-concentration time-curve after single dose of rosuvastin 40 mg (95% CI, log-transformed data).
1770
African-Americans has perhaps legitimised ethnicgroup targeting further.4 Practice guidelines on overthe-counter sales of simvastatin identified that being south Asian was a risk factor,5 although in the UK few people assigned to this category see themselves as belonging to this group.6 The Asian category has a wide geographical variability in its interpretation. Even within the same population, different constructions of the term might exist.7 In the UK, Asian usually refers to “brown” Asians. In the USA, Asian is typically used to describe, “yellow” Asians. One trial, led by a UK investigator,8 of gefitinib in chemorefractory non-small-cell lung cancer used the American vernacular definition, and excluded Asian Indians. A clear definition of the term is essential, as shown by subgroup analyses in that study, which suggested that Asians responded better to the tyrosine-kinase inhibitor (Thatcher N, Christie Hospital, Manchester, UK, personal communication). Data from Singh and colleagues9 further show the danger of inferring drug-response phenotype from ethnicity. Although all participants were west Bengali Asians, the frequency of non-tasters of phenylthiocarbamide within the different subcommunities showed wide variability. The pharmacokinetics of rosuvastatin provides further evidence of the complexity of inferring biological response from ethnicity.10 Although systemic exposure to rosuvastatin is usually smaller in whites than in other ethnic groups, this is not necessarily so for all SLCO1B1 T521→C (Val174Ala) genotypes (figure). For the CC genotype, the area under the curve for white and other participants overlaps. Only 16 drug labels in the UK comment on the response to drugs in Asians; only one label defines Asian. The main reason for the continued use of racial categorisation in therapeutics is the inability of molecular pharmacogenetic studies to provide the basis for definitive guidance.11 The use of frequencies of different polymorphisms in different populations to personalise therapy is generally imprecise. In a study12 of seven Mexican Americans who were phenotyped as poor metabolisers for CYP2C9, only two were identified by genotyping. Would a Mexican American be outwardly distinguishable from an Asian? They might be in some milieux but most probably not in others. www.thelancet.com Vol 369 May 26, 2007
Comment
Classifications provide the basis for language and scientific progress. Darwin and Linnaeus used categorisations to help us conceptualise the world. Genetic classifications carry the potential for both great medical progress and, as human history shows, malignant bigotry. When racial labels are used in drug datasheets and health advisories, inferences should be based on robust evidence. Racebased therapy relies on an average response to predict a higher probability of response for individuals. The least we can do is to better define racial labels so that inappropriate generalisations are not made from narrow criteria. Koreans are not necessarily the same as Chinese or Japanese people, nor Indian or Pakistani people, in drug response. Who is an Asian? A diverse person, usually misleadingly and variably defined only in the eyes of the beholder. Alain Li Wan Po National Genetics Education and Development Centre, Birmingham, UK; and Centre for Evidence-Based Pharmacotherapy, Nottingham NG9 3FD, UK [email protected] I have research funding from AstraZeneca for a study investigating ethnicity in drug response, and participated in a meeting with GlaxoSmithKline about over-the-counter availability of statins. I am a former member of the UK Committee on Safety of Medicines.
1
2
3
4 5 6 7 8
9 10
11
12
Department for Communities and Local Government. Connecting British Hindus, an enquiry into the identity and public policy engagement of British Hindus by the Runnymede Trust. 2006. http://www.hfb.org. uk/FileServer.aspx?oID=307&lID=0 (accessed April 10, 2007). Fargher EA, Tricker K, Newman W, et al. Current use of pharmacogenetic testing: a national survey of thiopurine methyl transferase testing prior to azathioprine prescription. J Clin Pharm Ther 2007; 32: 187–95. Committee on Safety of Medicines and Medicines and Healthcare products Regulatory Agency. Rosuvastatin (Crestor): introduction of 5 mg starting dose. Curr Probl Pharmacovigil 2006; 31: 4. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004; 351: 2049–57. The Royal Pharmaceutical Society of Great Britain. Practice guidance: OTC simvastatin 10 mg. Pharm J 2004; 273: 169–70. Bhopal R. Glossary of terms relating to ethnicity and race: for reflection and debate. J Epidemiol Community Health 2004; 58: 441–45. Rasanathan K, Craig D, Perkins R. The novel use of ‘Asian’ as an ethnic category in the New Zealand health sector. Ethn Health 2006; 11: 211–27. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005; 366: 1527–37. Singh KS, Bhalla V, Kaul V. The biological variation in Indian populations, 1st edn. Delhi: Oxford University Press, 1994. Lee E, Ryan S, Birmingham B, et al. Rosuvastatin pharmacokinetics and pharmacogenetics in white and Asian subjects residing in the same environment. Clin Pharmacol Ther 2005; 78: 330–41. Royal Society. Personalised medicines: hopes and realities. Sept 29, 2004. http://www.royalsoc.ac.uk/displaypagedoc.asp?id=23244 (accessed April 10, 2007). Luo HR, Poland RE, Lin KM, Wan YJ. Genetic polymorphism of cytochrome P450 2C19 in Mexican Americans: a cross-ethnic comparative study. Clin Pharmacol Ther 2006; 80: 33–40.
A strategy for translation The Cooksey report into UK health-research funding,1 which was highlighted in an editorial in The Lancet,2 was accepted in full by the UK Government. The report proposed that funding available from both National Health Service (NHS) Research and Development (via the National Institute for Health Research [NIHR]) and the Medical Research Council should be overseen by the Office for Strategic Coordination of Health Research. This Office will ensure that, although funding for basic biomedical science is constant, any future growth in research spending should drive innovation in translational biomedicine. To deliver this aim, excellence in basic scientific endeavour and clinical care will need to be bridged. Although there is general agreement that it is important to drive translation for the benefit of patients, the definition of translational research is less clear.3 In this context, new diagnostic, prognostic, preventive, and therapeutic strategies that have direct relevance to human disease can be considered as discrete but www.thelancet.com Vol 369 May 26, 2007
overlapping areas of research. This broad-based definition of translational research accords with the UK Department of Health’s strategy document, Best Research for Best Health.4 Through the NIHR, five Comprehensive Biomedical Research Centres were recently established by open competition and international peer review.5 The funding is substantial (£450 million over 5 years) in international terms and several times higher than that available to comparable centres in the USA,6 where translational research is a major focus of the National Institutes of Health.7 The past few months have seen a major shift in the structures that aim to deliver translational research. Thus we need a strong plan to enable these public resources to be of maximum benefit for patients. Successful redeployment of NHS Research and Development funding in this way requires the removal of significant barriers that prevent high-quality translational research.8,9 However, no real consensus about how this could be best achieved has emerged. The UK has 1771