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| Beyond skin deep |
3-May-2006 |
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The launch of a heart failure drug specifically targeted at African-Americans has forced a controversial medical question into the spotlight: Does race matter? By Bianca Nogrady
HEART failure drug BiDil burst onto the pharmaceutical scene last year amid the sort of public debate usually reserved for erectile dysfunction treatments.
The isosorbide dinitrate and hydralazine hydrochloride combination had been left for dead a decade earlier, after trials in a mixed population achieved poor results. But when a retrospective analysis revealed the drug had surprisingly high efficacy among African-Americans, US pharmaceutical company NitroMed launched a trial in that population. The trial was halted early in 2004 after it showed the drug was associated with a 43% reduction in all-cause mortality for African-American patients.1
Last year, US regulators approved the drug for treatment of heart failure in African-Americans, provoking a storm of controversy. While many welcomed the development as a step in the direction of “personalised medicine”, others claimed using race as a classification was crude and dangerous. As two Canadian bioethicists wrote in the Phar
macogenomics Journal: “The involvement of racial and ethnic communities in pharmacogenetic and pharmacogenomic research is contentious precisely because it touches upon the science, and politics, of studying racial and ethnic difference.”2
The issue of varying racial responses to medication is not a new one. From 1995 to 1998, labelling for 8% of new drugs launched in the US included some reference to racial or ethnic differences in effectiveness.3 But something about BiDil has really stirred the pot, prompting fierce debate about whether race is a meaningful or useful term from a medical point of view.
It’s a question that has divided the scientific community, according to Professor Alan Bittles, chairman of the centre for human genetics at Perth’s Edith Cowan University. Some researchers, particularly the anthropologically inclined, regard the concept of race as meaningless and counter-productive. Biomedical scientists, though, are more accepting of the idea of “racial” genetic variation, says Professor Bittles. Although most (83-95%) human genetic variation occurs within populations, “somewhere between 5% and 17% of genetic variation is between what [we] would happily refer to as major ethnic groups,” he says.
If you are Ashkenazi-Jewish parents-to-be, that 5-17% variation could be a matter of life and death. About one in 25 Ashkenazi Jews carries the gene for the otherwise rare metabolic disorder Tay-Sachs disease. Offspring of two carriers of the gene have a one in four chance of inheriting the full-blown disorder, which is generally fatal by age five. And that’s not the only example of a racial difference with medical implications. African and east and South-East Asian populations have a higher prevalence of haemoglobin mutations, such as sickle cell disease and beta-thalassaemias. And Chinese people generally require lower doses of warfarin or heparin because of a polymorphism in one coagulation factor.4
Despite this, some researchers challenge traditional racial classifications, such as ‘African-American’ or ‘Chinese’, saying they are too imprecise. Professor John Mattick, director of the Institute for Molecular Bioscience at the University of Queensland, suggests race is at best an indicator of underlying genetic variation.
“The racial component will just be a broad-brush thing that might be used in the first place in the absence of more specific information,” he says. “Most genetic disease and genetic susceptibilities may have an ethnic origin, but they only affect a small proportion of people from that ethnic group.”
As the leader of the Human Genome Project, internationally renowned geneticist Dr Francis Collins, wrote: “Race is an imperfect surrogate for ancestral geographic origin, which in turn is a surrogate for genetic variation across an individual’s genome.”5
Studies using various genetic markers have shown 10-15% of total human genetic variation can be attributed to differences between sub-Saharan Africans, northern Europeans and east Asians.6 In today’s global melting pot, someone identified as African-American may have ancestors from Europe and North America as well as Africa, but that’s not to say racial classifications are useless. There is good evidence people’s self-identification with a particular racial group correlates strongly with conclusions drawn from their genetic data.7 And often the best way of ascertaining a patient’s race or ethnic origin is simply to ask them — something doctors and others can be reluctant to do.
Indigenous doctor Dr Alex Brown, a senior research fellow at the Menzies Institute of Health Research in Alice Springs, says health workers should not shy away from the question. “I think we have to get away from feeling uncomfortableness in asking people’s ethnicity,” says Dr Brown, who is researching cardiovascular disease among Indigenous Australians.
“If you understand about people’s cultural background or their ethnicity or whether they’re self-identified as belonging to any group —however that might be defined — that has importance in terms of how they live their lives, whether they’ll get the most out of the things you’ve got to offer, how you communicate.”
The RACGP’s current practice standards say patients’ cultural backgrounds should be recorded as a way of “appropriately tailoring care to patients”. A recent survey of US patients found 80% believed doctors should collect information on race or ethnicity, although one-third said they felt significant discomfort reporting their race and more than half had some concern the information could be used to discriminate against them. African-American and Hispanic patients were more worried about this than white patients, the researchers reported.8
Knowledge about variations in disease frequency or drug response among populations can be medically valuable but, even when the information is there, it is not always applied. The high frequency of the Tay-Sachs mutation among Ashkenazi Jews has led to implementation of pre-natal screening and genetic counselling programs, but the African-American community has chosen not to screen for sickle cell disease despite its higher level of risk.
Human molecular geneticist Professor Jurgen Reichardt, professor of molecular biology at the University of Sydney, says different communities may respond differently to issues that seem similar from a scientific and medical viewpoint. The history of “unsavoury” medical experiments conducted in the past on African-Americans may have influenced the community’s decision not to opt for screening, Professor Reichardt suggests. The notorious Tuskegee syphilis study, for example, ran from 1932 to 1972, following the natural course of untreated syphilis in 400 African-American men who were not told they had the disease or offered new treatments such as antibiotics.
The issue can also be a sensitive one for racial groups that are concerned about being labelled as having “rubbish genes”, says Professor Bittles, particularly when it comes to communities who have been, “gravely disadvantaged in the past and really just [see] this as another means of putting them down”.
On top of that, there’s the question of whether variations in disease frequency between racial or ethnic groups can be attributed to genes alone. Take, for example, the higher morbidity and mortality associated with cardiovascular disease in Indigenous Australians. Age-adjusted cardiovascular death rates are three times higher in Aboriginal populations than in non-Aboriginals. Mortality rates from coronary heart disease among Aboriginal males aged 25-44 are up to 16 times higher than age-matched rates among non-Aboriginal people.9
Dr Brown says Aboriginal people are commonly worse off in all the traditional risk factors for cardiovascular disease. However, these factors alone are not enough to explain the huge increase in morbidity and mortality.
“There must be something else going on that contributes to the massive difference that’s experienced between Aboriginal and non-Aboriginal people,” he says. “We know that systems of care are important, particularly in the context of minority populations who may suffer institutionalised racism and poor access to services, less access to tertiary care, or have difficulty negotiating complexities of care.”
Aboriginal people have also been disadvantaged in terms of access to health information and education, with community health messages often not tailored to their needs. It makes Dr Brown wary of going straight to genetic risks as a “magic bullet” solution. “If you were to ask me is it all about genetic issues, I would say until we’ve dealt with the systems approach [and] disadvantage and disparity of care that exist, genetic issues have less prominence.”
Other examples of higher prevalence of diseases in particular ethnic communities can be at least partly blamed on environmental rather than genetic effects. The high risk of coronary heart disease among Indian people living in the UK — 50% higher than among people of European origin — has been blamed on the adoption of an ‘unhealthy’ Western lifestyle. Spiralling rates of obesity among Chinese immigrants to the US have also been attributed to the change from a Chinese to a Western diet.
So how can all this information be used? In the case of Indigenous Australians, Dr Brown argues targeting at-risk populations makes sense from a population health perspective. “I think specific services for Aboriginal people are incredibly important,” he says. “If we’ve got a better way of understanding risk and targeting those in need and providing the services in ... the way in which a person wants to be treated, then we should be doing it.”
For Professor Bittles, the issue of testing for Tay-Sachs disease is a good example of how racial information can be used sensibly. Genetic screening of all parents-to-be, rather than just those of Ashkenazi Jewish origin, would be “biologically meaningless” and “economic nonsense”, he says. “You would be testing lots and lots of people who haven’t got a hope in hell of having those genes.”
Knowledge of a baby’s ethnicity could be used to customise neonatal testing, Professor Bittles argues. “What worries me at the moment is the neonatal testing schedules which we follow in Australia are very strongly biased towards north-western European needs,” he says. For example, babies are tested for phenylketonuria and cystic fibrosis, which are more common in European populations.
With increasing migration from areas such as Asia and Africa, where sickle cell disease and beta-thalassaemias are much more common, Professor Bittles believes we should introduce selective testing for those disorders. “It’s saying to the migrant community, no longer are we ignoring your needs.”
While links between race and medical treatment may be controversial now, the debate could soon be a thing of the past, according to Professor Reichardt. Mapping of the human genome could eliminate the need for racial identification altogether, allowing us to provide “personalised medicine” with treatments tailored to fit each person’s genetic background.
“I don’t see ourselves in the future giving the same drug to everybody,” Professor Reichardt says. “We’re going to try and give person A the best drug for their genetic background and person B a different drug, or the same drug in a different amount, based on that person’s genetic background.”
The new science of pharmacogenomics will tell us how an individual patient will respond to a drug or whether they are at risk of a particular disease, leaving ancestry out of the equation altogether. As Professor Mattick puts it: “Race is so passé.”
DRUG RESPONSE: A RACE QUESTION?
ACE inhibitors: African-Americans may be less responsive than Europeans
Beta blockers: May be more effective in Europeans than African-Americans
Warfarin: Afro-Caribbeans may require higher doses than Europeans; Europeans may require higher doses than Asians
Glucocorticoids: Adverse effects such as steroid-associated diabetes are more common in African-Americans than in Europeans
Calcium-channel blockers: May be more effective in African-Americans than Europeans
Antipsychotics: Chinese have more extrapyramidal effects from haloperidol than non-Chinese
Source: Nature Genetics 2004; 36:S34-42.
References
1. New England Journal of
Medicine 2004; 351:2049-57.
2. The Pharmacogenomics
Journal 2004; 4:9-16.
3. Nature Genetics 2004; 36:S34-42.
4. The Pharmacogenomics
Journal 2006; 6:16-21.
5. Nature Genetics 2004; 36:S13-15.
6. Journal of the American
Medical Association 2005; 294:937-46.
7. ibid
8. Journal of General Internal
Medicine 2005; 20:895-900
9. Heart Lung and Circulation 2005; 14:158-62.
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