662
ApoEε4 confers a risk of Alzheimer’s disease in a population-specifi c manner.
As compared with the risk among those who do not carry an ApoEε4, the risk con-
ferred by homozygosity for this allele is increased by a factor of 33 among Japanese
persons, a factor of 15 in white populations, and by a factor of 6 among black
Americans. These increases indicate that there are modifying effects on ApoEε4–
mediated susceptibility in these populations, that other gene variants that are more
important than ApoE in conferring risk are enriched or depleted in these popula-
tions, or that both are true.
A study has compared the incidence of coronary heart disease (CHD) over a
15-year interval in the Atherosclerosis Risk in Communities study according to the
presence or absence of sequence variants in the proprotein convertase subtilisin/
kexin type 9 serine protease gene (PCSK9) that are associated with reduced plasma
levels of LDL cholesterol (Cohen et al. 2006 ). In black subjects examined, 2.6 % had
nonsense mutations in PCSK9 associated with a 28 % reduction in mean LDL cho-
lesterol and an 88 % reduction in the risk of CHD. In white subjects examined, 3.2 %
had a sequence variation in PCSK9 that was associated with a 15 % reduction in LDL
cholesterol and a 47 % reduction in the risk of CHD. In this study, the race question
proved decisive. The researchers found that these relatively rare alleles correlated
with low LDL, and did so in both blacks and whites, allowing them to conclude that
it was the gene change that was crucial. If the team had ignored race and simply
compared those who had heart disease with those who did not, and asked which
alleles were linked to the risk, they would probably have missed the clinical signifi -
cance of the alleles. This is because they would have appeared so infrequently – in
less than 0.3 % of the whole study population for version 142X – that their effects
would have been swamped. That is even truer for less populous racial groups; indeed,
the smaller the group, the less likely researchers are to fi nd important but rare alleles
unless they can break the population down. Ignoring race altogether would be to the
detriment of medical knowledge about the very people who might benefi t.
Infl ammatory bowel disease (IBD) affects American Jews of European descent
2–3 times more frequently than other ethnic groups. However, IBD is being diag-
nosed with increasing frequency now in Hispanics and African-Americans. One of
the explanations for these disparities is that most diseases are not single-locus genetic
diseases and environmental factors also play a role in the causation of disease.
It is because of the potential usefulness of gene variants in predicting risk and
targeting therapies that the quest for genes that underlie complex traits continues.
The goal of personalized medicine is the prediction of risk and the treatment of
disease on the basis of a person’s genetic profi le, which would render biologic con-
sideration of race obsolete. But it seems unwise to abandon the practice of recording
race when we have barely begun to understand the architecture of the human
genome and its implications for new strategies for the identifi cation of gene variants
that protect against, or confer susceptibility to, common diseases and modify the
effects of drugs.
Although past studies have shown that genomic diversity and allele frequency
patterns vary by population, those based solely on self-reported ancestry often do
not refl ect genetic ancestry and exclude individuals who are of mixed ancestry.
21 Ethical Aspects of Personalized Medicine