Transcript The Meaning of Race - Minority Health Project at the

The Meaning of Race in Medicine
12th Annual Summer Public Health Research
Videoconference on Minority Health
University of North Carolina at Chapel Hill
School of Public Health
June 26, 2006



Dr. Joseph L. Graves, Jr.
Dean, University Studies & Professor of Biological Sciences,
North Carolina A& T State University.
Fellow, American Association for the Advancement of Science
1
For a fuller treatment
see:

J.L. Graves, The Emperor’s New Clothes: Biological Theories of Race
at the Millennium, Rutgers University Press, 2001, 2005; The Race
Myth: Why We Pretend Race Exists in America, Dutton Press, author’s
preface to the soft cover edition, 2005.
2
Note on Definitions: Biological Race



morphology (phenotype)
Geographical location
Population based (frequency of genes)
Socially Constructed Race: Arbitrarily utilizes
aspects of morphology, geography, culture,
language, religion, etc. in the service of a
social dominance hierarchy.
3
Carolus Linnaeus - 1735



Introduces binomial classification system for
organisms. He describes four sub-species of
humans: Homo sapiens americanus, the
Americas; Homo sapiens europaeus, Europeans;
Homo sapiens asiaticus, Asians; and Homo
sapiens afer, Africans.
He did not explain how or why these groups are
different. He also includes Homo sapiens
monstrosus, which included people with
deformities, mythological giants, and the Khoikhoi
people of southern Africa; and Homo sapiens
ferus, which described wild children found
abandoned in forests.
Relies on morphological/behavioral features,
Europeans are gentle, optimistic and inventive,
while Asians are stiff and greedy.
4
Naturalists of the 19th century naturalists
used morphological traits to classify races:
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
Darwin doubted whether
human races were real.
Describes the racial
multiplication problem, 2 –
63 races named.
Calls human races, protean
or polymorphic, in The
Descent of Man, 1871.
Darwin pointed out that
most of the physical
differences noticed by
naturalists could not have
any significance, if so they
would have been removed
by natural selection.
Charles Darwin
5
Linneaus and the 19th century naturalists were wrong
because phenotypic characters are discordant.


Fig 2.2.3, Cavalli-Sfroza, Menozzi,
and Piazza., 1994
The physical features used to
define America’s social races
do not reveal our
evolutionary history, CavalliSforza and Edwards 1964,
and Montagu 1974.
Genes that control skin color
are not linked to those that
determine skull shape or
body proportions.
6
Populations have different
combinations of physical traits.

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
The failure of physical variation to
define races occurs because different
portions of the genome are selected
by different factors in any given
environment.
For example, solar intensity may
change consistently along a N – S
gradient, this may impact some
genetic systems, but not others.
Meanwhile, other portions of the
genome may be impacted by the
presence of a specific parasitic
disease, different diets, different rain
fall, or altitude.
7
By 1950 serious doubt existed concerning both morphological
and geographical conceptions of race.
From the Preamble


New York Times, July 17, 1950
Racial doctrine is the outcome of a
fundamentally irrational system of
thought and is in glaring conflict
with the whole humanist tradition
of our civilization. It sets at
nought everything that UNESCO
stands for and endeavors to
defend. By virtue of its very
Constitution, UNESCO must face
the racial problem…
In the body: From the
biological standpoint, the species
Homo sapiens is made up of a
number of populations, each of
which differs from the others in
the frequency of one or more
genes…
UNESCO Statement of 1950
8
Population subdivision is weak in humans.


Black bar represents humans
compared to other mammals, such as
white tailed deer, gray wolves, or
Grant’s gazelle; data from Templeton
(1998, 2002.)
Compared to other large
bodied mammals,
humans have little
genetic differentiation
between their
populations.
Humans have
considerable genetic
overlap across the
genome -- We have also
maintained relatively high
levels of gene flow
throughout our history,
Wright’s FST = 0.156.
9
Estimate of gene flow between human
 Wright’s Fst for human data =
subpopulations



Fig. 2.15.1, Cavalli-Sfroza,
Menozzi, and Piazza 1994.

0.156
We can calculate the effective
population size and the
migration rate for humans by
the equation:
Fst = 1/(4Nm + 1)
Thus Nm = 1.35
Thus modern human genetic
diversity can be explained by
the long term average of 1.35
individuals per 25 years, or
13.5 per 250 years, or 135 per
2,500 years.
Thus sporadic movements that
over long periods of time that
average out to these values
could easily explain human
genetic diversity.
10
Isolation by distance
Humans best fit a gene
flow, isolation by
distance model,
Templeton, 2002.
This means that human
populations that live
closest to each other,
share the most genetic
variation in common.
Figure 2.3 Templeton 2002
11
Human migration 101


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Anatomically modern humans
evolve in Africa > 160,000
ybp.
Some leave Africa sometime
around 75,000 - 55,000 ybp.
Replace Neanderthals in
Europe and archaic humans
around the world.
Arrive in Western hemisphere
between 34,000 and 18,000
ybp.
Multiple migrations in different
pre-historic periods, followed
by different migrations in
historical periods.
12
Most genetic variation is shared between
geographically separated populations
Figure 1. Apportionment of Human
Genetic Diversity
4
10
86
Polymorphic alleles found in all
world populations, 86%
Polymorphic alleles unique to a
given continent, 10%
Polymorphic alleles unique to a
specific local population, 4%
13
Nucleotide similarities

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Identical twins: 10,000/10,000
Siblings 9,995/10,000
Unrelated individuals: 9,990/10,000
Human/Chimp: 9,900/10,000
Human/Flowering plant: 6,700/10,000
However, with a genome estimated at 3 billion base pairs,
unrelated humans can be different at 3,000,000 base pairs.
14
Estimates of genetic distance are dependent
upon how they are calculated.
Methods that examine DNA directly reveal more variation than can be
seen at the protein level, particularly if portions of the genome that
are not coded are included.
Coding sequences produce transfer RNA’s, ribosomal RNA’s, or
proteins, while non-coding sequences include introns, regions that
flank coding regions, regulatory sites, and pseudogenes.
In Eukaryotes most of the genome is non-coding. For example, it has
been estimated that as much as 95% of human DNA is non-coding.
15
Non-coding DNA and ancestry
Genetic changes in introns and pseudogenes (often called “junk
DNA”), do not face selection and therefore accumulate mutations
freely. Thus, non-coding segments are exceedingly useful for
establishing ancestry. This is because due to chance historical
events, populations can differ in allele frequencies at these loci.
369 SNP
Af./Eu.
Af./As.
Af./Am.
Fst
0.152
0.228
0.232
Nm
1.395
0.846
0.828
migration
per 2500
yrs.
139.5
84.6
82.8
Fst data from Tischkoff and Kidd, 2004
16
Non-coding DNA and ancestry II
Rosenberg et al. Science 298, 2002 utilized an algorithm called structure.
They examined the sequences of individuals from various populations and
Showed they could be clustered in a variety of ways.
17
Non-coding DNA and ancestry III
Tischkoff and Kidd 2004, Least
Squared tree for 37
populations, using 80 loci with
~ 620 alleles. The populations
used are described in Allele
Frequency Database
(ALFRED). However, ALFRED is
still very incomplete, missing
suitable data on many regions
of the world, including North
Africa. In addition, the
populations had different
characteristics, some were
indigenous, while others had
greater amounts of admixture.
18
Within Population Distribution in the Genetically Defined Clusters
of Wilson et al. 2001.
Population
A
B
C
D
Bantu
4%
2%
93
%
2%
Ashkenazi
96%
1%
1%
2%
Ethiopian
62%
8%
24
%
6%
Norwegian
96%
2%
1%
1%
Armenian
90%
4%
2%
5%
Chinese
9%
5%
1%
84%
Papua, NG
2%
95
%
1%
2%
AfroCaribbean
21%
3%
73
%
3%
Wilson et. al. in Nature Genetics,
29: 265-69, 2001 using a panel of
39 microsatellite markers showed
that genetic variants of drug
metabolizing enzymes can be
clustered into four groups.
However the four groups did not
match the common social
definitions of race.
19
Actual membership in B Cluster
Population
Bantu
Ashkenazi
Ethiopian
Norwegian
Armenian
Chinese
Papua, NG
Afro-Caribbean
Percent
2.0
< 1.0
7.0
< 1.0
< 1.0
83.0
6.0
1.0
This is true because the
population sizes are different.
Thus every genetically defined
cluster will have significant
numbers of Chinese, simply due
to China’s size.
If other populations are
included, such as India, these
figures would shift again.
Thus, we should expect all
suitably large populations to
have people from all drug
metabolizing clusters.
20
Greater numbers of microsatellite markers (326) were able
to correlate self-identification with genetic clustering.
SIRE
A
B
C
D
Eu. Am.
1,348
0
0
1
Af. Am.
3
0
1,305
0
Mex. Am.
1
0
0
411
Chin. Am. &
Taiwanese
0
407
0
0
Jap.
0
160
0
0
Other
1
2
0
9
Tang, et al. 2005 used Structure with K = 2, 3, 4 or more clusters. When K = 2,
Chinese/Japanese emerged as a group from all others, K = 3, gives African Am.,
Eu. Am. & Mex. Am., & Chinese/Japanese; and K = 4 is shown above.
21
Structuring non-coding genetic variation weakly revealed
candidate markers for hypertension.
Prop.
Afr. Norm Afr. Hyp.
Sig.
Tested
Birmingham, AL
35
368
0.055
1799
Forsyth, NC
49
149
0.058
1055
Jackson, MS
61
389
0.042
1753
Maywood, IL
164
55
0.048
1173
Total
309
961
0.05075 Mean
Approximately 5% of the markers tested showed any significant difference
between normatensive and hypertensive individuals. For the Chinese sample it
Was about 4.4%, Mexican American 5.7%, and European American about 4.3%.
The paper did not report whether the significant markers were similar for all
Populations tested.
22
Gene Flow & Admixture
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Only 6% of the individuals
in this study who self-identified
as African American had a majority
of their genetic markers indicating
African Origin – this would differ by region.
However, 93% of self-identified European 
Americans had the majority
of their genetic markers originating in
Europe.
Self identified American Indians would
show the African American pattern and at
present, self-identified Asian
Americans would show the European
pattern, Sinha et al. 2006, NEJM, 354(4):
421-22.
There is a wide variety of admixture
percentages in North Americans with
African descent.
Recent measures suggest that the average
African Americans has on average 17 20% European admixture.
Also there could be as much as 10%
American Indian admixture.
Therefore, could be as much as a 30%
probability of African American genetic
predisposition actually originated in Asians
and Europeans.
Remember also that Asians and Europeans
began their genetic odyssey in Africa,
hence at any specific locus, a European or
Asian may have an allele that was
originally African, as opposed to one that
originated outside of Africa.
23
However, populations differ in specific coding gene
frequencies: phenylketonuria – mechanism,
mutation/selection balance or genetic drift.
Chinese
1/16,000
Irish, Scottish, Yemenite Jews
1/5,000
Japanese
1/119,000
Swedes
1/30,000
Turks
1/2,600
USA (Euro-Americans)
1/10,000
USA (total)
1/10,000
Note, that while the Chinese and Japanese belong to the same genetic cluster
as determined by SNP’s, they differ in orders of magnitude in phenylketonuria
frequency and while Nigerians and Icelanders are in different clusters they have
near identical frequencies of blood group O.
24
Drug Class
N
Is it real?
Evidence
Ace Inhibiters
1,196 Eu, 800 AA,
124 Eu, 207 Eu, 91
AA
Reasonable
physiological basis
Related to lower bioactivity of nitric oxide
BiDil
180AA, 450 Eu, 215
AA, 574 Eu
Reasonable
physiological basis
Related to lower bioactivity of nitric oxide
Vasodilator
antihypertensive
11 AA, 9Eu, 21AA,
19 Eu
Consistent difference
but no physiological
basis shown.
Attenuated responses commonly seen in AA,
but mechanism not understood.
Betaadrenoreceptor
blocker
365 AA&EU, 2708
Genetic causation
indicated
R389G polymorphism in b1 adrenergic
receptor.
Betaadrenoreceptor
blocker (b1selective)
1,105
Possibly false positive
No mechanism, and study not replicated.
Thiazide
(diuretic)
225 AA, 280 EU
Reasonable
physiological basis
Related to lower bioactivity of nitric oxide
Calcium-channel
blocker
1,105
Reasonable
physiological basis
Increased predisposition in AA to saltsensitive form of essential hypertension.
Betaadrenoceptor
gonist
27 AA, 27 EU,
18AA, 18 EU, 9 AA,
13 EU and 16
Consistent difference
but no physiological
basis shown.
Attenuated responses to multiple
vasodilators commonly observed in AA’s.
Mechanism not understood.
Summarized from Table 1, Tate and Goldstein, Nature Genetics 2004
25
Drug Class
N
Is it real?
Evidence
Glucocorticoid
9 Eu, 9 AA
Consistent difference but
no physiological basis
shown.
Altered pharmocogenetics between AA and EU
Hepatitis Antiviral
Treatment
100AA, 100 Eu, 4031
AA, 62 Eu
Reasonable physiological
basis
May be due to different immune abilities, AA
produce more cytokine than Eu.
Prostaglandin
analog
1381
Possibly false positive
Not replicated and no supporting evidence.
Cytotoxic agents
~14,000 Eu, 1500 His,
167 As, 1000 AA
Possibly false positive
Probably due to differences in health care, some
experiments not replicated.
Insulin
14 Eu, 15 AA, 28 His
Consistent difference but
no physiological basis
shown.
Differences remain after adjusting for body fat,
mechanism unknown.
Antipsychotic
~288 Eu, 800 AA, 65 As
Consistent difference but
no physiological basis
shown & false positive
Drug polymorphism has not been reliably associated
with Eu & As; different prescribing practices for
populations.
Analgesic
8 As, 40 Eu, 22 Am. Ind.
Possibly false positive
Conflicting results.
Totals
> 22,000 Eu, ~6,000
AA, 22 Am. Ind., 72 As.,
& 28 His.
1 genetic, 5 reasonable
physiological, 5 consistent
no, 4 false positives.
Sampling scheme alone is enough to doubt any
“racial” interpretation of this data.
Summarized from Table 1, Tate and Goldstein, Nature Genetics 2004
26
End Notes
27
The intellectual program of social
dominance
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The history of all hitherto existing society, is the history of individual
and groups of males attempting to sub-ordinate other males and
females (social dominance.)
Hierarchical society may have been fixed in our primate lineage:
Orangutans, Gorillas, Chimpanzees, and humans.
Found in all societies that produced a social surplus, such as
Egyptian, Greek, Roman, Aztec, Chinese, Japanese, etc.
Intellectual programs were developed to justify some groups
garnering more of the society’s production than others. This
ultimately translated into that group’s greater material well-being,
such as health, emotional satisfaction, and reproductive advantage.
28
Any genetic explanation of intelligence
would require that environments were
equalized.
No such equality of environments
exists or has ever existed for
minorities in America.
Furthermore, this is impossible
since by definition the social
environment of minorities must
be different from that of
majorities.
The environments are made even
more disparate by the social
dominance of the European
population.
29
Affirmative action for the dominant
population
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The vast majority of federal and
state government actions have
differentially benefited people of
European descent.
Consider the Indian Removal Act of
1830, the five civilized tribes were
forced to give up the land that now
comprises most of Tennessee,
Georgia, Kentucky, and Mississippi.
They were forcibly moved west of
the Mississippi River, 4,000 of
18,000 died during the “trail of
tears.”
They were promised this land, “as
long as the waters run and the
grasses grow.” Well we know what
happened to that promise.
30
Give me your huddled masses: so long
as they are “white.”
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US immigration policy was biased
toward “races” that could be
assimilated into America.
This meant in practice that 19th
century immigration was to match
the composition of the country in
the 1824 census (mainly AngloSaxons, Irish, Swedes, Germans,
and other northern Europeans.
After slave importation stopped,
there was virtually no legal
immigration of Africans or AfroCaribbeans.
Congress passed the Chinese
Exclusion Act in 1880.
Japanese immigration to the US
begins in earnest in the early 20th
century.
Population
Numbers
Percent
German
6,000,000
20.5
Irish
4,500,000
15.3
Italian
4,750,000
16.2
England
4,200,000
14.3
AustriaHungary
4,200,000
14.3
Scandanavians
2,300,000
7.8
Russian
3,300,000
11.2
31
Governmental action creates modern
America, leaves out non-whites

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Housing act of 1949
makes homes affordable
for the first time.
Between 1934 – 1962,
FHA guarantees 120
billion dollars of home
loans.
Less than 2% are made
to non-whites.
The suburbs are born,
housing values are
determined by how
“white” your
neighborhood is.
32
Social dominance can increase risk of toxic
exposure.
Source: www.scorecard.org
Income = high v. low
Ownership = owners and nonowners
Ratio
Ratio
by race by
Income
Ratio
by
ownership
Releases of toxic chemicals
1.43
1.54
1.56
Cancer risk from hazardous air
pollutants
1.50
1.31
1.47
Facilities emitting criteria air
pollutants
3.68
2.38
5.00
Superfund sites/per sq. mile
3.04
2.03
3.57
Race/ethnicity, income, and home ownership (NJ, 2003.)
33
Social hierarchy harms those who
are dominated
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Neuroscience has begun to look at many
genetic variants between individuals that
correlate to behavior, such as addiction.
Cocaine addiction is linked to dopamine
transporters, genetic variation exists in
humans at these loci.
34
One type of such harm has been shown
experimentally in other primates
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Social subordinate Macaques
were more likely to selfadminister cocaine
(addiction.)
This was lower in monkeys
housed alone or who were
socially dominant.
African American college
students who reported
suffering racist harassment
were twice as likely to use
tobacco daily, Bennett et al.
2005, AJPH.
Morgan et. al. Nature Neuroscience,
Vol. 5 No. 2, February 2002.
35
The impact of environmental differences
is complex
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Studies of malnutrition in rats

showed that maternal effects on
adult health extended over several
generations.
We have already seen that
differential stress exposure plays a
role in predisposing some African
Americans to hypertension.
Offspring of alcoholic mothers

show FA in their teeth, FA has
been linked to lower IQ in college
students.
Numerous studies show that
lasting adult pathology can
result from stress in the
maternal environment: Desai
et al. 1995; Hales et al. 1996;
Napoli et al. 1997; Waterland
and Garza 1999; Mustillo, S.
et al. 2004; Collins et al.,
2004.
Another recent study showed
parental exposure to racial
discrimination had negative
impacts on the mental health
of their pre-school aged
children, Caughy et al. 2004.
36
Distribution of Sickle Cell Anemia Allele is
discordant with “race.”


Distributed at high
frequency in “Negroids
and Caucasoids.”
Seen as “Black” disease
in U.S. due to importation
of slaves derived from W.
Africa.
37
Malaria in the USA


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
Did the presence of the allele help “Blacks”
fight off malaria relative to “Whites” in North
America?
In the early 20th century, an estimate of Blacks
heterozygous for the sickle cell trait was about
8%.
Yet, in 10 southern states, Blacks suffered
25/100,000 death rate v. only 7/100,000 for
whites in 1921 – 1923 (who supposedly did
not have the allele.)
Grover 1937, J. Negro Education (6), 281.
38
Genetic variation & hypertension



A number of gene loci
have been associated
with increased risk of
hypertension.
AGT -- which codes for
angiotensinogen a protein
made by the liver and
circulates in excess
ACE – angiotensin
converting enzyme
39
Genetic variation & hypertension II




Cooper, Rotimi, Ward 1999, pg. 42.
At the angiotensinogen locus
the 235T mutant has tyrosine
switched for methionine.
In Euro-Americans, 235T is
associated with an increased
risk of hypertension.
The 235T allele is found at a
frequency of 85% in African
Americans.
However, 235T is not
associated with increased
hypertension risk in Nigerians.
40
Genetic variation & hypertension III
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At the ACE locus there is a common alu
insertion polymorphism that affects the
activity of this enzyme.
The D allele is characterized by an absence of
these alu insertions, and thus have higher
enzymatic activity.
The available evidence shows that the
enzymatic activity of II, ID, and DD
genotypes are similar in Nigerians,
Jamaicans, and in the United States (all
populations.)
Hence the deletion genotypic doesn’t seem to
be influenced by “racial” background.
Source: R.S. Cooper (1997).
41
Genetic variation and hypertension
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There are at least 33 genetic systems with >
63 loci involved in hypertension predisposition.
In studies on hypertension published between
1997 – 2003, only 2/10 found frequency
differences in genetic variants in the direction
of the proposed health differential.
In 8/10 studies, genetic variation
existed, but it was not in the direction of
the hypertension rates seen in America!
42
Hypertension III

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

Genetic variation in doesn’t explain
hypertension differentials:
angiotensin converting enzyme
Angiotensinogen I and II
a- and b- adrenergic receptors
Plasma kallikrein
G protein-b3
43
b2-adrenergic polymorphisms The gly16 variant has been associated
with hypertension in Afro-Caribbean’s and Norwegians, but not African
or European Americans. The frequency of the gly16 variant was
slightly higher in European Americans it was not significantly different
between the normal and hypertensive in either group.
Gly16 genetic
variant
Af. Am.
Eu. Am.
frequency frequency
Normal study 1
Normal study 2
Avg. freq.
0.50
0.180
0.34
0.47
0.352
0.411
Hypertensives study 1 0.51
0.40
Hypertensives study 2 0.184
0.358
Avg. freq.
0.379
0.347
44
Hypertension?



Actually, when hypertension rates are stratified
by socioeconomic status, the differential is
located amongst African Americans in the higher
categories.
This is means that the hypertension difference
results from a biological response to
social/cultural factors (e.g. control racism,
reduce hypertension differential.)
Neser et al. 1986; Broman 1989; Calhoun 1992;
Light 1995.
45
Irrational resuscitation of race

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
Actually Wilson et al. examined population samples from
around the world including: Norwegians; Ashkenazi Jews;
Armenians; South China; Papua, NG; East and West Africa;
and Afro-Carribeans.
They found that 4/6 genetic variants they examined could
be formed into four clusters.
This, of course means that 2/6 could not be clustered! (a
fact not mentioned by Risch.)
Most importantly, Wilson et al. concluded that the
four genetic clusters they discovered, did not match,
socially constructed race or ethnicity (again a fact
not mentioned by either Risch or Wade.)
Goldstein and Chkhi 2002 interpret Wilson et al.:
“races in any meaningful sense of the term do not
exist in the human species…”, An. Rev. Genomics
and Human Genetics, vol. 3
46
Distribution of Sickle Cell Anemia Allele is
discordant with “race.”




Fig. 5.8, Ridley 1996
The origin of the allele is
uncertain.
However it is distributed
at high frequency in
“Negroids and
Caucasoids.”
High altitude Kenyans
don’t have any sickle cell.
Seen as “Black” disease
in U.S. due to importation
of slaves derived from W.
Africa were malaria was
prevalent.
47
Polymorphic loci vary in frequency


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

Distribution of CF D F-508 allele,
Fig. 2.14.10, Cavalli-Sforza, Menozzi,
and Piazza, 1994.
Polymorphic loci have
numerous alleles, with no
single allele at a
frequency > 99%.
Phenylketonuria, q = 0.01
Tay Sachs A, q = 0.017
Cystic Fibrosis, q =0.022
Sickle Cell Anemia, q =
0.050
48
49