Download advocacy vs. impartiality the problem is quite complex on one side

Paolo Vineis
Imperial College London
Nature vs nurture: genes and
environment
1. HISTORICAL BACKGROUND
Long-lasting debate: “nature” vs “nurture”, i.e. how
many diseases (and physiological traits) are attributable
to genes and how many to the environment, e.g.
1. “The Bell Curve” by Herrnstein and Murray (1994)
claimed that afro-americans have lower IQs for genetic
reasons
2. Is homosexuality a genetic “disease”?
3. Is depression genetically-based?
4. What about schizophrenia?
5. …and cancer?
6. ... and how many cases of baldness or myopia are
attributable to genes?
Crucial objections have been raised to the Bell Curve, in
particular:
- how the IQ is measured reveals more about the effects of
environment and education than of genes
- the IQ has increased by 21 points (more than the black
vs white difference) in the Netherlands between 1952 and
1982
- minorities in different parts of the world (eg Japan) have
low IQ when they are marginalized, but reach the same
level as others when marginalization ceases
(story of IQ measurement in “The mismeasurement of
Man” by SJ Gould)
In fact many objections were already raised in a seminal
paper by Richard Lewontin, against the “environment”
vs. “heritability” dilemma
The basic confusion is between heritability and genetic
determination.
Heritability has to do with DIFFERENCES: ratio of
variation inherited by parents to total variation
A characteristic is “genetically determined” if it is coded
in and caused by the genes in a normal environment
The two very often do not overlap, e.g.:
* humans have 5 fingers, and this is totally genetically
determined; however, heritability of 6 o 4 fingers is almost
zero (changes in numbers of fingers are caused by defects of
development, eg thalidomide, not by heredity)
* wearing earrings in 1950 had a very strong heritability (it
occurred only in women, today also in men): it was related to
having XX vs XY; however, it was not genetically determined
Therefore, when researchers say that IQ has 60%
heritability, academic performance 50% and occupational
status 40%, this does not mean that such characteristics
are inherited THROUGH GENES (DNA), i.e. that there is
genetic determination, but only that there is strong
association between the characteristic in the index subject
and the same characteristic in the parents:
ENVIRONMENTAL CHARACTERISTICS
THEMSELVES ARE HERITABLE
Genes and cancer
Key issue is penetrance
Penetrance is the strength of association between the
genetic variant and the phenotype (e.g. risk of cancer)
In general, highly-penetrant variants are rare
(darwinian explanation), while low-penetrant variants
are common
In fact examples of 100% penetrance (all or nothing)
are very rare
Modulation by environmental factors is the rule
rather than the exception
e.g. a gene variant for baldness is likely to be about
100% penetrant in men but about 0% penetrant in
women (role mediated by hormones)
Same with BRCA1, with penetrance depending on
hormones
SOME FIGURES
LIFETIME RISK OF BREAST CANCER IS 12.6% IN
WOMEN, OF PROSTATE CANCER IS 15.9% IN MEN,
AND OF COLON CANCER IS 5.6% IN BOTH SEXES
BRCA1 AND BRCA2 CONFER A RELATIVE RISK OF
BREAST CANCER OF 5-10
GENOTYPES AT MISMATCH REPAIR LOCI CONFER
A RR OF COLON CANCER OF 9.3
METABOLIC POLYMORPHISMS CONFER A RR FOR
SEVERAL TYPES OF CANCER OF LESS THAN 2
ABOUT 0.2% OF WOMEN CARRY BRCA1 OR BRCA2
SUSCEPTIBLE VARIANTS, AND 0.1% OF PEOPLE
HAVE SUSCEPTIBLE VARIANTS FOR MISMATCH
REPAIR LOCI
THESE GENOTYPES ACCOUNT FOR LESS THAN
5% OF BREAST OR COLON CANCERS
50% OF THE GENERAL POPULATION HAVE A
DELETION OF THE GSTM1 GENE, WITH A
RELATIVE RISK FOR LUNG CANCER OF 1.3
HOW MANY CANCERS ARE ATTRIBUTABLE TO
GENETIC PREDISPOSITION?
LICHENSTEIN ET AL, N ENGL J MED 343: 78-85, 2000
44,788 PAIRS OF TWINS STUDIED IN SCANDINAVIAN
COUNTRIES
ESTIMATES:
PROSTATE 42% (95% CI 29-55)
COLORECTAL 35% (10-48)
BREAST 27% (4-54)
However:
1. GENE-ENVIRONMENT INTERACTIONS ARE NOT
ACCOUNTED FOR (THESE ARE PROBABLY
OVERESTIMATES)
2. HERITABILITY IS NOT GENETIC
DETERMINATION
New data on twins suggest that even monozygotic
(identical) twins diverge in the course of life for the
expression of genes, and thus for their phenotypes.
Such divergence is related to methylation of genes, ie an
“epigenetic” mechanism, not related to mutations or
structural changes in the sequence of DNA.
Recent experiments in “agouti” mice suggest (a) that a
diet poor in folate administered to pregnant mice causes a
change in colour of the skin in the offspring; (b) that the
offspring and the following generations also have an
increase in the risk for chronic diseases (diabetes, CVD,
cancer), and (c) that these effects are mediated by DNA
methylation, which is transmitted from one generation to
the other.
What is genetic susceptibility on a
population scale?
2. Genetic Testing in Populations
Misconceptions about the use of genetic tests in populations
Paolo Vineis, Paul Schulte, Anthony J McMichael
THE LANCET • Vol 357 • March 3, 2001: 709-12
•The relation between the frequency of a
variant and its penetrance is inverse: the more
penetrant (i.e., deleterious) a mutation, the less
frequent in the population.
NNS: NUMBER NEEDED TO SCREEN
to Prevent 1 Case.
A reasonable NNS is attained only by
screening for highly-penetrant
mutations in high-risk families, not
for such mutations in the general
population or for low-penetrant
polymorphisms.
BRCA1 - Reduction of risk from
Tamoxifene (theoretical) = 50%
Cumulative risk from 40% to 20%
Absolute Risk Reduction (ARR)=20%
Number needed to treat=1/ARR=5
Number needed to
screen=5/0.2%=2500
Number needed to screen for a low penetrant gene
(GSTM1 in smokers),
and a highly penetrant gene (BRCA1)
Disease
Population
Gene
Relative risk
Breast cancer
General
population
BRCA1
Families
BRCA1
Lung cancer
Pah
Pah
EXPOSURE EXPOSURE
GSTM1 null GSTM1 wild
5
10
1.34
1.0
Cumulative risk
40%
80%
13%
10%
Risk reduction
Cumulative risk
after intervention
Absolute risk
reduction
50%
50%
50%
50%§
20%
40%
6.5%
5%
20%
40%
6.5%
5%
5
2.5
15
20
0.2%
50%
50%
50%
5
30
40
NNT
Frequency
NNS
NNS in all smokers
2,500
––
35
3. Ethics of Genetic Testing (with
contribution from Michael Parker,
ETHOX Centre)
Paolo Vineis, Habibul Ahsan, Michael Parker
Genetic screening and occupational and
environmental exposures: Scientific and ethical
issues
OEM, in press 2005
Arguments in favour
1. employers and legislators have a duty to
protect employees, particularly those who are
vulnerable, from avoidable risks in the
workplace.
2. One might argue that making an informative
test available would enable workers to make
informed choices about the kinds of jobs they
take- about whether or where to work.
3. A third argument that might be used to support
the use of genetic screening or testing in
employment, in at least some situations, arises
where this has the potential to be in the broader
‘public interest’. One might imagine a situation in
which the genetic screening of employees might be
of relevance to public safety. An example is
screening those who are to be responsible for flying
planes or working in air traffic control for
mutations conferring a higher risk of heart failure
4. A fourth and final argument in favour of the use
of genetic screening in the workplace might be that
this has the potential to bring about important
economic advantages through increased safety and
reduced health care costs. This might be of
particular relevance to companies operating in a
country such as the United States where health
insurance is tied to employment.
Arguments against
Possibly the strongest argument against the use of
genetic testing in employment is that it has the
potential to lead to increased discrimination. There
is indeed, good evidence that this is already
happening.
Recently, for example, the US Equal Employment
Opportunity Commission filed suit against the
Burlington Northern Santa Fe Railroad Co. for
defying the “Americans with Disability” Act (case
settled in 2002 for 2.2 M USD). The company
required employees to submit blood samples to test
them for genes predisposing to the carpal tunnel
syndrome
In addition to discrimination against individuals,
genetic screening in the workplace also brings with
it the potential for discrimination against groups
that come to be seen as ‘high risk’
“if one group is continually trumpeted in the media
in association with a host of genetic diseases, [or
vulnerabilities] members of the group may find
themselves considered less desirable as mates and
employees”
Secondly, in addition to its potential to lead to
increased discrimination, the use of genetic
screening in the workplace may lead to an
increased likelihood of invasions of the privacy and
confidentiality of workers e.g. in the writing of
references, the provision of information for the
purposes of insurance and so on.
Examples already exist of samples being testing for
outcomes other than that for which they were taken
e.g. in the case of Norman-Bloodsaw v Lawrence
Berkeley Laboratory employees provided blood
and urine samples for cholesterol testing but in fact
some of these samples were subsequently tested for
syphilis, pregnancy and sickle-cell trait (Desmond
and Gardner-Hopkins p.441)
A third set of arguments against the use of genetic
screening for low penetrance genes in the
workplace arises out of concerns that the
information provided by such tests is likely to be
extremely difficult to interpret and/or to
communicate.
The fourth and final set of arguments against the
use of genetic screening and testing in the
workplace is that this is a distraction from the
responsibility of employers and legislators to ensure
that the working environment is safe for all of those
who work there. Instead of using resources to
identify workers who are less at risk, the focus
should be on finding ways to make the workplace
safe for all.
Less attention in reducing exposure levels
can affect not only people in the working
environment but also patients of a GP: e.g. people
with the “wildtype” can decide not to quit smoking
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THE END