Paolo Vineis Imperial College London Nature vs nurture: genes and environment

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Paolo VineisImperial College LondonNature
vs nurture genes and environment
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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
reasons2. 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?
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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)
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In fact many objections were already
raised in a seminal paper by Richard Lewontin,
against the environment vs. heritability
dilemmaThe basic confusion is between
heritability and genetic determination.Heritabil
ity has to do with DIFFERENCES ratio of
variation inherited by parents to total
variationA characteristic is genetically
determined if it is coded in and caused by the
genes in a normal environment
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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
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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 parentsENVIRONMENTAL
CHARACTERISTICS THEMSELVES ARE HERITABLE
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Genes and cancerKey issue is penetrancePenetra
nce 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
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In fact examples of 100 penetrance (all or
nothing) are very rareModulation by
environmental factors is the rule rather than the
exceptione.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
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SOME FIGURESLIFETIME 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
SEXESBRCA1 AND BRCA2 CONFER A RELATIVE RISK OF
BREAST CANCER OF 5-10GENOTYPES AT MISMATCH
REPAIR LOCI CONFER A RR OF COLON CANCER OF
9.3METABOLIC POLYMORPHISMS CONFER A RR FOR
SEVERAL TYPES OF CANCER OF LESS THAN 2
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ABOUT 0.2 OF WOMEN CARRY BRCA1 OR BRCA2
SUSCEPTIBLE VARIANTS, AND 0.1 OF PEOPLE HAVE
SUSCEPTIBLE VARIANTS FOR MISMATCH REPAIR
LOCITHESE GENOTYPES ACCOUNT FOR LESS THAN 5 OF
BREAST OR COLON CANCERS50 OF THE GENERAL
POPULATION HAVE A DELETION OF THE GSTM1 GENE,
WITH A RELATIVE RISK FOR LUNG CANCER OF 1.3
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HOW MANY CANCERS ARE ATTRIBUTABLE TO GENETIC
PREDISPOSITION?LICHENSTEIN ET AL, N ENGL J MED
343 78-85, 200044,788 PAIRS OF TWINS STUDIED
IN SCANDINAVIAN COUNTRIESESTIMATESPROSTATE
42 (95 CI 29-55)COLORECTAL 35 (10-48)BREAST
27 (4-54)
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However1. GENE-ENVIRONMENT
INTERACTIONS ARE NOT ACCOUNTED FOR (THESE ARE
PROBABLY OVERESTIMATES)2. HERITABILITY IS NOT
GENETIC DETERMINATION
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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.
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What is genetic susceptibility on a population
scale?
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2. Genetic Testing in Populations
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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.

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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.

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• BRCA1 - Reduction of risk from Tamoxifene
  (theoretical) 50
• Cumulative risk from 40 to 20
• Absolute Risk Reduction (ARR)20
• Number needed to treat1/ARR5
• Number needed to screen5/0.22500

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Number needed to screen for a low penetrant gene
(GSTM1 in smokers), and a highly penetrant gene
(BRCA1)
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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
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Arguments in favour 1. employers and
legislators have a duty to protect employees,
particularly those who are vulnerable, from
avoidable risks in the workplace.
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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.
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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
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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.
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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.
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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
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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
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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.
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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)
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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.
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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.
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Less attention in reducing exposure levelscan
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(www.sciona example)http//www.sciona.c
om/coresite/index
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