Paolo VineisImperial 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

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?

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

•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.

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

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=5Number 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 Breast cancer Lung cancer

Population Generalpopulation

Families PahEXPOSURE

PahEXPOSURE

Gene BRCA1 BRCA1 GSTM1 null GSTM1 wild

Relative risk 5 10 1.34 1.0

Cumulative risk 40% 80% 13% 10%

Risk reduction 50% 50% 50% 50% §

Cumulative riskafter intervention

20% 40% 6.5% 5%

Absolute riskreduction

20% 40% 6.5% 5%

NNT 5 2.5 15 20

Frequency 0.2% 50% 50% 50%

NNS 2,500 5 30 40

NNS in all smokers –– 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 issuesOEM, 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 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.com/coresite/index

Welcome to Sciona

Science-Based Tools for Personalized Product Design Sciona is a leading provider of personalized, science-based healthcare solutions. Using the latest research, Sciona has created a powerful set of tools that enable manufacturers

to customize personal care and nutrition products. Sciona’s proprietary technology makes it both possible and cost-effective for manufacturers to offer their customers a

range of healthy, informed choices, specially tailored to fit

each client’s unique genetic makeup.

THE END