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

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

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

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  1. Paolo VineisImperial College LondonNature vs nurture: genes and environment

  2. 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?

  3. 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)

  4. 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.Heritability 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

  5. 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

  6. 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

  7. Genes and cancerKey issue is penetrancePenetrance 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

  8. 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

  9. 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

  10. 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

  11. 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 COUNTRIESESTIMATES:PROSTATE 42% (95% CI 29-55)COLORECTAL 35% (10-48)BREAST 27% (4-54)

  12. However:1. GENE-ENVIRONMENT INTERACTIONS ARE NOT ACCOUNTED FOR (THESE ARE PROBABLY OVERESTIMATES)2. HERITABILITY IS NOT GENETIC DETERMINATION

  13. 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.

  14. What is genetic susceptibility on a population scale?

  15. 2. Genetic Testing in Populations

  16. 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.

  17. 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.

  18. 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

  19. Number needed to screen for a low penetrant gene (GSTM1 in smokers), and a highly penetrant gene (BRCA1)

  20. 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

  21. Arguments in favour 1. employers and legislators have a duty to protect employees, particularly those who are vulnerable, from avoidable risks in the workplace.

  22. 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.

  23. 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

  24. 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.

  25. 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.

  26. 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

  27. 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”

  28. 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.

  29. 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)

  30. 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.

  31. 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.

  32. 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

  33. 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.

  34. THE END

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