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19 October 2000The Wellcome Trust and the Medical Research Council have published the results of an initial, qualitative study into public attitudes to the proposed UK Population Biomedical Collection: a collection of DNA samples and health and lifestyle information on 500,000 volunteers aged from 45 to 64 (see article in February 2000 newsletter ). The survey, carried out by the independent research group Cragg Ross Dawson, questioned a cross-section of people, including religious and community leaders and a small sample of GPs. The survey identified an initial high level of public support for the project and a general willingness to participate, particularly among people who were themselves ill or had relatives who were ill. This support was somewhat diminished when issues of potential concern were introduced into the discussion, but tended to rise again when these issues had been thoroughly discussed and thought through. The major area of unease concerned the divulging of health and lifestyle information rather than the provision of a DNA sample. People were worried about the confidentiality of this information and the potential for its misuse, even though it would be anonymised when provided to researchers. Informed consent was held to be vital and some people also felt that they should, if they participated, be entitled to feedback about any information arising from their own sample or from the project in general. GPs were concerned that this would be unworkable in practice and, if attempted, would have a serious impact on their workload. However, they and other groups were broadly supportive of the suggestion that GPs and practice nurses would be involved in recruiting volunteers and obtaining samples. This consultation exercise is the first stage in the Wellcome Trust's commitment to continuing public consultation on this issue. The Trust has also reported on progress to date with the project. The current plan is to recruit volunteers through a small number of regional centres, coordinated by a central office. There will also be an independent group or committee whose role will be to safeguard the interests of the volunteers and the public in general; this may go some way towards allaying concerns expressed about the initial proposal, which did not expressly include such a body.

At the same time, the Human Genetics Commission is launching a public consultation into the storage, protection and use of genetic information, and the Science and Technology Committee of the House of Lords is conducting an inquiry into human genetic databases. 

13 October 2000A consortium consisting of The Wellcome Trust, seven of the constituent institutes of the US National Institutes of Health, and three pharmaceutical companies, has been set up with the aim of accelerating the sequencing of the mouse genome (see press release from Sanger Centre). There is already a wealth of genetic information available about the mouse, the animal genetic model most closely related to humans. The hope is that combining this genetic information with the complete sequence of the mouse genome, and comparisons with the human genome, will speed up the rate at which genes can be identified in the DNA and their functions determined. The data generated by the work of the Mouse Sequencing Consortium (MSC) will be freely available. The announcement coincides with a claim from the private genomics company Celera that it has sequenced 95%  of the genome in three different mouse strains from the one to be targeted by the MSC (see Celera press release).   

11 October 2000There is evidence that in women with a strong family history of breast cancer, particularly those carrying a mutation in the BRCA1 or BRCA2 genes, use of the oral contraceptive (OC) pill may reduce the risk of ovarian cancer. Evidence has been mixed about the effect of  OCs on breast cancer risk in these families. A new study by Grabrick et al suggests that women with a family history of breast cancer are at increased risk if they use OCs, though the magnitude of the risk remains uncertain and it may depend on the hormone levels in the OC used [Grabrick, D.M. et al (2000) JAMA 284, 1791-1798]. This study examined breast cancer incidence in ever-users and never-users of OCs among first- and second-degree relatives of 426 women diagnosed with breast cancer between 1944 and 1952. In first degree relatives (sisters and daughters), the relative risk was 3.3 for ever-users compared with never-users. The relative risk rose higher if only very high-risk families (i.e., with multiple cases of breast cancer) were included in the analysis; these families may be the most likely to be carrying BRCA1 or BRCA2 mutations. Second-degree relatives and women marrying into the families were not at increased risk of breast cancer if they had used OCs. Interestingly, the increased risk with OC use in first-degree relatives was only seen for women using OCs before 1975. After this date, formulations changed and hormone levels in OCs dropped dramatically. This suggests that the increased risk may only relate to high-hormone-dose OCs, but this conclusion is premature at this stage because the fairly young age of women in the study who used OCs after 1975 (average age 43) probably means that some cancers in this group have yet to develop.

Comment: If OC use does prove to increase breast cancer risk substantially in women with a family history of the disease, these women face a difficult decision: whether to take this risk in the hope of reducing their ovarian cancer risk and in order to take advantage of the contraceptive benefits of OC use. It would certainly seem unwarranted for women with any family history of breast cancer to avoid OCs, but women with several affected relatives may need careful, individually tailored advice in order to make an informed decision. In an editorial accompanying the paper by Grabrick et al, Burke provides a clear and measured assessment of their dilemma [Burke, W. (2000) JAMA284, 1837-1838].  

16 October 2000The Genetics and Insurance Committee (GAIC) has approved a predictive genetic test for use by insurance companies (see text of their decision). The test is a predictive test for Huntington's disease. This follows the Government's decision not to accept the recommendation of the Human Genetics Advisory Commission that there should be a moratorium on the use of predictive genetic tests by insurers (see the report of the Human Genetics Advisory Commission and the Government response). Instead, the Government set up GAIC to assess the actuarial validity of tests the insurance companies would like to use. The Huntington's application is the first GAIC has considered after issuing, earlier this year, an application form setting out the information insurers must provide when applying for permission to use a test. This does not mean that genetic tests have not previously been used by insurers. In fact, some tests, including the Huntington's test, had been used already by insurers under the Association of British Insurers' own voluntary code of practice. The continued use of these tests now depends on favourable assessment by GAIC. There have been strong reactions to GAIC's decision and to the Government's stance on the issue. Some, including MP Ian Gibson, fear that it represents the start of a "slippery slope" towards the creation of an un-insurable genetic underclass. Genetics researchers are concerned that allowing insurance companies access to genetic test results will deter families from participating in research. This has already been seen in families affectd by mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 (tests not yet approved by GAIC).  Such families are generally advised to set their insurance affairs in order before consenting to testing.

On the other side of the argument, the ABI points out that genetic information, in the form of family histories, has been used by insurers for many years in assessing risk, and that genetic testing is merely a refined version of this same principle. Indeed, genetic testing may relieve an individual of the "burden" of a family history of a disease if the test reveals that he or she has not inherited the gene variant in question. On average, 50% of people with a parent affected by Huntington's disease will, if they decide to be tested, discover that they do not carry the mutation. These people will then be insurable at a standard premium whereas on the basis of family history alone they would have had to pay substantially increased amounts. It is important to note, too, that insurance companies may not require anyone to take a genetic test, but if someone has taken a test approved by GAIC then the company has the right to be informed of the result in any insurance proposal.

The questions surrounding genetic testing and insurance are difficult ones, and it has yet to be seen how far GAIC will be prepared to go in approving tests. Huntington's disease and other rare single-gene diseases are far more straightforward in this respect that genetic predispositions to common diseases such as cancer and Alzheimer's disease. It has been argued that genetic tests for the latter are unlikely to prove actuarially valid and will face far greater difficulty in obtaining approval from GAIC. The "slippery slope" may, one hopes, prove less slippery than some fear.

25 October 2000In its recently published second report, the National Screening Committee sets out the criteria it uses to judge proposals for screening programmes. It makes the important point that it considers not just the results of high-quality research projects carried out by skilled and dedicated teams, but the likely quality of a service once it is rolled out at a national level. The NSC's report also signals a clear move away from the past emphasis on increasing uptake of screening, towards a situation where people are able to make informed choices based on information about the pros and cons of the screening procedure they are being offered. The NSC sees it as vital to get across to the public the message that screening, like any other medical procedure, can never be 100% accurate and safe, nor can it guarantee that any disease detected will be curable. It intends to move towards a change in language, dropping the word "screening" wherever possible and talking instead about "risk reduction ", in the hope that this term may be better understood. The current work of the NSC is being organised into five population categories: antenatal, child, men, women and older people. It is intended that these programmes will not "stand in isolation", but that screening should operate within the overall context of the NHS Plan and the National Service Frameworks, and the establishment of the National Institute for Clinical Excellence and the Commission for Health Improvement. The NSC report sets out its recommendations on eight potential screening programmes considered during the last 18 months (including ovarian and prostate cancer) and describes progress with two current pilot programmes (bowel cancer and chlamydial infection). The work of the Antenatal Screening Subgroup is given little space in the report, which directs readers towards the group's web page for further information about its activities; the BMJ has reported recently that the group is concerned about the huge variation in antenatal screening programmes across the country and is planning to develop national policies on, for example, antenatal screening for Down Syndrome.  

4 October 2000A US couple who have a six-year-old child with the fatal genetic disorder Fanconi's anaemia have used preimplantation genetic testing combined with IVF to enable them to have a second baby who is both free of the disease himself and who can act as a compatible donor of tissue to his seriously ill sister (for further information see article in The Guardian newspaper). Preimplantation genetic diagnosis is used in an increasing number of cases to enable parents at risk of passing on a serious genetic disease to have a healthy child, but this is the first publicised case of the procedure being used for the additional purpose of creating a baby whose tissue can be used to treat another child. Ethicists are sharply divided over the case, some claiming that it represents the "slippery slope" towards "designer babies", while others say that, as long as the new baby is also loved and wanted for his own sake, no-one is harmed and a life may be saved. It is likely that new genetic and reproductive technologies will lead to many more ethically difficult cases such as this. It seems sensible to approach each on its own merits rather than trying to formulate blanket policies. In the UK the Human Fertilisation and Embryology Authority was set up for the express purpose of providing a mechanism through which society can consider the issues and decide how to respond. The HFEA is currently considering the results of a consultation on preimplantation genetic diagnosis.

16 October 2000There is some evidence that mutations in genes such as the prothrombin and Factor V genes predispose women to late fetal loss (after 20 weeks of pregnancy), though not all studies have not observed this effect. Martinelli et al have compared the frequency of specific thrombophilic mutations in 67 women who experienced a first late miscarriage and 232 control women [Martinelli, I. et al (2000) N Engl J Med 343, 1015-1018 (Abstract)]. The combined frequency of the two thrombophilic mutations was 16% in women who had had a late miscarriage and 6% in women who had not. The calculated relative risks for each of the mutations was about 3. A previous study that included women who had experienced recurrent fetal loss reported a relative risk of 7. In contrast to these Factor V and prothrombin mutations, Martinelli et al found no difference between subjects and controls in the frequency of a putative thrombophilic mutation in the methylenetetrahydrofolate reductase gene.

Comment: The authors of this study conclude that testing for these thrombophilic mutations is indicated in women who experience an unexplained late fetal loss. However they concede that the best management for such women in subsequent pregnancies is still unclear. Almost half of the women had had a previous successful pregnancy and might well go on to have further unaffected pregnancies without any treatment. It is difficult to judge at present whether the benefits of anticoagulant therapy for these women would outweigh the risks.