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22 January 2001Umans-Eckenhausen et al report, in The Lancet, the results of a five-year study in which they tested for familial hypercholesterolaemia (FH) mutations among 5442 relatives of 237 people who had a known FH-associated mutation in the LDL receptor gene [Umans-Eckenhausen, M.A.W. et al (2001) Lancet 357, 165-168]. Initially, first-degree relatives of the index cases were tested and then, in turn, any additional first degree relatives of those people. 2039 people were identified as heterozygous for an FH-associated mutation. Of these, 69% already knew of their condition and were receiving treatment, and most of the remainder are now also being treated with cholesterol-lowering drugs. The authors compared DNA analysis with measurement of blood cholesterol for diagnosis of FH and conclude that 18% of mutation carriers would have been misdiagnosed on the basis of blood cholesterol alone. Similarly, there would have been 18% "false positives" among non-mutation carriers.

Comment: This study shows that case-finding among relatives of people with FH is an effective way of identifying people with FH, many of whom may be presymptomatic. The same conclusion was reached recently by a UK study, and in an HTA report (see article in December 2000 newsletter). The question remains, however, as to the best means of diagnosing FH. Umans-Eckenhausen recommend DNA analysis as the gold standard. However, this is only feasible if a mutation has been identified in the index case in a family. Moreover, it is uncertain how many of the mutation carriers who did not have raised blood cholesterol would actually go on to develop disease if untreated.  

12 January 2001A National Confidential Inquiry into counselling by non-geneticists in the UK revealed evidence of some poor practice, including the lack, in many centres, of written policies on antenatal screening for such conditions as Down's syndrome, neural tube defects and haemoglobinopathies. Subsequently, the Royal College of Obstetricians and Gynaecologists issued guidelines on this issue. A survey by Lane et al shows that there has been little improvement, however [Lane, B. et al (2001) BMJ 322, 22-23]. Only 20% of responding centres, for example, had a named individual in charge of antenatal screening, and fewer than 40% had clear statements on the criteria for deciding if a test result was abnormal. These disappointing findings may help to spur initiatives to develop agreed national (or at least regional) guidelines for antenatal screening programmes.

11 January 2001The US Patent Office has issued new guidelines on the patenting of gene-related inventions (see recent press release). The PTO rejected calls for genes and gene-based products to be removed from the scope of patent protection altogether, but the new guidelines tighten up the requirements for applications to demonstrate utility, stating that the utility must be "specific, substantial and credible". The guidelines also imply that the onus of proof of such utility rests with the applicant, and that patent examiners may reject applications if they consider that utility has not been clearly demonstrated. Some commentators in the biotechnology industry fear that the new rules will stifle research but others have welcomed them as a spur to companies to strive to find truly novel gene-based approaches to disease diagnosis and therapy. The full guidelines are available on the web site of the US Patent Office

8 January 2001Three papers in the December 22 (2000) issue of Science present evidence for a gene or genes on chromosome 10 that may be involved in genetic susceptibility to late-onset Alzheimer's disease [Bertram, L. et al (2000) Science 290, 2302-2303 (Abstract); Ertekin-Taner, N. et al (2000) Science 290, 2303-2304 (Abstract); Myers, A. et al (2000) Science 290, 2304-2305 (Abstract)]. Myers et al studied a large set of affected sib pairs, looking across the genome for alleles shared by these sibs significantly more often than would be expected by chance.  Ertekin-Taner et al looked for genes linked to elevated levels of the blood protein Ab42, which are thought to be associated with Alzheimer's susceptibility. Both groups pinpointed a specific region of chromosome 10, which can now be examined in further detail. The third group carried out a linkage study in families, reporting linkage of late-onset Alzheimer's in these families to a different region of chromosome 10 from that identified in the other two studies.

Comment: It is too soon to say what the eventual fate of these reported linkages will be. The fact that two of the studies, using completely different approaches, have homed in on the same region of the same chromosome is encouraging, but further independent verification is still needed. Eventually, of course, a specific candidate gene must be identified in the region and susceptibility must be convincingly linked to a specific allele or alleles.  

19 January 2001Marking its 40th anniversary, the British Heart Foundation has announced that it is supporting, to the tune of £2.5 million "The British Heart Foundation Family Heart Study", which aims to identify genetic variants associated with coronary heart disease. The BHF claims that this is the largest study ever undertaken of heart disease in families. It will take at least two years to complete, and is also being supported by the Medical Research Council. Researchers aim to enrol 2000 sibling pairs who have experienced coronary heart disease under the age of 65. DNA samples from these people will be anonymised and kept in a central "library", from which they will be made available to participating research groups in the UK. The aim will be to identify gene variants that are shared by affected siblings more often than would be expected by chance. Studies of this type need large very sample sizes - hence the need for an effective national campaign to recruit volunteers. 

25 January 2001"Health Care 2020", the report of the Healthcare Panel of the Government's Foresight Programme, includes a section on research, development and technology that focuses almost exclusively on genetics. The Panel, which includes representatives from the NHS, the Department of Health, research institutions, the pharmaceutical industry and health insurance providers, predicts that in the next 20 years both the availability and demand for genetic tests will increase, and that SNP-based personal "genetic profiles" that may predict susceptibility to common disease could become part of an individual's health record. With this in mind, the Panel recommends that the Government should "ensure that there are well-defined criteria for genetic testing and screening", and that "the genetic information it is feasible or desirable for an individual to have and retain should be clarified". Noting recent developments in the area of genetics and insurance, the Panel suggests that government and industry representatives should, together with geneticists and other stakeholders, attempt to predict the impact of possible advances in genetic "profiling" on the insurance industry and society. The Panel also thinks that Government should create a climate that will enable a continuing commitment to innovation in the healthcare industries, particularly by indicating clearly what sorts of products and services are likely to be acceptable, avoiding excessive bureaucracy, and providing an effective means for educating the public and ensuring that people understand and sympathise with the objectives of health care research and development. Alongside this facilitation would go an effective means of ethical scrutiny of new developments - one in which the public must have confidence.  

10 January 2001There has been much discussion about the role of the GP in identifying people who are at increased genetic risk of disease, particularly breast or bowel cancer. Some hold the view that the GP should take a family history from every patient at the initial consultation, while others think that GPs should only respond to concerns raised by the patient about a family history of disease. Two papers in the BMJ contribute to this discussion. de Bock et al found that genetic advice given by GPs about familial breast cancer was often not satisfactory, partly because a substantial proportion of GPs (30%) did not follow national-guideline-based advice about the patient's risk given by a clinical geneticist, and partly because of the women's poor compliance with the advice they were given [de Bock et al (2001) BMJ 322, 26-27]. GPs tended to err on the side of caution, recommending increased breast surveillance or referral to a specialist genetics centre more often than was warranted. In a study in Cambridge, the Women's Concerns Study Group found that worries about a family history of breast cancer were raised by women in only about 0.5% of consultations, while GPs raised the topic 6-7 times more often [Women's Concerns Study Group (2001) BMJ 322, 27-28]. They conclude that concerns about a family history of breast cancer are not common among patients, and suggest that these women may be managed "by training a team member in assessment and management techniques, possibly with computer support". Their study implies that, rather than being due to attention by the media, the large increase in referrals to genetics centres of patients with a family history of cancer may be mainly attributable to over-zealous GPs.

Comment: The results of these studies suggest that it may not be advisable for GPs to take a strongly proactive stance on genetics. However, family history does remain an important indicator of susceptibility to common disease, and it would surely be remiss of GPs to ignore it altogether. The difficult task of the GP is to identify those patients who would benefit from more specialist genetic advice, while not raising arousing unwarranted fears in those who do not have a substantially increased genetic risk. The debate about how GPs can achieve this will no doubt continue. 

9 January 2001In a vote on 19 December, MPs in the House of Commons approved, by a substantial majority, an extension of the purposes for which very early human embryos may be used and created (also see item in November 2000 newsletter for a discussion of some of the issues). Previously, under the 1990 Human Embryology and Fertilisation Act, embryos up to 14 days old could be used for research purposes concerned with human reproduction and infertility. The new regulations allow embryos to be used, in addition, for work on human embryonic stem cells, with a view eventually to using stem cells in new therapies for degenerative diseases such as Parkinson's disease and multiple sclerosis. Some MPs were concerned that the issue was being rushed through parliament, and that the pre-Christmas timing was not ideal, but the debate was thorough, the turn-out high and the vote conclusive, with 376 MPs voting for the motion and 174 against.  

30 January 2001Recognising a need to respond swiftly to new developments that need its attention, the Human Genetics Commission has established a Business Committee that will meet monthly to set priorities and coordinate progress on existing work, making suggestions to the full HGC and to the various subcommittees. Membership of the Committee will rotate, but any HGC members are free to attend its meetings. At its first meeting, just before Christmas, the Business Committee discussed the need for the HGC to have an input into developments in the area of genetics and insurance. There is a view among some HGC members that there is confusion about the roles of the HGC and the Genetics and Insurance Committee and that the HGC should consider the issues in depth before GAIC makes any further decisions about genetic tests that may be used by insurance companies. The business committee recommended that a planned one-day workshop on the topic on 9 February should be opened to the public. During 2001 the HGC will prepare a report for Ministers setting out its views on genetics and insurance. The Business Committee also discussed progress on the joint consultation (with the Human Fertilisation and Embryology Authority) on preimplantation genetic diagnosis, the imminent publication of a new code of practice on paternity testing, and the need for closer liaison with the Wellcome Trust and the Medical Research Council over their plans to set up a large database of genetic information linked to medical records.

24 January 2001The House of Lords has voted in favour of amending the regulations governing research on human embryos, so that embryos up to 14 days old may be used for research on the derivation and potential of human stem cells (see text of debate). Eventually it is hoped that stem cells may be used in novel treatments for degenerative diseases such as Parkinson's disease and multiple sclerosis. The new regulation also makes it lawful (subject to licensing of research proposals by the Human Fertilisation and Embryology Authority) for "cloned" embryos to be created for this purpose by replacing the nucleus of an unfertilised egg with a donor nucleus from an adult cell. (It is actually already legal to create embryos by this means, but not for the purpose of research on stem cell therapy.) However, there was considerable opposition to the proposed new regulation, with some Peers expressing the view that there has been insufficient time for people to consider all the implications, particularly the danger of a "slippery slope" towards the cloning of human beings. The regulation was passed but the Government has agreed that the HFEA will grant no licences for human embryonic stem cell research until a parliamentary select committee has conducted an inquiry into the issue. Existing legislation prohibiting the cloning of a human being (that is, implanting a cloned embryo into a woman's uterus and allowing it to develop) will also be strengthened. It is perhaps unfortunate that so much of the debate and press commentary has focused on the "cloning" issue, whereas most of the initial research would probably concentrate on exploring the potential of stem cells, using donated "left over" IVF embryos that would otherwise be destroyed. 

18 January 2001The child health subgroup of the National Screening Committee (NSC) has recently published, on the NSC website, its decision not to recommend the introduction of universal neonatal screening for cystic fibrosis. The NSC assessed the case for neonatal CF screening according to a standard set of criteria that it uses for all such assessments. It concluded that, although the case is "finely balanced", the evidence in favour of screening is not, at present, sufficiently strong. The main difficulties were the lack of a "simple, safe, precise and validated screening test", the lack of agreement on how positive test results should be followed up, and the equivocal evidence as to whether earlier detection as a result of screening improves the treatment and long-term wellbeing of children with CF. Already, nearly 18% of newborns in the UK are screened for CF, using a variety of different tests and protocols. It seems unlikely that screening will be extended nationally in the foreseeable future. The antenatal subcommittee of the NSC has also rejected the suggestion that there should be universal antenatal carrier screening for CF.

30 January 2001

As recommended in the NHS Executive's recent report on laboratory services for genetics, a new national advisory group is about to be set up, to provide a "strategic steer" on commissioning genetic services. Its remit will include establishing criteria for evaluating genetic tests, designating national service providers for tests for very rare disorders, advising on research needs, "horizon scanning" to identify new developments that will have an impact on genetic services, and advising on the coordination of resources for the funding of genetic services. The group will be a subgroup of the National Specialist Commissioning Advisory Group (NSCAG), and will include clinical, scientific and academic geneticists, as well as representatives from the Regional Specialist Services Commissioning Groups in England, and service commissioners from the devolved administrations in Wales, Scotland and Northern Ireland. The Group will have close links with the National Institute for Clinical Excellence, the Health Technology Assessment programme, and the new "knowledge parks" to be set up as part of the NHS plan. It is hoped that the membership of the group can be finalised in time for a first meeting during March 2001.

12 January 2001The Human Genetics Commission (HGC) is continuing to honour its commitment to make its deliberations available to the public. The minutes of the recent meeting of the Public Involvement in Genetics subgroup report that the public event held in Newcastle at the end of November was considered to have been generally successful. The subgroup discussed holding annual events of this type in the future, as well as other ways of involving the public, perhaps including e-mail consultation. Full meetings of the HGC are to be open to the public as observers from this year, with the first of these scheduled for 2 March. Members of the public will be able to apply for tickets, with a certain number of places reserved for representatives of special interest groups. Some future HGC meetings may even be televised via the Parliamentary Channel. The HGC considers it important that its discussions should be informed by an understanding of the views of people directly affected by genetic disorders, and for this reason is planning to set up a Patients' Panel. The Public Involvement subgroup felt it was important that the Panel should represent the full range of opinion among such patients, their carers and families, and that it should have an independent secretariat. 

19 January 2001Earlier this month, the Nuffield Council on Bioethics announced that it has set up a working party to look into the ethics of research into genetics and human behaviour. The working group will investigate the scientific basis for such studies, survey current work in this area, and consider what effects research on "behavioural genetics" might have both on individuals participating in the research and, as a result of any findings, on society in general. Any wider effect on society might include, for example, changes in attitudes to people with particular behavioural characteristics, or the development of genetic tests related to behaviour; such tests might have an impact in the areas of employment, legal cases, education and reproductive decisions. In March, the Council will launch a public consultation on this issue. This, together with the deliberations of the working party, will inform a report that is expected to be completed during 2002.

18 January 2001Abnormal concentrations, in the blood, of factors involved in the coagulation cascade and fibrinolysis are thought to be implicated in increased risk of heart disease. In a study that compared monozygotic (identical) and dizygotic (non-identical) twins, de Lange et al have attempted to estimate the heritability of blood concentrations of several such factors [de Lange, M. et al (2001) Lancet 357, 101-105]. The assumption underlying twin studies such as this is that if monozygotic twins resemble each other with respect to a trait more closely than dizygotic twins do, the difference can be attributed solely to genetic effects. de Lange et al estimated substantial heritability, around 60%, for a range of haemostatic factors including Factor VII, Factor VIII and tissue plasminogen activator. Even higher heritability was calculated for von Willebrand factor (75%) and Factor XIII (82%). The authors conclude that blood levels of these factors are influenced to a large degree by genetics and that studies on variation in the genes involved in their regulation will reveal genetic factors that predispose to heart attack and stroke.

Comment: Twin studies are a well-established method for estimating heritability. However, several assumptions underlie such studies, including the idea that the extent to which environment is shared is no greater for monozygotic than for dizygotic twins. In an editorial in the same issue of Lancet as the de Lange et al paper, Harrap and Souto question the validity of this assumption and point out that other methods of assessing heritability of haemostatic factor levels have yielded significantly lower estimates: around 35% on average rather than 60% [Harrap, S.B. and Hopper, J.L. (2001) Lancet 357, 83-84]. There seems little doubt that genetic variation in the control of haemostasis makes an important contribution to risk of heart disease. It may, however, be a rather sterile exercise to attempt to put a figure on the degree of heritability. A more productive approach may be to attempt to unravel how genes and environmental factors interact to affect disease risk though, as Harrap and Hopper point out, this will be a very complex task.