News

29 June 2007A new centre is to be established by Cold Spring Harbor Laboratory in the US to study the genetics of common psychiatric disorders such as schizophrenia and bipolar disorder (see press release). Schizophrenia and bipolar disorder (previously known as manic depression) affect around 2% of the population in developed countries. They are complex mental disorders, thought to arise from a genetic predisposition to disease affected by multiple genetic factors, combined with the influence of environmental factors.

The Stanley Center for Psychiatric Genomics will allow researchers to compare genome sequences from large numbers of people affected by the disorders; it is hoped that this will lead to identification of contributory genetic factors. Greater understanding of the genetics of such psychiatric disorders may help prompt diagnosis, and potentially lead to the development of improved treatments. Current treatments for schizophrenia and bipolar disorder have very variable effects in different individuals, and in many cases are selected to relieve symptoms rather than the underlying disease process.

The new centre is to be set up using a $25 million endowment from the Stanley Medical Research Institute, which is focused on research into the causes and treatments of severe mental illnesses.

28 June 2007The US National Office of Public Health Genomics is seeking additional members for a stakeholder group established to assist the development of the EGAPP (Evaluation of Genomic Applications in Practice and Prevention) project. The goal of EGAPP is “to establish and test a systematic, evidence-based process for evaluating genetic tests and other applications of genomic technology in transition from research to practice”. Its independent, multidisciplinary working group has so far completed two evidence reports on applications of genomic tests proposed for use in clinical practice.

For its stakeholder group, EGAPP wants to recruit representatives from a variety of designated groups including healthcare providers, public health professionals, advocacy groups, the biotech and diagnostics industry, news media and policy makers. The main role of the group is to act as facilitators in identifying and communicating the key ‘messages’ from EGAPP’s work to different sectors. The stakeholder group is also expected to contribute their expertise to the evaluation process, by advising on stakeholder surveys and on specific aspects of EGAPP’s reviews and recommendation statements.

The closing date for nominations is 18 July.

27 June 2007The Gates Foundation is to invest $105 million over 10 years to set up a new public health institute, the Health Metrics and Evaluation Institute (see press release). The University of Washington in Seattle, where the Institute will be based, is also contributing $20 million to the venture. The Institute will complement current efforts by organisations such as WHO to collect, analyse and archive data on key public health metrics such as incidence and prevalence of disease and disability, burden of disease, mortality and causes of death, and health risks. Dissemination is seen as a key task for the Institute, which will “make key health data and information freely available to decision-makers, researchers and the public”.

Crucially, the Health Metrics and Evaluation Institute will also carry out, and provide training tools for, rigorous evaluation of health systems and new health programmes, particularly in the developing world. The dearth of reliable information about the performance of such programmes and interventions is seen as hampering efforts to improve the health of the world’s poorest people.

There may be opportunities, through the work of the new Institute and its collaborating centres, to improve understanding of the global burden of genetic disease, and strengthen the evaluation of new genomics-based initiatives. 

26 June 2007As anticipated, US president George Bush has again used his presidential veto to block government-approved legislation to increase access to state funding for embryonic stem cell research (see previous news), reportedly saying "I will not allow our nation to cross this moral line" (see Nature news). The proposed legislative amendments would permit federal funding of stem cell research using excess embryos from fertility clinics; these unused embryos are otherwise destroyed. Although both the US Senate and House have previously voted in favour, a two-thirds majority is required to override presidential veto. Further attempts to pass the legislation are expected.

In the same week, researchers from a US company claim to have grown human embryonic stem-cells by a method that does not harm the embryos, taking just one cell from an early stage embryo in a similar manner to that used for pre-natal diagnosis of genetic disease in embryos for in vitro fertilisation. Advanced Cell Technology reported the approach at the meeting of the International Society for Stem Cell Research (see Reuters news). Preliminary results for the production of stem cell lines from a single embryonic cell were published last year (see journal club article), but no live embryos were preserved at that time. The company hopes that this approach could bypass ethical objections to embryonic stem cell research, but nevertheless expressed disappointment with the president’s veto (see press release).

25 June 2007The UK’s Medical Research Council, together with the British Heart Foundation and pharmaceutical and biotechnology companies, are jointly sponsoring a £17 million research programme to evaluate novel genomic biomarkers for conditions such as cardiovascular disease, cancers, stroke and Parkinsons disease (see press release). Research on biomarkers related to disease status, progression and responsiveness to treatment will be included among the 18 new projects supported by the funding.

The Medical Research Council is contributing £8 million to the total, with £1 million coming from the British Heart Foundation. The £8 million contribution from industry will be partly in the form of direct financial support, and partly “in kind”, in the form of drugs and reagents, commitment of time or access to technology.

21 June 2007Researchers at Egenis (the ESRC Centre for Genomics in Society) have developed an annotated bibliographic database that aims “to make the science [of genomics] and its implications more accessible to those with philosophical, historical and sociological interests in the various fundamental questions being asked and answered by genomics and related forms of molecular biology”. The database, consisting of over 300 papers from the scientific literature that are indexed in PubMed, is searchable and may also be browsed by author, title, category, type of article, year of publication or publisher. In addition to genomics (including ‘post-genomic’ fields such as proteomics and metabolomics) it covers several of the newer areas of scientific research, such as systems biology and metagenomics, that attempt to move beyond the listing of genes and their products to consider their higher-order interactions, organisation and evolution. Each entry in the database is accompanied by a brief description of the contents of the paper and its significance from a philosophical, historical or social science standpoint.

In an article accompanying the database on the Egenis website, philosophers Maureen O’Malley and John Dupre explain the rationale for the database and provide a brief introduction to the philosophical issues and questions raised by the scientific concepts and research fields it covers.

19 June 2007The independent UK Academy of Medical Sciences has released a new report on inter-species embryos combining human and animal material (cytoplasmic hybrid, human transgenic or human chimeric embryos), which concludes that such research is vital for understanding and treating human disease. This follows the publication of the Government's draft Human Tissues and Embryos Bill and the launch of a public consultation into human-animal hybrid research by the Human Fertilisation & Embryology Authority (HFEA).

Inter-species embryos are said to include animal embryos containing human genetic material, or human embryos containing animal genetic material; chimeric animals are already produced for some forms of research, by introducing human DNA into laboratory animals such as mice. The report, which considers ethical and safety issues alongside the potential scientific benefits, calls for hybrid embryo research to be permitted under regulation in the UK, in order to further understanding of human development, somatic cell nuclear transfer (cloning) techniques and human embryonic stem (ES) cells.

Professor Martin Bobrow, who chaired the working group that produced the report, commented: “There are no substantive ethical or moral reasons not to proceed with research on human embryos containing animal material under the same framework of regulatory control” (see press release)

The Academy report concludes that current research on inter-species embryos can be appropriately regulated by existing mechanisms, but suggests that it will become necessary “to consider the appropriate conceptual and regulatory framework for transgenic and chimeric animals that contain significant amounts of human genetic material”. It notes that dual regulation of this area of research is undesirable, and welcomes the proposed new provisions of the HFE Act that should define which inter-species embryos fall within the remit of the HFEA and successor Regulatory Authority for Tissue and Embryos (RATE), and exclude those that fall within theremit of the Home Office animal research regulations. The report calls for proper channels of communication and consultation between those bodies regulating human embryos, human stem cells and animal research. It also supports continuation of current legal restrictions that prevent culture of potentially viable human embryos beyond 14 days, and prohibit implantation of hybrid embryos into either an animal or human woman.

The authors observe that: “We do not consider that concern about slippery slopes is a good argument forprohibiting valuable research; it is a good argument for rigorous and ethically informed regulation”.

15 June 2007A group of Oxford scientists, led by Professor Walter Bodmer, is seeking DNA samples from 3500 people living in different regions of Britain, in an attempt to chart patterns of DNA variation across the British Isles. It is hoped that the results of the People of the British Isles project will shed light on historical patterns of settlement and migration both within Britain and involving neighbouring regions such as Scandinavia, France and Germany.

A second aim of the project is to aid research on the relationship between genomic variation and disease, by making it possible to distinguish potential disease-related variation from the underlying pattern of variation established by history and geography. Recent UK-based whole-genome association studies have shown that some interesting geographical variation does exist in the UK; in particular, a predominant pattern of variation along a NW/SE axis (see newsletter article). However, the researchers found that the overall effect of population structure on the results of their association studies was small. The People of the British Isles study may add some further detail to the picture.

In order to obtain samples that are truly representative of different regions, the People of the British Isles project is looking for participants whose parents and both sets of grandparents were born in the same locality. Just over 2000 people have already volunteered to take part in the study. Further recruitment events are planned at regional agricultural shows over the summer months.

14 June 2007The UK Government has launched a consultation on proposals for a single Equality Bill for Great Britain (England, Scotland and Wales). The proposals have been developed as a result of the work of the Discrimination Law Review, which was set up to explore the idea of creating a single, modernised framework to protect people who experience disadvantage as a result of unfair discrimination; and the Equalities Review, which considered the broader causes of inequality in society. The proposed Equality Act will be the legislative basis for the work of the new Commission for Equality and Human Rights, which will replace the current Equal Opportunities Commission, Commission for Racial Equality, and Disability Rights Commission.

Part 3 of the consultation paper, A Framework for Fairness, addresses the need to modernise discrimination law, acknowledging that new knowledge and changing social attitudes may require new legislative provisions. Within this section of the proposals, Chapter 8 discusses whether there need to be changes to the grounds or personal characteristics that are protected under discrimination law. Genetic predisposition to disease is considered specifically. The consultation paper proposes there should be no specific legislative prohibition of discrimination on the grounds of genetic predisposition. It notes that there have been very few documented cases of unfair discrimination against people with a genetic predisposition to disease, and that current non-legislative provisions such as the voluntary moratorium on the use of genetic test results in insurance underwriting, and the Information Commissioner’s code of practice for use of genetic test results by employers, appear to be working satisfactorily. It also rejects the suggestion that people with a genetic predisposition to disease should be considered ‘disabled’ while they are still asymptomatic.

However, the paper does endorse the view that “no-one should be unfairly discriminated against on the basis of their genetic characteristics” and proposes that the situation should be kept under review, with the possibility of further non-legislative measures being introduced in the future if justified by the emergence of any evidence of unfair discrimination. The overall philosophy of the proposals is that the law should only be changed “if there is evidence that to do so would be a proportionate response to a real problem”.

These proposals run counter to current thinking in the United States, where legislation outlawing genetic discrimination appears likely to become law in the near future (see recent newsletter article). The difference in approach may partly reflect the close link between employment and health insurance in the US, and perhaps a stronger tradition of non-legislative regulation in the UK.

The consultation is open until 4 September 2007. The Government states that it is committed to taking forward its proposals on a participative basis, and that contact with stakeholders will continue as the proposals are developed and refined.

13 June 2007The Parliamentary Joint Committee on the Draft Human Tissue and Embryos Bill has launched an econsultation forum which will run until 26 June. The terms of the consultation is limited to four areas which have already been scrutinised by Committee in oral evidence sessions. Firstly, the Committee has questioned whether the more permissive regime advocated by the Science and Technology Committee should be reproduced in the Bill. This would allow research on inter-species embryos created by mixing animal and human gametes to proceed subject to licensing by the Regulatory Authority. The draft Bill currently prohibits this area of research with limited exceptions.

Other areas of debate include the sex selection of embryos for family balancing purposes, and whether Parliament (on the face of the Bill or by regulation), the Regulatory Authority or research scientists or individual clinicians in consultation with their patients should take decisions about the use of embryos in research and fertility treatment. For policy makers and researchers alike, these questions are crucial because they dictate how flexibly regulation can respond to scientific advances and shifts in public opinion. The forum is available at:

http://forums.parliament.uk/human-tissue-bill/index.php?index,1

11 June 2007The US National Human Genome Research Institute has allocated the first grants in a four-year project called modENCODE, which aims to identify all the functionally important elements in the genomes of the fruit fly Drosophila melanogaster and the roundworm Caenorhabditis elegans. modENCODE is part of a larger initiative, ENCODE, (EnCyclopaedia Of DNA Elements), that is working towards building a complete catalogue of these elements in humans. Functionally important elements include not just protein-coding genes but also regulatory sequences that control gene expression, genes encoding functional RNAs (which are also turning out to be important players in gene regulation), and sequences important for the structure and dynamics of chromosomes.

Past studies on the fruit fly and the worm have yielded a wealth of information on gene functions and properties that is also relevant to the much more complex human genome. The rationale behind modENCODE is that many of the functional elements identified in the genomes of the fly and the worm will turn out to be present and have similar properties in humans, but can be more easily studied and characterised in these simpler model organisms.

10 June 2007New South Wales, the most populous of Australia’s states, has voted 65 to 26 in favour of new legislation to permit the use of cloned human embryos for stem cell research. NSW is the second of the Australian states to ratify the Stem Cell Research Bill, which requires support from all states to become law (see news story).

10 June 2007The US House of Representatives has voted 247 to 176 in favour of new legislation to remove some of the current restrictions placed on the use of federal funding for stem-cell research; the Senate passed it earlier this year. A similar vote passed the legislation last year, but Republican President George W. Bush issued a veto (see news story), and reportedly intends to do so again; a presidential veto can only be overridden by a majority vote of at least two-thirds.

Proponents of the legislation, which would lift the current restrictions limiting researchers to apply for federal funding for research using human embryonic stem-cell lines only where those cell lines were established before 9th August 2001, claim that stem cell research has massive potential for the treatment of serious medical conditions. Opponents object to the use of stem-cells derived from human embryos, since the process destroys the embryos. In a statement President Bush reportedly said: "If this bill were to become law, American taxpayers would for the first time in our history be compelled to support the deliberate destruction of human embryos…Crossing that line would be a grave mistake. For that reason, I will veto the bill passed today" (see BBC news story).

The day before the stem cell bill, the House voted 213-204 against a bill to ban human reproductive cloning, which would have required a two-thirds majority to be passed. Democrats were largely in favour of the bill, but Republicans said that it would support the creation of cloned human embryos for purposes other than reproduction, ie. medical research.

8 June 2007The Canadian Government and the Government of the province of Quebec have announced  funding of $28.5 million over three years for the CARTaGENE project, a biobanking initiative that will involve recruiting 20,000 Quebec citizens aged 40-60. Participants will provide DNA and other biological samples, together with health and lifestyle information, for studies aimed at identifying the genomic determinants of health and disease in an ageing population.

An additional $6 million has been allocated to support the P3G (Public Population Project in Genomics), an international collaboration that aims to harmonise scientific approaches and standards for ethical governance of large-scale projects in genomic epidemiology around the world. P3G is led by Professor Bartha Knoppers of the University of Montreal and Dr Tom Hudson of the University of Toronto; in addition to CARTaGENE its members include UK Biobank, the Estonian Genome Project and Generation Scotland.

6 June 2007According to BBC News, cardiac specialists are calling on the government to honour commitments to improve services for individuals and families affected by sudden cardiac death syndromes [also known as SADS, for sudden adult (or arrhythmic) death syndromes]. These syndromes, which are often genetic, include a variety of conditions causing hearth arrhythmias, including longQT syndrome and hypertrophic cardiomyopathy. Affected individuals are at risk of a sudden catastrophic heart attack, which often strikes without warning during adolescence or young adulthood. It has been estimated that about 500 young people under the age of 35 die each year in the UK as a result of one of these conditions.

The 2005 revision of the National Service Framework for Coronary Heart Disease specifies that, in the case of sudden unexplained death in a young person, an expert post-mortem should be carried out to ensure accurate diagnosis of the cause of death, with retention of tissue for possible genetic testing, dependent on legal consent. It also requires that NHS services should have systems in place to identify family members who may be at risk and provide them with personally tailored diagnosis (including genetic testing if appropriate), treatment, information and support.

However, heart specialists, coroners and patient support groups such as CRY (Cardiac Risk in the Young) claim that these services are not being delivered and that there has been virtually no improvement since the National Service Framework was published. Professor Bill McKenna, a specialist on hypertrophic cardiomyopathy, points to a lack of funding and systems for specialist clinics, expert pathologists, retention of post-mortem tissue samples, and family support.

The Government rejects these criticisms, claiming that coroners can seek advice from a network of specialist pathologists and that nine specialist centres have been set up to deliver services for sudden cardiac death syndromes.

5 June 2007Ensuring that the law takes account of relevant scientific developments and changing public opinion is one aim of the draft Human Tissue and Embryos Bill, published on 17May 2007. The draft Bill will update parts of the Human Fertilisation and Embryology Act (1990) and the Human Tissue Act (2004) to ‘ensure that the law remains effective and fit for purpose in the early 21st century’. If the Bill is enacted in its current form, it will allow the creation of human-animal hybrid embryos for research under licence, on condition that the resulting inter-species embryo is destroyed within 14 days of creation.

The Bill also proposes the following changes:

• That existing regulators, the Human Fertilisation and Embryology Authority and the Human Tissue Authority be dissolved and replaced by a new body – the Regulatory Authority for Tissue and Embryos (RATE)
• Clarifying the basis upon which research on embryos can be licensed
• Clarifying the basis upon which licences for prenatal testing of embryos can be issued – to include serious mitochondrial abnormality and selection of an embryo to be used to treat an affected sibling using umbilical cord blood stem cells
• New provisions enabling information to be passed between donor-conceived siblings (subject to appropriate counselling and age restrictions)
• Removing the ‘need for a father’ for children resulting from treatment while requiring account to be taken of the welfare of a resulting child. This is consistent with other parts of the Bill which establish new parenthood provisions for civil partners and same sex couples

The Bill will be scrutinised by a Joint Parliamentary Committee which will report to Parliament by 25 July 2007. Because of these time constraints, the committee has chosen to limit the scope of its enquiry, calling for written evidence to be submitted by 15 June 2007. In particular the Committee will consider whether the Bill strikes the right balance between Parliamentary control of primary legislation, secondary legislation in the form of regulations and regulation by statutory bodies, and the extent to which it assures appropriate flexibility and freedom for clinicians and researchers and individuals accessing treatment.

In the context of hybrid embryo research, some have welcomed the draft Bill as a pragmatic response to scientific advances: others worry that if ground breaking research necessitates secondary legislation, then the process becomes arduous and bureaucratic. These critics suggest that the longevity of the existing Human Fertilisation and Embryology Act bears testament to the general ethical principles established within that Act as a robust and durable means of future proofing.

Others question whether the new Authority can take proper account of the range of interests for which it will be responsible, particularly as it will take on licensing responsibilities for material for human application, under the EU Tissue and Cells Directive, including responsibility for blood and blood products transplantation from the MHRA. Whilst there is provision for the new Authority to have assistance from expert advisory committees (currently limited to three areas, reproductive medicine and embryo research, anatomy and pathology and blood and transplantation) the lack of a similar representative process for other sectors seems to prioritise the interests of some sectors over others.

4 June 2007Nobel laureate Jim Watson, who co-discovered the double-helix structure of DNA, has been presented with a DVD containing his complete genomic sequence. Said to be a landmark as the “first individual genome to be sequenced for less than $1 million” (see Nature news article), the US Baylor College of Medicine of Houston and the firm 454 Life Sciences, who together sequenced the genome, reported that it had taken two months to complete (see press release). The first complete human genome sequence (a composite sequence from the DNA of several anonymous volunteers), released in 2003, cost in excess of $1 billion and took thirteen years to produce. It is hoped that eventually, the rapidly developing technology will make it possible to sequence complete genomes for as little as $1000, and in a period of hours (see previous news story).

With this step towards a future of readily available and relatively affordable genome sequencing  (the National Human Genome Research Institute is planning to sequence a hundred different individual human genomes), concern has been expressed about the potential consequences. For example, making your genome sequence publicly available, as James Watson has done, has implications for relations who have similar genomes, especially as understanding of the links between genetic variants and disease susceptibility increases. Watson has reportedly opted to withhold the sequence of the APOE gene, a certain variant of which is associated with an increased risk of Alzheimer’s disease (see Observer news article), because he does not wish to know whether he has any genetic predisposition towards the disease. In addition to issues of genetic privacy, ethical objections have also been raised about equity of access to genome sequencing based on cost.

30 June 2007Women with breast cancer who carry a mutation in either the BRCA1 or the BRCA2 gene have a substantial risk of a developing a second primary breast tumour or ovarian cancer in the absence of prophylactic intervention such as mastectomy, oophorectomy or tamoxifen treatment. Risk prediction models to estimate the probability that a woman carries a BRCA mutation have mostly been developed using large families and include family history as part of the analysis. Such models might not be well suited for women with few or no female relatives.

A study of 306 women with breast cancer diagnosed under the age of 50, and no first- or second-degree relatives with breast or ovarian cancer, has found that mutation-prediction models do indeed perform poorly in this situation [Weitzel JN et al. (2007) JAMA 297, 2587-95]. Although none of the women had close affected relatives, half had a family structure considered ‘adequate’ for risk analysis (that is, an adequate number of maternal and paternal female relatives), and half were classified as having ‘limited’ family structure (fewer than 2 females who lived to age 45 in each lineage). The probability that a woman with early-onset breast cancer and limited family structure had a BRCA mutation was found to be 13.7%, compared to a 5.2% probability for those with adequate family structure. None of the three risk prediction models tested (the Couch, Myriad and BRCAPRO models) performed well in predicting mutation risk for the women with limited family structure.

Comment: The results of this study suggest that criteria for considering BRCA mutation testing in women with early-onset breast cancer may need to be modified in cases where family structure is limited, if knowledge of mutation status is likely to affect medical management. Women in this situation may also wish to know their mutation status if they have children or are thinking of starting a family. Current UK guidelines recommend that genetic testing should only be offered in cases where there is at least a 20% probability of finding a mutation; the 13.7% probability identified in this study falls short of that figure but is higher than the 10% threshold used in some US guidelines.      

26 June 2007One of the UK Government’s commitments in its 2003 White Paper on genetics was to fund a set of pilot service development projects for risk assessment and cancer prevention based on family history. The projects have been run jointly with Macmillan Cancer Care. A paper published recently in the journal Familial Cancer has drawn together the experience of these pilot projects in determining what new practitioner roles are needed to operate such services, and what resources and support these practitioners need [Bennett C et al. (2007) Fam. Cancer 6(2): 171-180].

A workshop, followed by a survey of 11 individuals working in new cancer genetics roles within six of the pilot projects, revealed that most of the new roles were undertaken by practitioners who were not genetics specialists. Many of the new roles were filled by nurses who added cancer genetics competences to their existing experience in primary care, community nursing or cancer nursing. The competences required by these practitioners were found to map well to a general competence framework for genetics in clinical practice for non-genetics healthcare staff that is being developed by the NHS National Genetics Education and Development Centre and the NHS agency Skills for Health. Key competences included an understanding of genetics within the practitioner’s own area of clinical practice, identifying patients with or at risk of genetic conditions, gathering and interpreting a multi-generational family history, and assessing genetic risk. In general, however, follow-up activities such as ordering genetic tests, communicating test results to patients, genetic counselling, and discussing invasive preventive options such as mastectomy, were referred to specialist genetics practitioners.

Competences in non-clinical activities such as information technology, promoting public and professional awareness, marketing, audit and evaluation, and project management were also seen as important but were not generally addressed by the pilot projects in the context of a formal competency framework.

All of the new practitioners identified a need for ongoing support and training in their new roles, including access to suitable courses (and time and funding to attend them) and access to mentoring and advice from genetics specialists.

The authors conclude that the key factors for successful development of new genetics roles in mainstream medical services are development of clear pathways and guidelines for risk assessment and referral; definition of the relevant competences for each role; allocation the necessary resources for achieving these competences; and securing the necessary support from specialist genetics services.

Comment: This paper makes an important practical contribution to thinking about how genetics can be applied in mainstream services outwith the specialist genetics departments. It is a cause for some concern that such a heavy reliance on support from genetics services was identified, as these over-stretched services will not be able to supply this level of support as applications of genetics in mainstream services become more widespread. As the authors of this paper point out, it will be important to cascade genetics learning and experience more effectively throughout other areas of medicine so that specialist genetics services are required only for the most complex cases and for essential clinical supervision.  

20 June 2007As part of a review on the genetics of cardiovascular disease (CVD) published in the journal Circulation, the American Heart Association has made a list of recommendations “intended to help incorporate usable knowledge into current clinical and public health practice” [Arnett DK et al. (2007) Circulation 115, 2878-901].

The article explains the major approaches that have been used to identify genes implicated in common diseases, and summarises the evidence for some potential gene candidates for myocardial infarction and atherosclerotic CVD, hypercholesterolaemia and hypertension. Rare Mendelian subsets of these conditions are also discussed. Additional sections of article review current knowledge on gene-environment interactions in CVD and the pharmacogenetics of drugs commonly used in cardiovascular medicine.

The paper concludes with a list of 17 specific recommendations in five main areas:

1. The use of family history as a screening tool to identify susceptible individuals and families

2. The development of a multidisciplinary research infrastructure that includes translational research and public-private partnerships

3. The prioritisation of research on characterising relevant genes and genetic variants and evaluating their interactions with environmental and  behavioural factors, developing new methods for risk assessment and outcome prediction, and assessing gene-drug interaction

4. Preparing pro-actively for effective genetic screening programmes by establishing prevalence criteria that would trigger such programmes, establishing standards for testing facilities, matching treatments to susceptibility findings and assessing cost-effectiveness of screening

5. Education of researchers, clinicians, public health professionals and the general public

Comment: Recent whole-genome association studies whose results have overlapped with the publication of this review confirm, to some extent, the optimism of the review’s authors that a more complete understanding of genetic susceptibility to CVD will soon be possible. However the recent studies have not so far confirmed an involvement for most of the candidate genes discussed in the review. Two of the new studies do, however, independently identify a previously unknown variant on chromosome 9 as highly significantly associated with CVD, with relative risks of at least 1.4 for heterozygotes and 1.6-2.0 for homozygotes (see previous news articles posted on 7 June and 10 May).

The American Heart Association’s recommendations summarise well the steps that will be needed along the route to implementation of new genetic knowledge into clinical and public health practice. However the time scale of developments is still unclear and some may regard it as premature to ‘prepare pro-actively for effective genetic screening programmes’.

18 June 2007The first report from the ENCODE (Encyclopedia of DNA Elements) consortium suggests that we might need to make some quite fundamental adjustments to our thinking about how the human genome functions [The ENCODE Project Consortium (2007) Nature 447, 799-816 (abstract)]. The consortium used a range of high-throughput techniques to study the functions of an estimated 1% of the human genome, corresponding to about 30 million base pairs of DNA. Where possible, a combination of techniques was used to address a particular question, thus strengthening the conclusions.     

The biggest surprise was that, instead of a discrete and tidy set of genes that are transcribed into RNAs and translated into proteins, the genome appears to encode a vast network of overlapping transcripts, for many of which there is as yet no known function. A corollary to this finding is that many regulatory DNA elements that were thought to be far away from the genes whose expression they regulate are in fact quite close to the transcription start site for one or more of the newly identified transcripts. Regulatory sequences also turned up just as frequently ‘downstream’ as ‘upstream’ from the transcriptional start, again overturning conventional wisdom. Studies on the short- and long-range ‘architecture’ of the genome confirmed many previous findings but also revealed a more sophisticated picture of the relationships between regulatory sites for transcription and DNA replication, chromatin packaging and histone modification.

Another ‘rule of thumb’ in genomics has been that functionally important DNA elements are likely to be evolutionarily conserved. The ENCODE results suggest that although there is indeed overlap between evolutionarily constrained sequences and functional sequences, some functional sequences appear to show considerable variability, not just among different mammals but even in different human populations. The ENCODE authors suggest that this pool of variable functional elements – if confirmed in higher-resolution studies – might serve as a ‘warehouse’ of raw material for natural selection.

Comment: The ENCODE results are an exciting milestone in functional genomics. As pointed out by Greally in an accompanying News and Views article [Greally JM (2007) Nature 447, 782-3], the findings relating to the transcriptional activity of the genome may prove to be particularly important in understanding how gene variants affect disease susceptibility, as many of the highly significant associations emerging from whole-genome associations implicate single nucleotide polymorphisms (SNPs) not located within any known genes. But this vast piece of work is just the tip of the iceberg: we don’t yet know whether the 1% of the genome studied so far is typical of the other 99%, or what might emerge from studying a wider set of cell types.

7 June 2007Striking results from another genome-wide association (GWA) study have been published in Nature [The Wellcome Trust Case Control Consortium (2007) Nature 447, 661-78 (abstract)]. A consortium of over 50 research groups funded by the Wellcome Trust has identified 24 highly significant associations between genetic variants and six common diseases: 1 for bipolar disorder, 1 for coronary artery disease, 9 for Crohn’s disease, 3 for rheumatoid arthritis, 7 for type 1 diabetes and 3 for type 2 diabetes. An additional 58 gene variants showed moderate evidence of association with these or a seventh condition studied, hypertension.

The researchers used genotyping ‘chips’, arrayed with DNA sequences representative of nearly 500,000 single nucleotide polymorphisms (SNPs) in the human genome, to compare the DNA of 14,000 cases (2,000 for each of 7 diseases) and 3,000 shared controls. Controls came from two sources: 1500 from the 1958 British Birth Cohort, and 1500 blood donors from UK Blood Services.

Odds ratios for the highly significant risk alleles were generally between 1.1 and 2, with the exception of some well known risk alleles for the autoimmune conditions rheumatoid arthritis and type 1 diabetes, for which much higher odds ratios were observed. Interestingly, several loci were found that influence susceptibility to more than one autoimmune condition.

About half of the associations identified in this study confirm findings from previous research, notably gene variants implicated in Crohn’s disease, rheumatoid arthritis, and type 1 and 2 diabetes. In addition, several new risk alleles were found, most of which, according to the authors, have also now been confirmed in follow-up studies. Although it is not always possible to say exactly what the biological risk variant is (as the SNPs simply act as markers for a genomic region), many of the regions highlighted do contain biologically plausible candidate genes that can now be investigated further in functional studies. Some candidate genes identified in previous linkage or association studies were not identified as risk alleles in this study; for example, several biologically plausible candidates for involvement in coronary artery disease were not confirmed, and no strongly significant risk alleles for hypertension were discovered, though 6 alleles reached moderate significance.

The study is important not just for its findings but for aspects of its methodology that will be valuable for future work. The researchers were able to demonstrate that, although there is some geographical genetic heterogeneity in Britain (predominantly variation along a NW/SE axis), these differences are not large enough to distort the findings of a study of this size, provided recent immigrants of non-European ancestry are not included. They were also able to show that the same set of unaffected controls can be used in GWA studies for several different diseases, thus making future studies easier and cheaper.

Comment: The power of the GWA approach has been amply demonstrated by this and other recent headline-hitting studies. The authors suggest that no common variants of large effect remain to be found for the 7 common diseases they investigated but that there are likely be many more variants of modest effect, as the variants identified to date account for only a small proportion of the familial aggregation of these diseases. Future studies will need to be even larger than this one if the aim is to find alleles with odds ratios less than about 1.2.

 The results of this and other GWA studies still to be reported (the authors mention studies on breast cancer, multiple sclerosis, ankylosing spondilitis, autoimmune thyroid disease and tuberculosis) will shed valuable light on the pathophysiology of common diseases and should, in time, lead to new approaches to treatment and perhaps prevention. However, it is important yet again to caution against the seemingly inevitable assumption, at least by the news media, that genetic testing for susceptibility to common disease is imminent. Indeed the authors of this study comment on “the limited potential of the variants thus far identified (singly or in combination) to provide clinically useful prediction of disease”.

4 June 2007How can genetic tests be evaluated for clinical use? Experience of the UK Genetic Testing Network. Kroese M, Zimmern RL, Farndon P, Stewart F, Whittaker J (2007) Eur J Hum Genet. May 30; [Epub ahead of print]. Review of the UKGTN and the evaluation process for genetic tests (PubMed). See also: The evaluation of genetic tests. Zimmern RL, Kroese M (2007) J Public Health (Oxf) May 24; [Epub ahead of print] (PubMed).

Prohibiting genetic discrimination. Hudson KL (2007) N Engl J Med. 356(20):2021-3. Perspective article considering the US Genetic Information Nondiscrimination Act (PubMed).

The mixed promise of genetic medicine. Elliott C (2007) N Engl J Med. 356(20):2024-5. Perspective piece looking at the ethics of medical ‘enhancements’ and exploring whether or not ‘liberal eugenics’ is a credible threat (PubMed).

The locked code. Watts G (2007) BMJ 19;334(7602):1032-3. Feature article on the ongoing legitimacy of patenting genes and the implications of such patents (PubMed).

Reestablishing the Researcher-Patient Compact.Kohane IS, Mandl KD, Taylor PL, Holm IA, Nigrin DJ, Kunkel LM (2007) Science 316(5826), 836-837. Policy forum piece proposing that regulations designed to protect clinical research subjects and guard their privacy is in fact preventing them from accessing information about their own health risks or benefits; the authors propose an alternative regime involving an extensive informed consent process and an oversight board to communicate results back to participants [Abstract].

Closing the Net on Common Disease Genes. Couzin J, Kaiser J(2007) Science 316(5826), 820-822. News focus article on the emerging genome-wide association studies, and the implications of their findings for understanding of common, complex diseases with multiple contributory genetic (and environmental) factors [Abstract].

Personalised medicine: who is an Asian? Po AL (2007) Lancet 369(9575):1770-1771. Commentary in the poorly defined racial category ‘Asian’ and potential implications for pharmacogenetic drug labelling (PubMed).

Genome-wide transcription and the implications for genomic organization. Kapranov P, Willingham AT, Gingeras TR (2007) Nat Rev Genet. 8(6): 413-23. Review of genomic organization and how it may influence the observed complexity of transcription (PubMed).

Network motifs: theory and experimental approaches. Alon U (2007) Nat Rev Gene. 8(6): 450-61. Review on recurring regulation patterns in the control of gene expression (PubMed).

Can we develop ethically universal embryonic stem-cell lines? Green RM (2007) Nat Rev Gene. 8(6): 480-5. Perspectives piece on the prospects for developing a source of human embryonic stem-cells likely to be acceptable to those who object to methods that involve the destruction of human embryos (PubMed).

A strategy for translation.Lord GM, Trembath RC (2007). Lancet 369(9575): 1771-3. Commentary calling for a translational medical research strategy for the UK (PubMed).

Ancillary risk information and pharmacogenetic tests: social and policy implications. Henrikson NB, Burke W, Veenstra DL (2007) Pharmacogenomics J. May 8; [Epub ahead of print]. Literature review with discussion of the implications of disease risk information from pharmacogenetic tests, calling for this to be taken into consideration in evaluation of such tests (PubMed).

DNA repair pathways and hereditary cancer susceptibility syndromes. Spry M, Scott T, Pierce H, D'Orazio JA (2007).Front Biosci. 12: 4191-207. Review ofmolecular mechanisms of DNA repair and how defects in these systems can cause predisposition to cancer (PubMed).

Advances in genetic findings on attention deficit hyperactivity disorder. Thapar A, Langley K, Owen MJ, O'Donovan MC (2007). Psychol Med. May 17; 1-12 [Epub ahead of print] Review of current understanding of the genetic influences on ADHD (PubMed).

Personalized medicine: elusive dream or imminent reality? Lesko LJ (2007) Clin Pharmacol Ther. 81(6):807-16. Commentary on how the emerging scientific, social and healthcare structures are paving the way for personalized medicine, and looking at challenges to obtaining suitable clinical evidence for its introduction (PubMed).

The Nature Insight supplement for May is on epigenetics:

Epigenetics. Eccleston A, Dewitt N, Gunter C, Marte B, Nath D. (2007) Nature 447(7143): 395. Editorial (full text).

Perceptions of epigenetics. Bird A (2007)Nature 447(7143): 396-8. Piece addressing the question of what epigenetics really is (full text).

Transcription and RNA interference in the formation of heterochromatin. Grewal SI, Elgin SC(2007) Nature 447(7143): 399-406. Review (full text).

The complex language of chromatin regulation during transcription. Berger SL (2007) Nature 447(7143): 407-12. Article presenting a model of complex and dynamic chromatin modifications regulating transcription (PubMed).

Nuclear organization of the genome and the potential for gene regulation. Fraser P, Bickmore W (2007) Nature 447(7143): 413-7. Article on communication within and between chromosomes and whether this affects or merely reflects gene function (PubMed).

Stability and flexibility of epigenetic gene regulation in mammalian development. Reik W (2007)Nature 447(7143): 425-32. Article comparing restriction of gene expression in the development of specialized cell types with long-term epigenetic silencing (PubMed).

Phenotypic plasticity and the epigenetics of human disease. Feinberg AP (2007) Nature 447(7143): 433-40. Article looking at the role of epigenetics in disease (PubMed).

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