News

30 July 2009UK National Health Service (NHS) laboratory scientists are to receive new training to equip them to advise health professionals on the purpose and interpretation of genetic tests. Department of Health chief scientific officer Dr Sue Hill is quoted in the Times newspaper as having said that “Genetic scientists may actually start to sit in clinics with medics and play a key role, explaining to patients what the results are showing. This isn’t about scientists replacing medics, it’s about working together in a team” (see Times report). Scientists could be asked to help interpret the results of private genome scans or advise on pharmacogenomic testing to direct treatment decisions.

There has been increasing recognition of the growing role of genomics across different fields of medicine and the need for change within the health service, as evinced by the recent House of Lords report on Genomic Medicine (see previous news); for example, the need to incorporate useful forms of genetic testing into healthcare, along with improved understanding of genetics among health professionals.

Health Minister Ann Keen announced a new £4.5 million pilot training scheme to enhance training for healthcare scientists in genetic technologies and clinical applications. The aim is to create the capacity for scientists to ‘respond to breakthrough scientific advances and their applications for patients and the public’ (see press release). This pilot, part of the UK Modernising Scientific Careers (MSC) programme, establishes a national School of Genetics in the West Midlands and will begin later this year, with a view to subsequent national implementation. Training will include new preparation for direct interaction between scientists and patients.

29 July 2009The American College of Clinical Pharmacy (ACCP) has published a position statement on direct-to-consumer genetic testing, calling for federal government oversight of companies offering such tests. The ACCP expressed concern about the potentially adverse impact from advertising of DTC genetic tests to consumers, saying that it could have "both immediate and long-term effects on public health and the future adoption of pharmacogenetic/genomic testing" [Ameer B, Krivoy N (2009) J Clin Pharmacol. 49(8):886-8]. 

The US Food and Drug Administration (FDA) regulates the advertising of prescription drugs, and the ACCP called for this oversight to be extended to genetic testing. Their primary concerns are that poor consumer experiences of DTC genetic testing (for example, in the absence of a clinician or geneticist to explain the reliability or meaning of results) might lead to widespread distrust of genetic testing in general, and potentially lead to the development of inequitable regulatory policy that could stifle “innovation in the creation of validated genetic tests" and hinder the translation of pharmacogenetic testing into clinical practice.

They propose that clinical pharmacologists should help members of the public who have or are considering purchasing DTC genetic tests (see press release) by suggesting that they:

• Obtain advice from a ‘genetic clinician’ about advertisements of genetic testing
  
• Appreciate that many DTC genetic test providers do not offer interpretation of results
  
• Recognise the scientific limitations of each test, particularly with respect to the lack of (genuine) clinical implications

It is noted that direct assistance with specifically pharmacogenetic testing may be provided by pharmacologists .

Recently, a report from the US Federal Coordinating Council for Comparative Effectiveness Research made recommendations for the application of personalised medicine in comparative effectiveness studies. The Annual Report on Comparative Effectiveness Research noted the increasing potential to use genomic patient information to “use more effectively the therapies we have now and to identify significant areas where research and development of new products may be needed", adding that pharmacogenomics “is expected to be a hallmark of this approach”. In the report, the council also noted the need to include racial and ethnic subgroups in some study designs, to avoid potential health disparities.

28 July 2009Major UK medical research charity the Wellcome Trust recently released new guidelines for primary care practitioners on the use of patient data in research, developed following a national meeting of GPs, researchers and patient groups to discuss this issue last year. Towards Consensus for Best Practice: Use of patient records from general practice for research proposes that:

• Patient confidentiality and privacy must be safeguarded
• GPs and healthcare professionals should play the role of patient advocate
• Public awareness and understanding of the use of records in research should be improved

The guidelines cover the use of anonymised, coded and identifiable data from patient records and include recommendations on how to identify and approach potential research participants and ensure they receive appropriate information to allow them to make an informed choice about whether or not to participate. They have been endorsed by the British Medical Association (BMA) and the Royal College of General Practitioners (RCGP). BMA Head of Science and Ethics Dr Vivienne Nathanson commented: "The first priority of GPs must be to deliver high-quality healthcare. But they must also protect patients if their records are to be used in research and ensure that the confidentiality of patient data is safe and secure at all times" (see press release).

 

Meanwhile, the UK General Medical Council (GMC) has launched a new consultation on two pieces of draft guidance for doctors on research, Good practice in research and Consent to research, intended to update existing guidance Research: the role and responsibility of doctors (2002).The consultation is open ‘anyone with an interest in research’ and closes on 25th September 2009.

16 July 2009The PHG Foundation has produced a detailed response to the current public consultation from the Nuffield Council on Bioethics on “Medical Profiling and online medicine: the ethics of ‘personalised' healthcare in a consumer age" (see previous news). The consultation focuses on the ethics of health-related services and technologies that are available direct-to-consumer (DTC), such as DNA profiling and whole body imaging.

It is likely that ‘personalised’ medicine will have an important role to play in the future of health care, both for stratifying the population into sub-groups based on risk in order to improve targeting of preventative interventions such as screening, and encouraging a more individually tailored approach to treatment and patient care. The increasing significance accorded to individual autonomy within modern society, partially driven by an explosion in the amount of scientific information available, has created and fostered both consumer healthcare and the concept of personalised medicine.

However, the application of personalised medicine in the absence of appropriate evidence of clinical benefit may be premature. In keeping with our previous work on the topic of evaluation and regulation of genetic tests, we encourage the use of the ACCE model as a framework for evaluation, particularly focussing on the need for evidence of clinical validity and utility. Nonetheless, we support the current two-tier system of regulation, in which a higher burden of evidence is required for a product to be offered as part of a state-funded health care system (like the NHS) versus being made available on the marketplace, to ensure the best possible use of public resources.

Thus the key question for DTC tests and services relates to their potential for harm. Conceptually this can be divided into direct harm caused by the test itself, and indirect harm caused by knowledge of the result of the test. For DNA profiling services, which generally use a simple saliva sample or buccal swab, the main concern is therefore about indirect harms such as false reassurance or inappropriate interventions caused by invalid results. However, this issue is not unique to genetic tests, and may actually be substantially more pertinent for numerous other health-related tests which have a higher predictive ability than DNA profiling. Therefore, transparency regarding the level of evidence associated with any product (and, where appropriate, risk of direct harm) should be the guiding principle in a liberal society in which consumerism and personalised medicine is a reality.

Since the PHG Foundation is broadly against the notion that genetic information is sufficiently different from other kinds of health-related information to warrant special or exceptional treatment, we therefore suggest simply that only the following five criteria should be made a minimum legal requirement for DTC genetic testing services:

1) all laboratories should undergo formal accreditation;

2) appropriate consent procedures are put in place;

3) the available scientific evidence supports the claimed gene-disease association;

4) appropriately qualified professionals are available to provide advice and support;

5) misleading or unsubstantiated claims are prevented through consumer protection legislation.

The full text of this and other consultation responses from the PHG Foundation is publically available in the Consultation Responses section of our website.

15 July 2009The UK Academy of Medical Sciences (AMS) has released a report of an invited symposium held in October 2008 which reviewed the status of genome-wide association (GWA) studies. Entitled “Genome-wide association studies: understanding the genetics of common disease”, the report showcases recent findings from GWA studies and discusses the steps needed to “facilitate the translation of findings into commercial and clinical applications.” At the time of publication, nearly 350 GWA studies had been conducted, revealing common genetic variants associated with over 80 common diseases and traits, giving scientists an unprecedented wealth of novel insights into the disease aetiology. The potential for using these findings to improve the targeting of screening programmes is highlighted, bringing an end to the “one size-fits-all approach to medical care.”

The report concludes that “there is considerable scope to further capitalise on the opportunities [offered by GWA studies] and secure real benefits for healthcare”, and goes on to offer several recommendations. In addition to resequencing of DNA regions of interest, the importance of assessing the role of structural variations, joint effects (gene-gene or gene-environment interactions) and epigenetics is highlighted, as well as designing better studies and collecting samples across a diverse range of ethnicities. Similar to the recent House of Lords Science and Technology Committee report on Genomic Medicine (see previous news), the AMS also recognises the need for investment in disciplines such as bioinformatics and statistics as a crucial aspect of the drive to “translate the wave of genetic findings on common disease into improved diagnostics, preventions and treatments.”

Comment: Unfortunately, as is so often the case, the exact method by which the findings from basic genetic science and GWA studies will be translated into clinical practice is not discussed. Although the first steps along the “translational journey”, from ‘bench-to-bedside’, are indicated – namely, finding the causal variant, understanding the underlying biological mechanism, and developing relevant functional models for the disease – the widely acknowledged second gap in translation, from ‘practice-to-policy’, is not addressed. The responsible and effective translation of new findings into practice also requires not only scientific and clinical research, but also extensive clinical evaluation, analysis of the broader ethical, legal  and social issues, and development of both health care services and public policy.

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10 July 2009A new database has been launched by the European Molecular Biology Laboratory’s European Bioinformatics Institiute (EMBL-EBI) based at Hinxton near Cambridge that should enable more comprehensive comparisons of gene expression data than have been previously possible. The Gene Expression Atlas contains the extensively annotated results collected from over 1000 separate independent studies.

Gene expression fundamentally determines how cells - and the body parts they make up - behave. Although all the body’s cells contain the same genome (excepting gametes and red blood cells), different genes are expressed or suppressed in different cell types; indeed, this is what makes them different cells. Many diseases are characterised by an altered gene expression pattern. The new database will allow comparisons between the expression of genes in different tissues, different developmental stages, and between healthy and diseased states aiding both the determination of gene function and the development of new directed therapies.

There are other existing databases that offer the facility to compare gene expression data, such as the US Gene Expression Omnibus and the Swiss Genevestigator, but the Gene Expression Atlas is the most thoroughly annotated and curated resource so far. It has been developed from the EBI’s ArrayExpress and presents a subset of that database’s contents in an enriched form – essentially a meta-analysis - that is much more accessible to biologists who are not experts in the field of functional genomics arrays. A simple interface allows particular diseases, tissues or stages of development to be selected from drop-down menus and the expression patterns compared between them.

EBI say that they plan to continue expanding and improving the Atlas with a monthly release of new data and added features. The latest developments will be posted on the project blog.

8 July 2009The UK House of Lords Science and Technology Committee has published a new report, Genomic Medicine, the result of a long-running inquiry into recent advances in genomics and related fields and their implications for healthcare, the UK Government and the National Health Service (NHS). It calls for a new Government White Paper to update the 2003 Genetics White Paper, since rapid scientific developments have greatly widened the potential applications of genomics for health care from the earlier focus on the management of rare single-gene disorders to 'patient care across the NHS' (see press release). It is recommended that the new White Paper should include the Department of Health’s plans to facilitate the translation of genomic advances into mainstream clinical practice, including a long-term funding programme.

The overarching aim of the PHG Foundation is to drive the effective translation of genomic understanding and innovation into improved healthcare (see About us), including efforts to eliminate unnecessary delays in this process. Our submission of evidence to the House of Lords inquiry drew attention to the current lack of resources devoted to the essential final stages of clinical translation typified by the practice of public health genomics, including clinical and public policy development, service review and reorganisation, and health service staff education and training (see previous news).

The Committee recognises the existence of some of these barriers to translation within the NHS (see section 3.6 of the report), recommending that the National Institute for Health Research (NIHR) should make funding available specifically for research into the use of genomic tests within the NHS, and that the Office for Strategic Coordination of Health Research should outline a strategic vision to overcome translational barriers. The report also proposes that the NIHR should regularly monitor ‘developments in genomic medicine and their implications for the NHS now and in the future’ (see section 4.6), although whether a body whose function is to create and support health research can provide a suitably holistic overview of implications (for example, including ethical, legal, social, practical and clinical issues arising from new technologies) is debatable.

The PHG Foundation project Cell-free fetal nucleic acids for non-invasive prenatal diagnosis was cited by the report as an exemplar of the development, evaluation and implementation of new genetic technologies into healthcare (see submission of evidence on this issue) and our separate recommendations on the need for the development of new service models for the application of genomics in mainstream medicine duly noted. The Committee recommends that ‘the Secretary of State for Health should ensure that any necessary NHS operational changes, as a result of a shift in the provision of genomic services to mainstream medicine in the NHS, are implemented in the NHS’ and suggests that to facilitate this process ‘the Secretary of State should identify whether the NHS is fit to handle such changes and also what new service models are needed’ (see section 4.19).

Although their recommendations have a particular focus on translational research (as opposed to end-stage translation into clinical practice), the Committee does acknowledge that significant policy development and operational changes would be required to deliver equitable and cost effective genetics services, noting the need for updated commissioning procedures for new genetic tests, consolidation of laboratory services, and new efforts to integrate genetic information with other medical records and data.

With respect to genetic testing, the report recommends that the remit of the National Institute for Health and Clinical Excellence (NICE) should be extended ‘to include a programme for evaluating the validity, utility and cost-benefits of all new genomic tests for common diseases, including pharmacogenetic tests’ (section 3.38 of the report), referring to the requirement to assess clinical validity and utility in specific clinical pathways noted by the 2008 PHG Foundation / Royal College of Pathologists document The evaluation of diagnostic laboratory tests and complex biomarkers (see section 3.28 of the report). The report also considers in more detail concerns about privacy and issues surrounding the appropriate regulation of genetic tests (including direct-to-consumer tests), supporting the Human Genetics Commission’s intention to develop a voluntary code of practice for DCT providers and calling for this to include a requirement for firms to publish details of the effectiveness of the tests they offer.

The PHG Foundation will issue a formal response to the Genomic Medicine report in due course.

7 July 2009

The European Biobanking and Biomolecular Resources Research Infrastructure (BBMRI) was launched in February 2008 and aims to form a central computerised system linking the records of biological samples held in different research centres and biobanks across Europe (see previous news). It has recently completed a review of over 300 major European Biobanks, and is hoping to develop a prototype system which will allow European researchers access to a wide collection of quality-assessed samples and data by 2010 (see news story). Currently the infrastructure includes information from 51 participating institutes and 190 associated organisation representing 30 EU and associated countries. The prototype system will initially work with the most advanced biobanks that pose the fewest difficulties and add on others as they are ready.

A number of difficulties have to be overcome prior to creating a functional system. As data is being aggregating from a wide variety of systems, information about samples may have been collected differently and to different degrees depending on the country. Quality assessment of these samples, especially those which had been collected many years ago may be difficult due gaps in information about them. With regards to samples that will be collected in the future, and agreement has to be reached between all participating biobanks in order to ensure standardisation and harmonisation of sample collection procedures. According to the project managers a potential bottleneck may be the harmonisation of the varying ethical and legal requirements of the different Member states (see news story). Along with differences in interpretation of EU legislation, public attitudes may vary between countries. It is also likely that attitudes to research may change over time, meaning that the governance structure will have to be able to respond to future challenges. In order to gauge public perspectives on biomedical research, the BBMRI is conducting a focus group and has included questions about biobanking in the Eurobarometer survey which is conducted by the European Commission to monitor social and political attitudes.

 

 

1 July 2009Certain areas of stem cell research are dependent on a sufficient supply of human oocytes, for example for somatic cell nuclear transfer (SCNT). SCNT involves removal of DNA from the nucleus of an unfertilised egg and replacement with DNA from an adult cell and may aid in the generation of patient-specific stem cells to create replacement tissue, also known as therapeutic cloning (see previous news). Currently the main source of human oocytes for stem cell research is eggs left-over from in vitro fertilisation procedures but the number and quality of available oocytes is a limiting factor. Another source of oocytes is through the recruitment of women willing to donate their eggs for research; however, such endeavours have largely been unsuccessful. Earlier this month members of the Empire State Stem Cell Board (ESSCB), which advises the New York State Stem Cell program on matters of funding and ethics, adopted a resolution in favour of compensating women who donate their eggs solely for the purpose of stem cell research. They hoped this move would overcome the shortages of human eggs for research purposes.

The resolution allows reimbursements of up to $10,000 for “out-of-pocket expenses, including payments for travel, housing, medical care, child care and similar expenses incurred as a result of the donation of the oocytes for research purposes and compensated for the time, inconvenience and burden associated with the donation”. All reimbursements will have to be reviewed by the Embryonic Stem Cell Research Oversight (ESCRO) committee and the Institutional Review Board. The US National Institute of Health (NIH) in its guidelines recommends against reimbursing egg donors except for direct expenses incurred for the process. However, in the US women are compensated when they donate eggs for reproductive purposes, which have led the ESSCB to argue that “There is no principled reason to distinguish between donation of oocytes for reproductive purposes and research purposes when determining the ethicality of reimbursement”. Furthermore, they state “that a policy prohibiting reasonable payments because they may interfere with a woman’s ability to weigh the risks and benefits of donation is unnecessarily paternalistic”.

Comment: Harvesting human eggs for any purpose is an uncomfortable and potentially risky procedure; for example, ovarian hyperstimulation syndrome is a rare but potentially fatal complication. In countries such as in the UK, women who donate eggs solely for research are not paid, but may receive financial compensation for expenses incurred during the donation process (as well as loss of earnings - the latter being subject to a maximum of £250, around US $400 per cycle; see previous news). The situation is different in most US states, where women who donate eggs for research purposes are not compensated, whilst those who donate eggs for reproductive purposes are routinely paid, sometimes very substantial sums.

The statutory basis for reimbursement being limited in this way in the UK is Article 12(1) of the EU Tissue and Cells Directive (2004) which provides that Member States should endeavour to ensure that donations of tissues and cells are voluntary and unpaid but in default that "Donors may receive compensation which is strictly limited to making good the expenses and inconveniences related to the donation. In that case, Member States define the conditions under which compensation is paid". The question of reimbursement was discussed in the HFEA SEED report which was followed by public consultation and debate. Within the UK, there is no distinction made between those women who donate eggs for stem cell research and other types of research.

Some argue that it is unethical to compensate those who donate eggs solely for research, as it may encourage women to put themselves at risk with no immediate benefit. However, others argue that such a view is overly paternalistic and women can understand the risks associated with egg donation and make an appropriate decision. Altruistic egg donation for stem cell research is more of a contentious issue than for reproductive purposes (the intended result of which is the birth of a child), especially in countries where such research is still controversial. It is possible that ambivalent attitudes to stem cell research in the US accounts in part for the more generous level of reimbursement (compared with the UK) that is now available.

30 July 2009Numerous genome-wide association (GWA) studies have shown that single nucleotide polymorphisms (SNPs) in a region of chromosome 8q24 confer an increased susceptibility to both colorectal and prostate cancers. Resequencing of the region suggests that one particular SNP (rs6983267) may be the causal variant; the high-risk G allele of this SNP has a frequency of around 50% in individuals of European decent and 100% in populations of African origin, and confers a relative risk of around 1.2 in heterozygotes and around 1.5 in homozygotes. Like many susceptibility loci revealed through GWA studies, the SNP is located in a so-called gene desert, a region of the genome that contains no genes. Therefore, the biological mechanism underlying these associations has thus far been unclear.

 

Two new studies, published back-to-back in the journal Nature Genetics, use numerous complementary functional genomics approaches to uncover the role of 8q24 in the development of cancer. The first analyses the effect of rs6983267 upon the expression of the closest gene, which lies around 335 kilobases away and encodes the oncogenic transcription factor MYC [Pomerantz M. et al (2009) Nat Genet 41(8);882-4]. The team showed that, although the region containing rs6983267 is largely devoid of transcription, that the DNA itself physically interacts with the MYC gene and its promoter. Moreover, when this region of DNA was linked to a reporter gene, the G allele significantly increased the expression of the gene relative to the T allele. Both of these pieces of evidence, together with an analysis of the epigenetic modifications around 8q24, are consistent with the region acting as an enhancer, i.e. a stretch of DNA that literally enhances the transcription level of a gene (or genes) outside that region, often through binding and co-localising various proteins that are required for transcription.

 

The second study reports that genomic rearrangements only occur around the 8q24 region when the high-risk G-allele of rs6983267 is present [Tuupanen S et al. (2009) Nat Genet 41(8):885-90]. This results in a preferential copy number increase of the region during the development of colorectal cancer. They further showed that rs6983267 is part of a conserved binding site for TCF4, a transcription factor which is activated in most colorectal cancers, and that the G-allele substantially increases the affinity of this protein for the site. Therefore, through a complex set of signalling pathways, rs6983267 probably affects the expression of numerous genes and thus could be directly causal in the development of cancer.

 

Comment: The accompanying editorial suggests that these papers might offer a “general methodology to move from association to function” [Harismendy O & Frazer KA (2009) Nat Genet 41(8):868-9]. Following the identification of genetic variants that are associated with a particular disease (or trait) through GWA studies, functional characterisation of the associated genomic region is undertaken using a two-pronged approach: firstly, a bioinformatics analysis to assess the cross-species sequence conservation of the region and look for any predicted transcription factor binding sites; and secondly, laboratory experimentation to detect epigenetic modifications and assess the accessibility of the DNA in that region, as well as measure the activity of the region using in vitro and in vivo assays. Whilst this method does little to either support or refute the use of such genetic variants in susceptibility testing (see previous news), it will undoubtedly improve our understanding of gene regulation and the causal pathways underlying common disease.

24 July 2009

Huntington’s disease (HD) is a rare inherited autosomal dominant disorder cause by increased CAG repeats in the huntingtin gene leading to the production of mutant huntingtin protein. The accumulation of this mutant protein within the brain leads to selective loss of neurons in certain regions of the brain, most notably in the striatum. Neurodegeneration causes progressive cognitive and motor deficits that manifest most commonly between the ages of 35 and 44 years and is ultimately fatal. Although treatments are available to combat the psychiatric symptoms associated with this disease, there is no effective treatment to combat neuronal loss.

One possible method of inducing brain repair is through neural transplantation (i.e. grafting of healthy neural tissue in order to repopulate lost neurons), which was suggested as a possible treatment for HD in the 1990s following a number of experiments in rodents and primates which demonstrated the feasibility of this approach. These studies showed that embryonic striatal grafts were able to survive, induce behavioural recovery and establish connectivity in rodent brains. Several programs evaluating the safety, tolerability and potential efficacy of neural transplants were initiated and preliminary studies of neural transplants in patients with HD demonstrated 2-4 years of modest clinical benefits. However, this was followed by clinical deteriorations similar to the natural course of the disease.

In a paper published in the Proceedings of the National Academy of Science this week, Cicchetti et al. have analysed the brains of three people with HD who received fetal striatal-tissue transplants a decade before they died in order to determine why the transplants were not effective for longer [Cicchetti et al (2009) PNAS doi:10.1073/pnas.0904239106]. The brains were examined for the presence of the grafts, markers of projection neurons, abnormal huntingtin protein deposits and inflammatory cells. The study identified that loss of clinical benefit was due to damage and loss of the grafts, which had undergone disease-like neuronal degeneration even though they did not possess the genetic mutation causing HD. Previous studies had reported healthy graft survival at 18 months and 6 years post-tranplantation, suggesting that over the long-term graft survival is attenuated. This is thought to be as a result of the toxic environment to which the grafts were exposed, which itself is thought to be the mechanism by which neuronal loss of the host tissue occurs.

The authors conclude that future trials of fetal-cell transplantation are probably unwarranted, as the risks of the procedure and the disease-like graft degeneration outweigh its benefits, which are short term and mild. They suggest a better approach would be strategies aimed at altering the inflammatory or immune responses, host-derived neurotoxicity, and providing neurotrophic support in order to encourage growth and differentiation of new neurons and survival of existing ones, all of which may still be based on neurotransplantation.

22 July 2009 The association between different alleles of the apolipoprotein E (APOE) gene and an increased susceptibility to late-onset Alzheimer’s disease (AD) has been known for more than 10 years. The relative risk of developing AD increases around 4-fold for individual’s with a single copy of the ApoE4 variant (approximately 25% of the population), and around 12-fold for those with two copies (less than 1% of the population, see previous news). However, a test for APOE status is not useful for predicting for who will actually develop the disease.

A recent publication reports a study examining the effect of genotype disclosure of APOE status, in adults who had a parent with AD, on levels of anxiety, depression and test-related stress [Green RC et al. (2009) N Eng J Med 361(3):245-54]. This New England Journal of Medicine paper builds on earlier research conducted by the same group in the Risk Evaluation and Education for Alzheimer’s disease (REVEAL) study (see previous news).

In their previous study [Roberts JS et al. (2004) Genet Med 6(4):197-203], the group conducted a randomised control trial (RCT) examining both the uptake and impact of genetic risk susceptibility testing for AD. As part of the randomisation process, individuals were assigned to two groups, one in which APOE status was disclosed (n=111), the other without APOE disclosure (n=51). Preliminary results indicated that the vast majority of RCT participants did not experience adverse psychological effects. In their more recent paper, the data support no statistically significant differences between the two disclosure groups in terms of changes in time-related measures of anxiety, depression or test-related stress. Unsurprisingly, baseline scores for anxiety and depression were strongly associated with post-disclosure scores of these measures.

Comment: People with a family history of AD are already at a higher risk than those without. Would testing for genetic predisposition to this disease cause further anxiety, depression or any other type of distress? APOE testing is not currently recommended for asymptomatic persons, partially due to its limited clinical utility and partially due to concerns over the emotional effects of the genetic-risk assessment. This study suggests that there are no short-term psychological risks associated with APOE genotype disclosure. However, due to the short-term nature of the evaluations conducted (after 6 weeks, 6 months and 1 year), it is possible that persons in the disclosure group testing positive for the risk allele may react to this information many years later and so, as noted by the study authors, larger studies with longer periods of follow-up are required to investigate any long-term effects. The participants in this study are also quite a select group in that they are a well educated, high socioeconomic status group interested in this research with genetic counselling provided throughout the study. Individuals with low scores in the depression and anxiety tests were excluded from this study meaning that the results are not generalizable to the public. Moreover, no distinction is drawn beween heterozygotes and homozygotes for the ApoE4 variant, which given the large difference in relative risk between them, could substantially affect the phsychological impact of the result. Nonetheless, the greatest value derived from this study is the empirical data which starts to provide evidence that genetic tests (with appropriate counselling) do not cause serious psychological harm and thus should not be treated any differently to other medical tests.

20 July 2009Cancer is a disease of genomic alterations; genetic mutations, epigenetic changes, copy number variations, and chromosomal rearrangements all contribute to the development and progression of malignancies. Nowhere is this more apparent than in glioblastomas – the deadliest of all brain tumours – which exhibit a diverse pattern of genetic alterations. Two studies, published back-to-back in the Journal of the American Medical Association (JAMA), apply a combination of genetic, epigenetic and functional genomics approaches to uncover some of the key genetic changes that cause the disease.

Bredel et al. hypothesise that, rather than being driven by separate mutations in independent genes, glioblastoma is caused by a network of interacting genetic changes working together [Bredel M et al. (2009) JAMA 302(3):261-275]. By examining changes in gene dosage (i.e. copy number) and gene expression (i.e. RNA levels) across the genome in over 500 glioblastoma samples, a network of highly connected “hub” and “hub-interacting” genes was identified, which act cooperatively to promote tumour formation. The prognostic ability of a multigenic risk model based on just seven of these “hub” genes was then tested in over 500 patients with glioblastoma, indicating a significant association with survival.

Yadav et al. extended this work by looking at just two of the putative interacting partners from this network: epidermal growth factor receptor (EGFR) and annexin 7 (ANXA7) [Yadav AK et al.(2009) JAMA 302(3): 276-289]. The former is frequently found to be over-represented and the latter under-represented in glioblastoma cells, due to frequent copy number gains or losses in the respective chromosomal regions. Using small inhibitory RNA to turn off the ANXA7 gene in glioblastoma cells in the laboratory caused a concomitant increase in the level of EGFR; moreover, the tumour forming capacity of the cells was significantly increased in cells engineered to under-express ANXA7 and over-express EGFR, indicating synergism between the two gene products.

Comment: As is highlighted in an accompanying editorial [Pasche B & Myers RM (2009) JAMA 302(3):325-326], these complex and multidimensional studies have several important clinical implications for our understanding of cancer biology. Firstly, the work showcases the application of multiple different and complementary technologies to investigate the aetiology of disease. Secondly, it highlights the role of networks of interacting gene products in the development of disease, which may suggest novel therapeutic strategies. Thirdly, it underscores the importance of altered gene dosage and gene expression (rather than changes in sequence) in the development of cancer. And finally, it links basic research to the development of multigenic prognostic tools, which have now been reported for numerous cancers and may play an important role in guiding therapeutic interventions and providing advice in the future.

12 July 2009 A recent publication reports on a study to assess the value of genetic testing for the mutations most commonly associated with increased susceptibility to thrombosis in prevention. The JAMA paper summarises the findings of research by the US Agency for Healthcare Research and Quality (AHRQ) on behalf of the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) initiative. Venous thromboembolism (VTE) is a term for clots in the blood vessels, typically deep-vein thrombosis (DVT) and the life threatening complication pulmonary embolism. Factor V Leiden (FVL) and prothrombin G20210A are the most common mutations known to be associated with increased susceptibility to DVT, and genetic tests for these variants are among the most commonly performed genetic tests (see previous news); however, their clinical utility has long been contested.

The study examined previously published data relating to the rates of VET among the family members of adult individuals with a knowna FVL or prothrombin G20210A mutation, and whether the testing of adults with VTE for these mutations improved their clinical outcomes [Segal JB et al. (2009) JAMA. 2009 301(23):2472-85]. The presence of one or two FVL alleles was found to be predictive of recurrent VTE for individuals and their family members (compared with VTE patients without the FVL mutation). However, heterozygosity for the relatively rare prothrombin G20210A mutation was not found to be predictive of recurrent VTE, and there was insufficient evidence to determine whether homozygosity for this mutation was predictive of recurrent VTE.

Lack of evidence was a general problem; the reviewers concluded that there was good evidence to support the assertion that treatment with anticoagulants (such as warfarin) reduced the probability of recurrent VTE in individuals with previous VTE and an identified FVL orprothrombin G20210A mutation. There was weaker evidence suggesting that the benefit was similar to that in individuals with previous VTE but no such mutations. However, there were no studies that assessed whether genetic testing for FVL or prothrombin G20210A in family members of those individuals improved outcomes in terms of reducing their risk of developing VTE.

Comment: Referring to the research, AHRQ Director Carolyn Clancy commented: “While genetic testing shows great promise to improve treatment and prevent disease, this report clearly shows that we need more research and evidence to achieve its full potential" (see press release). However, whether in fact genetic testing for either the FVL or prothrombin G20210A mutations has any clinical benefit at all even in VTE patients remains non-proven, let alone in family members. The authors suggest rather hopefully that “If testing is done in conjunction with education, it may increase knowledge about risk factors for VTE”, but more practically call for prospective randomized trials to reliably determine whether or not testing has any influence on clinical outcomes. Meanwhile, millions of genetic tests for FVL are performed worldwide annually – perhaps not the best example of evidence-based genetic medicine.

6 July 2009Schizophrenia is a complex psychiatric disease, with both environmental and genetic factors implicated in its development. Three large-scale international collaborative research studies by the International Schizophrenia Consortium (ISC), the SGENE-plus consortium (see previous news) and the Molecular Genetics of Schizophrenia (MGS) consortium, published in the Journal Nature, conducted genome-wide association studies (GWAS) in order to identify further genetic variants associated with schizophrenia (see previous news).

The ISC [International Schizophrenia Consortium (2009) Nature July 1 doi:10.1038/nature08185] conducted a GWAS of 3,322 cases and 3,587 controls. The most strongly identified association was on chromosome 22, located within the first intron of the MYO18B gene (P = 3.4 x 10-7), a candidate tumour suppressor gene. The second strongest association was made up by 450 SNPs within the major histocompatibility complex (MHC) on chromosome 6p (P = 3.7 x 10-7). The SGENE-plus [Stefansson et al. (2009) Nature July 1 doi:10.1038/nature08186] conducted a GWAS of 2,663 cases and 13,498 controls. This study also identified an association with the MHC region (strongest P-value = 2.3 x 10-4) and when combined with additional follow-up samples (4,999 cases and 15,555 controls), further strengthened the association identified in the MHC (strongest P-value = 4.4 x 10-9). The MGS consortium [Shi et al. (2009) Nature July 1 doi:10.1038/nature08192] conducted a GWAS of 2,681 cases and 2,653 controls of European-ancestry and 1,286 cases and 973 controls of African-American ethnicity. The strongest association identified was on chromosome 2q37.2 in the European-ancestry sample (P = 4.59 x 10-7) and chromosome 2q34 in the African-American sample (P = 2.14 x 10-6). However, when the European-ancestry data were combined with data from the ISC and SGENE-plus studies in a meta-analysis (8,008 cases and 19,077 controls), seven SNPs in the MHC region showed significant association (strongest P-value = 9.54 x 10-9).

Comment: By exchanging their GWAS summary results, these three large consortia were able to verify each other’s results, showing a statistically significant association between schizophrena and the MHC region. Due to the strong linkage disequilibrium within the MHC, as well as the gene-rich nature of this region, much work remains to identify the cause of any true association, with much larger samples and resequencing technology needed. Larger samples are also required to detect (and understand the causal nature of) further common (and potentially rare) gene variants that contribute to the underlying genetic risk of schizophrenia. The association with the MHC also supports previous hypotheses regarding the role of the immune system in schizophrenia.

3 July 2009With a view to keeping track of enormous amount of research into the genomics of complex diseases that has arisen in the last few years, the US National Human Genome Research Institute has launched an online catalogue of published  genome-wide association studies (www.genome.gov/gwastudies). The curated, searchable and publically accessible database contains information on over 350 publication, linking around 1,640 single nucleotide polymorphisms (SNPs) to more than 80 different diseases and traits.

 

This catalogue allows some of the trends and genomic characteristics of trait or disease associated SNPs to be analysed across multiple different publications [Hindorff LA  et al. (2009) PNAS doi/10.1073], leading to a number of important insights. The effect sizes are generally small (odds ratios of less than 1.5) and, unlike genes associated with Mendelian disorders, the vast majority of genetic variation associated with complex diseases or traits lies outside of the coding regions of the genome – 45% of SNPs are located inside introns, which are located within genes but are spliced out prior to translation into functional proteins, and 43% of SNPs lie between genes. Whilst in some ways this result is unsurprising, as coding genes only account for around 1% of the genome, it is still unexpected and suggests that regulation of gene expression plays an important role in determining common traits and diseases.

 

Interestingly, amongst those associations that have been attributed to specific genes (which are located near the trait or disease associated SNPs), 18 regions have been linked with multiple different diseases, suggesting a common underlying aetiological pathway. For example, the major histocompatibility complex (MHC), which plays an important role in the immune system, has been implicated in 10 different conditions ranging from autoimmune disorders to lung cancer. Discoveries of a shared underlying genetic basis for different diseases are likely to become increasingly common as more gene-disease associations are uncovered, and raise a complex set of ethical implications with regards to genetic testing (see previous news).

 

2 July 2009Genetics. The promise of a cure: 20 years and counting
Couzin-Frankel J. Science. 2009 Jun 19;324(5934):1504-7.

Clinical practice. Prenatal screening for aneuploidy.
Driscoll DA, Gross S. N Engl J Med. 2009 Jun 11;360(24):2556-62.

Genetic discrimination in Huntington's disease.
Tibben A. BMJ. 2009 Jun 9;338:b1281. 

Are electronic health records ready for genomic medicine?
Scheuner MT, de Vries H, Kim B et al. Genet Med. 2009 May 27.

Potential etiologic and functional implications of genome-wide association loci for human diseases and traits
Hindorff LA, Sethupathy P, Junkins HA, et al. PNAS 2009 Jun 9;106(23):9362-7.

The genetic contribution to non-syndromic human obesity.
Walley AJ, Asher JE, Froguel P. Nat Rev Genet. 2009 Jul;10(7):431-42.

From DNA sequence to transcriptional behaviour: a quantitative approach.
Segal E, Widom J. Nat Rev Genet. 2009 Jul;10(7):443-56.

Understanding what determines the frequency and pattern of human germline mutations.
Arnheim N, Calabrese P. Nat Rev Genet. 2009 Jul;10(7):478-88.

Challenges of translating genetic tests into clinical and public health practice.
Rogowski WH, Grosse SD, Khoury MJ. Nat Rev Genet. 2009 Jul;10(7):489-95.

Genetics of psychosis; insights from views across the genome.
O'Donovan MC, Craddock NJ, Owen MJ. Hum Genet. 2009 Jun 12.

The brain collector

Miller G. Science. 2009 Jun 26;324(5935):1634-6.

Population Screening for Genetic Disorders in the 21st Century: Evidence, Economics, and Ethics.
Grosse SD, Rogowski WH, Ross LF et al. Public Health Genomics. 2009 [Epub ahead of print]

Confidentiality and sharing health information
Sheather J. BMJ. 2009 Jun 15;338:b2160.

HFE-associated hereditary hemochromatosis.
Alexander J, Kowdley KV. Genet Med. 2009 May;11(5):307-13.

Narcolepsy and the T-cell receptor
Vyse TJ. Nat Genet. 2009 Jun;41(6):640-1.

Stem-cell clarity
Nature. 2009 Jun 4;459(7247):615-6. N

Science innovation. Assessing the impact of science funding
Lane J. Science. 2009 Jun 5;324(5932):1273-5.

The sharing principle
Nature. 2009 Jun 11;459(7248):752.

Science has a special edition on stem cells including reviews, prospects for clinical translation and US regulation:

Steps to the clinic.
Purnell BA, Hines PJ. Science. 2009 Jun 26;324(5935):1661.

FDA Regulation of Stem Cell–Based Products
Fink DW Jr. Science. 2009 Jun 26;324(5935):1662-3.

Medical Innovation Versus Stem Cell Tourism
Lindvall O, Hyun I. Science. 2009 Jun 26;324(5935):1664-5.

The Increasing Complexity of the Cancer Stem Cell Paradigm
Rosen JM, Jordan CT. Science. 2009 Jun 26;324(5935):1670-3.

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