News

25 June 2008The American Medical Association (AMA), the largest physician group in the US, held its Annual Meeting this month; among the policies adopted were recommendations relating to direct-to-consumer (DTC) advertising and provision of genetic tests (see press release). The AMA recommended that genetic testing should be carried out under the supervision of a qualified health care professional and physicians be provided with more information on the types of genetic tests available so that patients can be appropriately counselled on the potential harms. They also recommend that appropriate organizations should be encouraged to develop criteria for the advertising of DTC genetic tests. The American College of Medical Genetics released a policy statement in April containing similar views and similar recommendations have been made by a number of other organisations (see previous news).

The number of DTC genetic tests is steadily increasing and the clinical utility of these tests and the extent to which the public and clinicians are able to understand the information generated by them is unclear. Such concerns have led some states in the US such as New York and California to clamp down on companies which provide DTC genetic tests (see previous news). Health regulators in California have recently asked companies to halt sales of genetic tests until they prove that they have met state standards; among which is the requirement for the test to be ordered by a doctor (reported by the Guardian). 

In order to gain a better understanding of the value of genetic tests, the Coriell Institute for Medical Research in New Jersey, has launched a project whose goal is “to better understand the coming impact of genome-informed medical practice and to guide its ethical, legal and responsible implementation”. The Corriel Personalized Medicine Collaborative will offer free genetic testing to 10, 000 local volunteers and provide them with information about their risk of a number of condition (see news source). The information reported back to participants will not be as extensive as that provided by private companies, but will be restricted to information which is deemed by an advisory board to be medically actionable, as such the risk to conditions like Alzheimer’s disease which cannot be altered by lifestyle or medical interventions will not be revealed. In addition, a web portal allowing participants to share this information with their physician if they wish and containing educational material will also be launched. It is hoped that through this project the clinical utility of genetic susceptibility testing can be examined together with understanding the steps needed to incorporate them into clinical practice.

23 June 2008A recent front page article describing a risk-free blood test for Down syndrome in pregnancy (see The Times, 21st June) has generated considerable online discussion, primarily centring on the worth of individuals with Down syndrome and the ethics of abortion.

 

The technique in question detects cell-free fetal nucleic acids (DNA and RNA), from the placenta, which can be extracted from maternal blood from around 7 weeks gestation to determine the genetic status of the fetus. There are a number of potential applications of the technique for antenatal care in addition to testing for Down syndrome, including sex determination (for families with inherited sex-linked diseases), diagnosis of certain single gene disorders, and blood Rhesus factor status (in the case of Rhesus D-negative mothers).

 

A number of different methods have been developed for non-invasive prenatal diagnosis (NIPD) of Down syndrome based on cell-free fetal nucleic acids. Perhaps the most promising method detects circulating RNA from genes that are only expressed during pregnancy by the placenta [Lo et al. Nat. Med. (2007) 13: 218-213]. Recently, the company Sequenom® announced that it has achieved 100% accuracy in a trial of 200 clinical samples (see press release), although much larger trials will be needed to definitively establish the clinical validity of the test relative to the current gold standard.

 

Whilst the article itself provides an informative overview, much of the public debate has focused on the ethical questions raised by this technique in isolation, rather than in comparison with current Down syndrome screening programmes. In the UK, pregnant women are routinely offered a battery of blood screening tests for different purposes, one of which is to assess their risk of carrying a fetus with Down syndrome. Test results are combined with maternal age to estimate this risk, and women at high risk are offered an invasive procedure to sample fetal cells (normally amniocentesis) for diagnostic testing during the second trimester. However, the screening tests are only accurate in around 85% of cases, and the subsequent invasive diagnostic test is not only unpleasant for the mother, but also results in miscarriage in around 1% of cases. Some women therefore opt out of diagnostic testing because of the risk to a potentially unaffected fetus.

 

NIPD for Down syndrome should be looked at simply as a replacement technology, in which diagnosis (rather than risk prediction) is achieved earlier in pregnancy and without risk to health of the fetus. Key ethical issues are therefore centred not on whether or not offering testing for Down Syndrome is acceptable – current UK practice is based on the assumption that it is, although any woman can choose not to undergo testing – but rather the differences that NIPD would make relative to the current status quo. By offering early non-invasive diagnosis, as opposed to later risk assessment and the option for invasive diagnosis, will the relative ease of such a test result in more terminations of Down syndrome fetuses? Will there be increased social pressure to have the test and terminate the pregnancy if it is positive? What will be the effect of direct-to-consumer testing?

 

Comment: The PHG Foundation is currently undertaking a project on NIPD, looking at the technical issues and the ethical, legal and social implications of each of the applications of cell-free fetal nucleic acids. The project was commissioned by the Joint Committee for Medical Genetics and is being led by an expert steering group in conjunction with a working group of wider stakeholders. The project seeks to identify barriers to implementation of this technique within the NHS, and highlight the wider implications of NIPD both for the health service itself and to the public at large. The report is expected to be available by early 2009, following a second meeting of the working group in September 2008.

20 June 2008A new Canadian biobanking initiative has been launched by the Canadian Partnership Against Cancer, a federally- funded independent organization; the prospective cohort study aims to recruit 300,000 Canadians aged between 35 and 69, and follow them for the next 20-30 years while collating biological specimens including blood and urine, along with information on health and lifestyle factors. The intention is to recruit participants in a random fashion rather than calling for volunteers, although there will be a degree of self-selection since individuals invited to participate may not choose to do so.

The Canadian Partnership for Tomorrow Project intends to investigate the role of genetic, environmental, and behavioural factors in the development of cancer, although the data will also be applicable for to the study of other common complex diseases. Phillip Branton, head of the Canadian Institutes of Health Research's Institute of Cancer Research, reportedly said that the initiative is intended to fit in with other international biobanking studies and commented: "One of the biggest questions to be tackled is, who are the people first at risk for cancer as diets and lifestyles rapidly change in different societies?"(see Science news). The impact of public health screening and prevention programs will be assessed, and possible patterns of common factors among people who develop cancer sought. It is hoped that the project will be facilitated by the centralized public health systems in the Canadian provinces that are capable of handling large volumes of data.

In addition to $42 million funding from the Canadian Partnership Against Cancer, the project is supported and funded by five key partner organizations: the BC Cancer Agency; the Alberta Cancer Board; Cancer Care Ontario and the Ontario Institute for Cancer Research; Quebec’s CARTaGENE project (see previous news); and Cancer Care Nova Scotia with Dalhousie University. These regional groups have committed an additional total of $41 million in funding.

20 June 2008An independent report on the social and ethical challenges associated with research into synthetic biology has been published this month (see press release). The report, ‘Synthetic Biology: social and ethical challenges’, has been written by Andrew Balmer and Paul Martin of the Institute for Science and Society at the University of Nottingham and was commissioned by the BBSRC’s Bioscience for Society Panel.

The report begins by giving an overview of synthetic biology and summarising the main areas of research in this field. It then goes on to review the main social and ethical issues raised in public debate and the corresponding policy responses. The key issues were identified as uncontrolled release, bioterrorism, patenting and the creation of monopolies, trade and global justice and creating artificial life. The authors concluded that a number of questions need to be addressed by the government, research funders and the scientific community in order for effective governance of synthetic biology. They also recommend early public engagement in order to ensure that the technology does not get ahead of public attitudes and the potential benefits are not overhyped. In addition, they recommend a review of existing controls and regulations in order to ensure a robust governance framework is in place prior to introduction of the applications of synthetic biology.

The BBSRC is working with sister research councils in order to address the ethical and regulatory issues that may arise as a result of synthetic biology research; they are considering the recommendations in the report and will use its conclusions to inform policy in this area. The Royal Society is also involved in addressing policy issues in relation to synthetic biology and called for views on this subject in July 2007 (see previous news).

18 June 2008The Association of British Insurers (ABI) announced last week that a temporary moratorium on the use of genetic test results will be extended until 2014 (see BBC news). The moratorium, first established in 2001 (see previous news) and revisited in 2005 (see previous news), allows consumers to obtain insurance for themselves and their families without having to disclose adverse results of predictive genetic tests that might indicate a risk of serious disease in the future. The announcement follows a recent review of the moratorium; the next review will take place in 2011.

The moratorium applies to life insurance policies worth up to £500,000, critical illness coverage up to £300,000 and income protection of up to £30,000, comprising about 97% of insurance policies sold (see press release). Even above these thresholds, insurers are not permitted to ask for results of genetic tests unless they have been specifically approved by the Government’s Genetic and Insurance Committee (GAIC); the only test approved by GAIC so far is that for Huntington’s disease. This  condition is unusual in that the probability of eventually developing the disease is almost 100% for  individuals with a positive test result, whereas the presence of most disease-associated mutations is associated with rather lower probabilities of ever developing the disease (such as breast or ovarian cancer for individuals with BRCA1/2 mutations).

The moratorium came about as a result of a concern that the significance of genetic test results for life expectancy or onset of disease might be exaggerated by insurers and could lead to genetic discrimination. Although the ban is supported by the ABI and was recommended by the Human Genetics Commission (see previous news), some experts do not agree with it on grounds that the information generated by genetic tests is just like any other medical information and its disclosure to the insurers should not be prevented [Holm, S. (2008), BMJ, 334(7605):1196].

16 June 2008The British Fertility Society (BFS) has published new guidelines on the use of preimplantation genetic screening - PGS (see BBC news). PGS involves testing cells removed from early embryos produced during in vitro fertilisation (IVF) to detect chromosomal abnormalities prior to implantation. Embryos with chromosomal abnormalities can appear normal during the early stages of development; however, following implantation they may not develop properly leading to a reduction in the chances of a successful pregnancy. Currently, the Human Fertilisation and Embryology Authority (HFEA) allows clinics to use this procedure to treat older women, those who have had several unsuccessful IVF attempts and those who have had several miscarriages.

The new guidelines produced by the BSF are published in the journal Human Fertility following a review of published research on the safety and success rates of PGS. The lack of robust evidence in favour of PGS has led the authors to recommend that it should “preferably be offered within the context of well-designed randomised trials performed in suitably experienced centres” (see press release). The guidelines also state that clinicians should inform patients about the lack of evidence and recommend that further research be carried out to assess the safety and efficiency of this procedure. They stress that these guidelines refer to preimplantation genetic screening and not preimplantation genetic diagnosis (PGD), which is a specific test, offered to patients who are at a high risk of transmitting a known genetic disorder to their child.

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12 June 2008The Human Fertilisation and Embryology Bill received considerable media and Parliamentary coverage in May as members of the House of Commons spent two days debating its most contentious clauses on which they had been given a free vote. Gordon Brown briefed Labour members of Parliament in advance by letter which set out utilitarian arguments in favour of the proposed legislation, suggesting that Britain’s ongoing support for stem cells was ‘not only in our own interest, but also the global interest’. Despite speculation that a government defeat might be imminent, in a debate on 19 May there was support for the legislation with many MP’s justifying these advances on the basis of their potential for developing effective treatments in the future. The majority of MP’s supported clauses to allow the creation of human admixed embryos within a tightly regulated research environment.

They also supported the selection of embryos which could be used to treat siblings affected by a serious genetic condition, (so called ‘saviour siblings’). In responses to questions about the scope of this clause, the Minister of State for Health, Dawn Primarolo acknowledged that the Human Fertilisation and Embryology Authority (HFEA) had licensed more than 80 conditions for pre-implantation genetic diagnosis including Huntington’s disease, muscular dystrophy and cystic fibrosis and that the selection of diseases which could qualify as ‘serious’ and utilise the techniques described in the Bill was a matter for the HFEA’s ethics committee. In the same debate, Dawn Primarolo also signalled the prospect of further regulation concerning the use of stem cell lines for treatment rather than research, acknowledging that the regulatory oversight by the HFEA ‘finishes once a stem cell line is derived’. Interim guidance has been published by the Human Tissue Authority.

The House of Commons also supported changes to the Human Fertilisation and Embryology Act 1990 to require clinicians to consider the need of any child born as a result of assisted reproduction to have supportive parenting (which replaces an explicit requirement to consider the need for a father). The Bill was also used as a vehicle to debate the ethics of abortion. One contentious area was the extent to which the time limit for certain types of abortion (excluding those carried out on grounds of fetal disability) should be reduced from the current limit of 24 weeks. It was argued that care of premature babies had improved and some evidence suggested that babies born at 22 or 23 weeks had improved viability. After considerable debate, MP’s voted for existing time limits to be retained.

In subsequent committee debates in the House of Commons, the Bill has been further amended to set out the basis for using cells from those lacking capacity (either as children or adults) or where the donor can no longer be identified or has died. These amendments are in line with the legislative framework laid down by the Mental Capacity Act 2005 and the Human Tissue Act 2004. With the House of Commons committee stage due to be completed by 17 June, one might expect the Bill to receive Royal Assent before Parliament breaks for the summer recess (22 July) although no dates have yet been published.

4 June 2008Scientific progress requires the use of clear and standardised terminology by different stakeholders such as academia, industry, government and regulators. This month saw the publication of guidelines for describing genomes and metagenomes by the Genomic Standards Consortium (GSC), as well as publication of guidelines on terminology used in regenerative medicine by the British Standards Institute (see press release).

The GSC is an open membership international body bringing together researchers in varied fields ranging from ecology to computer science. Their aim is “to promote mechanisms that standardize the description of genomes and the exchange and integration of genomic data”. In an article published in Nature Biotechnology, Field et al. describe the necessity of standardised descriptions and propose mechanisms for providing this information as well as its implications for genetic databases [Field et al. (2008) Nat. Biotech. doi:10.1038/nbt1360]. The minimum information about a genome sequence (MIGS) specifies a formal way to describe genomes and metagenomes and extends the minimum information already available in genomic databases such as The International Nucleotide Sequence Database Collaboration (INSDC). Information requested by MIGS relate to the geographical location, sampling date and experimental methods used to gain the genomic data amongst others; thereby allowing it to be used in comparative genomic analysis and to gain a better understanding of the source of each genome. The GSC hopes that MIGS specification will promote discussion and solicit further feedback from the community, its ongoing efforts include an open call for participation and collection of MIGS reports and vocabulary terms for use in the description of genomes and metagenomes.

The Publicly Available Specification (PAS) published by the BSI: PAS 84 – Regenerative medicine is a glossary explaining terminology in regenerative medicine and defines over 200 terms such as “tissue bank” and “cell authenticity”.  This glossary supports and build on the terminology in PAS 83 - Guidance on codes of practice, standardised methods and regulations for cell-based therapeutics – from basic research to clinical application and is intended to help UK stakeholders to:

• Facilitate a common understanding of the science of regenerative medicine
• Prepare for legal, commercial and societal issues
• Improve communication and understanding of the science of regenerative medicine
• Demonstrate best practice and product quality
• Reduce research, development, production and transaction costs

Comment: As scientific research progresses and produces increasing quantities of raw data (particularly in areas such as genomic and post-genomic research), standardised terminology allows efficient and effective communication between stakeholders. They are also important for the development of easily accessible and interoperable databases as well as regulatory guidelines, both at the international and national levels. Moves such as those described here are likely to become increasingly common as the number of international collaborative research initiatives continue to rise.

30 June 2008A second major common susceptibility allele has been discovered for increased risk of Alzheimer’s disease [Dreses-Werringloer U. et al. (2008) Cell 133: 1149-1161], through a combination of epidemiological studies, bioinformatics and molecular biology.

 

Although the aetiology of Alzheimer’s disease is complex, the presence of clumps of amyloid precursor protein (APP) – known as amyloid plaques – is common to all sufferers of the disease, and is believed to be related to neurodegeneration. Whilst a number of genetic causes of the rare familial early-onset form of the disease have been identified (including mutations in APP itself and the presenilin enzymes involved in processing it), the much more common late-onset Alzheimer's disease is caused by a complex interplay between numerous genetic and environmental factors (see Bird TD (2008) Genet Med. 10(4):231-239 for a review).

 

Currently, only one common genetic allele with a substantial effect on Alzheimer’s disease risk has been verified. The APOE gene, more commonly associated with cardiovascular disease risk, is thought to play a role in clearing amyloid protein from the brain, possibly through its interaction with cholesterol. The disease risk associated with this gene remains one of the largest known for a complex disease; the APOE e4 allele (present in 15% of the population) increases the risk of late-onset Alzheimer’s disease by threefold for a single copy and up to 12-fold when two copies are present (see previous news). Several other genes are currently under investigation and many more are expected to be uncovered through an extensive genome-wide association study of 14,000 samples currently underway in the UK (see previous news).

 

The new gene proposed in this study – calcium homeostasis modulator 1 (CALHM1) – is located on a region of chromosome 10 that has previously been linked with Alzheimer’s disease (see previous news). It encodes a calcium ion channel protein present on the cell surface of neurons and is believed to be involved in controlling the cellular concentration of calcium ions, which is critical for the regulation of APP processing. Combined case-control studies, with a total of 3404 participants, indicate that a common polymorphism located within in the coding region of the gene has an overall allele-specific odds ratio of 1.44, resulting in approximately double the risk of disease when two copies are present. Like the APOE e4 allele, the high risk allele of CALHM1 is also associated with an earlier age of onset of the disease.

 

Comment: According to the Alzheimer’s Society, most of the current 700,000 people in the UK with dementia have late-onset Alzheimer’s disease, and the disease is becoming an ever increasing burden upon the health system and society at large as the population ages. There is therefore an urgent need to elucidate the underlying mechanisms of the disease, and the novel multi-disciplinary methods used in this study may play a crucial role towards that end. Although there is currently no way to prevent or cure the disease, it is hoped that identifying genetic factors associated with Alzheimer’s disease will help to identify those at highest risk, and ultimately to design better preventative and therapeutic strategies. However, translation of this hard-earned scientific knowledge into tangible clinical benefits is likely to take years of further research and development.

27 June 2008A paper in the British Journal of Cancer presents evidence that male carriers of mutations in the BRCA1 or BRCA2 genes (associated with hereditary breast-ovarian cancer syndrome) are not only at five-fold increased risk of prostate cancer compared with the general male population, but also show much more rapid disease progression [Narod SA et al. (2008) Br J Cancer. Jun 24. Epub ahead of print]. This work replicates earlier findings by Icelandic researchers who found a significantly reduced survival for a smaller group of male BRCA2 mutation carriers with prostate cancer [Tryggvadottir L et al. (2007) J Natl Cancer Inst. 99(12):929-35.]

The researchers identified prostate cancer patients from a panel of almost 2700 families with a BRCA1 or a BRCA2 mutation. They compared the median survival times after diagnosis of the 119 men who were “known or probable carriers of a BRCA1 mutation” with 183 men who were ”known or probable carriers of a BRCA2 mutation”. The two groups showed a similar age at diagnosis but median survival time was 8 years for BRCA1 carriers and 4 years for BRCA2 carriers. This compares with an average survival of twelve years from diagnosis for prostate cancer patients in general. Repeat analysis including only the confirmed mutation carriers found a median survival time of 15 years for BRCA1 carriers (37 in total) and 5 years for BRCA2 carriers (67 in total).

Referring to men with BRCA2 mutations, Dr Lesley Walker, of the charity Cancer Research UK, commented: "It is important that more research is done in this area to ensure that this group is targeted effectively so cancer is picked up at an early stage and, more importantly, that they are given the most appropriate treatment” (see BBC news). Confirmed male mutation carriers should receive increased levels of PSA screening for prostate cancer, from an earlier age than the general population.

Comment: Improved understanding of genetic predisposition to cancers can refine screening strategies and improve survival for high risk groups without imposing excessive screening on those at lower risk. This is an important example of public health genomics in practice. Such information may also be important for clinical management of cancer patients.

The researchers acknowledge limitations to this study, notably the relatively small sample size and the lack of a control group of non-mutation carrier prostate cancer patients. They do, however, note that the ten-year death rate of prostate cancer patients has been reported as 27-32% compared with 75% for the BRCA2 carriers in their own study. It is proposed that a larger study should investigate the prognosis of BRCA2 mutation carrier prostate cancer patients and their response to alternative treatments, in particular whether they might benefit from specially targeted chemotherapeutics.

26 June 2008New research published in the New England Journal of Medicine suggests that testing individuals for their genetic risk for breast cancer could play an important role in population screening [Pharoah PDP et al. (2008) NEJM 358(22): 2796-2803].

 

The research focussed on just seven common breast-cancer susceptibility alleles that have been well validated through genome-wide association studies (excluding rare genes that are responsible for familial breast cancer risk, such as BRCA1/2 and TP53). Although the risk conferred by each individual locus is small (relative risk of less than 1.3), by modelling the combined effect of multiple risk alleles using a simple multiplicative model, and converting that information into an absolute risk over a specified time period, a woman’s overall risk of breast cancer can vary approximately sixfold.

 

The results suggest that risk profiling based on genetic susceptibility is not clinically useful at an individual level, as it does not provide sufficient discrimination to warrant personalised prevention. However, it may be valuable for stratifying the population in order to target screening programmes more effectively; the authors state that “the efficiency of population-based preventative programs such as mammography could be improved by targeting women who are at the greatest risk for breast cancer according to genotype”. For example, the NHS currently offers screening to all women at the age of 50, when their 10-year risk of breast cancer is around 2.3%. If genetic screening were used to stratify this population, around 20% of women would be classified as low risk and never reach this threshold value (due to the effects of competing mortality), and therefore should not be compelled to go for screening, whilst the top 5% of women at highest risk would reach the threshold value at only 41 years of age.

 

The paper is accompanied by an editorial [Hunter DJ, et al. (2008) NEJM 358(22): 2760-2863], which provides an overview of the process of finding new gene-disease associations through systematic genome-wide searches. It highlights the difficulties and limitations of the technique, and the complexities of understanding the results in a clinical situation, suggesting that “patients should be wary of companies that seek to sell such information” prior to further elaboration, interpretation and validation.

 

The research has also been covered in most of the National newspaper, including the Sun, the Daily Mirror, the Daily Telegraph, the Independent and the Guardian, as well as the BBC News.

 

Comment: This paper is the first of its kind to try to apply individual genetic risk calculations to population screening, and is particularly unusual in its consideration of the implications for both individualised disease prevention and public health policy. As such, it provides a major step forward in thinking as regards how to use information about genetic risk factors in standard health practice. Nonetheless, as the editorial highlights, the greatest impact of these discoveries may still lie in an improved understanding of the pathology of disease, and the ultimate translational challenge remains to develop this plethora of data into detailed mechanistic understanding, clinically useful risk prediction and novel therapeutic strategies.

11 June 2008Schizophrenia is a complex psychiatric disease influenced by multiple genetic and environmental factors, affecting around 1% of the population (see press release). The disorder may be familial or non-familial (sporadic), the latter being cases where there is no family history of the disease in first- or second-degree relatives. Rare de novo (ie. new) copy number (CN) mutations have been shown to be risk factors for sporadic cases of autism spectrum disorders (see previous news).

New research published in Nature Genetics suggests that this type of mutation may also account for predisposition towards schizophrenia in sporadic cases [Bin Xu et al. (2008) Nat. Genet. doi:10.1038/ng.162]. DNA samples from family trios (subjects plus their biological parents) were analysed using computer programs to identify copy number variant (CNV) regions indicative of new CN mutations. Any regions that showed 50% overlap with a parental CNV were excluded, to ensure that inherited CNs or common CNVs from unstable genomic regions (with unusually high new mutation rates) were not counted as new mutations.

152 subjects with sporadic schizophrenia were compared with 159 unaffected controls from the same South African population. New mutations showed significant association with sporadic schizophrenia, occurring around eight times more frequently in affected subjects (10%) than unaffected controls (1.3%). In comparison, no new mutations were identified in an analysis of 48 subjects with familial schizophrenia. The researchers also looked at rare inherited mutations in the same cohorts, and found that they occurred only slightly (around 1.5 times) more frequently in the affected individuals than the controls.

The authors of the paper conclude that new mutations play an important role in the pathogenesis of sporadic cases of schizophrenia, much more significant than that of inherited mutations, although these could also contribute to disease vulnerability. It is suggested that this may explain in part why schizophrenia persists in populations despite the fact that individuals with the disease do not have as many children as those without it. Secondly, they propose that the observation that mutations at multiple different positions in the genome can contribute to schizophrenia causation may account for the difficulty in identifying genetic ‘risk’ variants that contribute significantly to predisposition to the disease.

Comment: This research contributes to a growing body of evidence that new mutations in multiple genomic regions (including genes thought to influence neurodevelopmental pathways) may be significant factors in the genetic contribution to sporadic cases of schizophrenia, as previously also suggested for autism spectrum disorder. It seems that seeking new mutations may be a solution to dissecting the complex genetic factors involved in multifactorial disorders that have proved refractory to analysis via standard genetic association studies, and could also contribute to understanding of genetic contributions to other common complex conditions such as diabetes and obesity.

1 June 2008A biomarker is any form of biological molecule (present in tissues, blood or other body fluids) that is associated with a particular pathological or physiological state, and which can be used to indicate or measure the presence of a substance, event or condition. For example, detection and measurement of a specific protein might indicate the presence and /or progress of a certain disease.

For cardiovascular disease, it is already possible to assess an individual’s risk based on a number of clinical characteristics and biomarkers such as levels of blood cholesterol, all of which have been reliably shown to affect risk. More recently, additional biomarkers have been reported to correlate with increased cardiovascular risk. New research published in the New England Journal of Medicine has reported that rthe addition of multiple biomarkers can improve cardiovascular disease risk prediction. Accurate risk stratification is important in public health because it allows clinicians to identify individuals at greatest risk of the disease, who may then be targeted for preventative interventions.

The researchers looked at data gathered from a cohort of over 1100 elderly Swedish men (including 661 without detectable cardiovascular disease at the start of the study) and their ten-year outcomes [Zethelius B et al. (2008)N Engl J Med 358(20):2107-16]. Over this period, a total of 315 subjects died, 136 of them from cardiovascular disease. Four biomarkers were considered: 

• troponin I (a biomarker for myocardial heart cell damage)
• N-terminal pro–brain natriuretic peptide (a biomarker for left ventricular heart dysfunction)
• cystatin C (a biomarker for renal / kidney failure )
• C-reactive protein (a biomarker for inflammation)

These biomarkers reflect pathological processes that have been linked with an increased risk of cardiovascular disease and death, but are not used in current risk assessments. The question was whether or not the use of biomarker data could improve risk stratification beyond that achieved by a standard assessment using established risk factors for cardiovascular disease: age, systolic blood pressure, use of anti-hypertensive or lipid-lowering treatments (for example, beta-blockers or statins), total and high-density lipoprotein blood cholesterol levels, presence or absence of diabetes, smoking status, and body-mass index.

Statistical analysis suggested that all the selected biomarkers showed a significant degree of predictive ability with respect to the risk of death from cardiovascular disease, and especially when combined in a predictive model with established risk factors. This was true both for the sample as a whole, and for the sample sub-group in whom there was no detectable cardiovascular disease at the start of the study.

Previous studies have failed to demonstrate a statistical improvement in risk stratification from the inclusion of biomarker levels in the risk assessment criteria. The authors propose that their findings may have been influenced by the increased age of the study participants compared with those in earlier studies; the risk associated with the established risk factors decreases with increasing age, so that the information provided by the new biomarkers becomes more significant. They also note that previous work had evaluated biomarkers singly for their effect on risk prediction, whereas they showed that none of the biomarkers had a significant effect on risk prediction when individually added to the established risk criteria.

Comment: In demonstrating that the use of combined data from a number of different biomarkers can successfully refine risk stratification, despite the fact that each biomarker taken singly did not do so, this study may pave the way for further developments in the identification of useful combinations of biomarkers associated with disease risk, for risk prediction. Further research will be necessary to determine whether or not these particular biomarkers are robust enough to be used in standard clinical practice for the prediction of death from cardiovascular causes, based on their performance in different cohorts (women, younger people, and different ethnic groups). However, it may be that risk prediction of many different diseases could potentially be improved by the inclusion of multiple new biomarkers in risk assessment, if these biomarkers can be identified and validated.

2 June 2008A HapMap harvest of insights into the genetics of common disease
Manolio TA, Brooks LD, Collins FS. J Clin Invest 2008 May;118(5):1590-605

Common and rare variants in multifactorial susceptibility to common diseases.
Bodmer W, Bonilla C. Nat Genet. 2008 Jun;40(6):695-701.

Genome wide open.

Lancet. 2008 May 3;371(9623):1478.

From human genetics and genomics to pharmacogenetics and pharmacogenomics: past lessons, future directions.
Nebert DW, Zhang G, Vesell ES. Drug Metab Rev. 2008;40(2):187-224.

Medicine may change our genes.
Christakis NA. BMJ. 2008 May 17;336(7653):1101.

Can a cell have a soul?

Burn J. BMJ. 2008 May 17;336(7653):1132.

 

Genetic testing for everyone
Pearson H. Nature. 2008 May 29;453(7195):570-1.

False hopes, unwarranted fears: the trouble with medical news stories
PLoS Medicine Editors, Barbour V, Clark J, Peiperl L, Veitch E, Wong M, Yamey G. PLoS Med. 2008 May 27;5(5):e118.

Pharmacogenetic testing: not as simple as it seems
Haga SB, Burke W. Genet Med. 2008 May 16. [Epub ahead of print]

A malaria fingerprint in the human genome?
Daily JP, Sabeti P. N Engl J Med. 2008 Apr 24;358(17):1855-6.

Detecting genetic responses to environmental change.
Hoffmann AA, Willi Y. Nat Rev Genet. 2008 Jun;9(6):421-32.

Educating the general public about multifactorial genetic disease: applying a theory-based framework to understand current public knowledge.
Smerecnik CM, Mesters I, de Vries NK, de Vries H. Genet Med. 2008 Apr;10(4):251-8

Molecular screening for new fusion genes in cancer

Heim S, Mitelman F. Nat Genet. 2008 Jun;40(6):685-6.

 

New susceptibility genes for ulcerative colitis

Dubois PC, van Heel DA. Nat Genet. 2008 Jun;40(6):686-8.

 

Prader-Willi and snoRNAs.

Peters J. Nat Genet. 2008 Jun;40(6):688-9.

Long-term follow-up after diagnosis resulting from newborn screening: statement of the US Secretary of Health and Human Services' Advisory Committee on Heritable Disorders and Genetic Diseases in Newborns and Children.
Kemper AR et al. Genet Med. 2008 Apr;10(4):259-61.

HuGE Watch: tracking trends and patterns of published studies of genetic association and human genome epidemiology in near-real time
Yu W, Wulf A, Yesupriya A, Clyne M, Khoury MJ, Gwinn M. Eur J Hum Genet. 2008 May 14. [Epub ahead of print]

Genomic medicine and developing countries: creating a room of their own
Séguin B, Hardy BJ, Singer PA, Daar AS. Nat Rev Genet. 2008 Jun;9(6):487-93.

The genetics of gestational diabetes mellitus: evidence for relationship with type 2 diabetes mellitus.
Robitaille J, Grant AM.Genet Med. 2008 Apr;10(4):240-50.

The molecular genetics of type 1 diabetes: new genes and emerging mechanisms
Ounissi-Benkalha H, Polychronakos C. Trends Mol Med. 2008 May 14. [Epub ahead of print]

The genetics and immunopathogenesis of inflammatory bowel disease
Cho JH. Nat Rev Immunol. 2008 Jun;8(6):458-66.

DNA methylation landscapes: provocative insights from epigenomics.
Suzuki MM, Bird A. Nat Rev Genet. 2008 Jun;9(6):465-76.

Linkage disequilibrium - understanding the evolutionary past and mapping the medical future.
Slatkin M. Nat Rev Genet. 2008 Jun;9(6):477-85.

Bona fide genetic associations with bone mineral density.
Hirschhorn JN, Gennari L. N Engl J Med. 2008 May 29;358(22):2403-5. 

Preliminary results of gene therapy for retinal degeneration.
Miller JW. N Engl J Med. 2008 May 22;358(21):2282-4.

Activating a Repressor.
Cohen S, Zhou Z, Greenberg ME. Science. 2008 May 30;320(5880):1172-3.

 

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