In the news

Following the legal ban on the use of human embryonic stem (HES) cells by government-funded researchers (see previous news), the National Institutes of Health (NIH) has reportedly instructed all scientists who use hESC lines to ‘initiate procedures to terminate these projects’ (see Washington Post). The researchers have been told that procedures to ‘conserve and protect the research resources’ (i.e. maintain the living cell lines, which would die without ongoing culturing) should be followed, but they are nevertheless expected to send descriptions of the research that has been suspended and – chillingly, for those hoping for a swift legal resolution and a resumption of research – how funds freed by this cessation may be used instead.

This move affects only those stem cell researchers working directly for the NIH – eight projects in all are affected. NIH-funded researchers at universities can continue their work, although they are probably all scrambling to find non-federal funding to secure the future of their projects, since all current funding applications and renewals have been suspended. There is also considerable confusion about what is not and is not permissible under the current injunction – for example, publication of findings from federally funded HES cell research.  International researchers who have US collaborators are also concerned about the impact on their joint projects (see The Australian).

Meanwhile the Obama administration is said to be lodging an appeal (see ABC news) and NIH Director Francis Collins has officially slammed the developments, citing the medical promise of HES research and saying “The injunction threatens to stop progress in one of the most encouraging areas of biomedical research, just as scientists are gaining momentum—and squander the investment we have already made" (see NIH statement).

Research on stem cells derived from adult cells is not affected by the injunction, since it does not involve cells of embryonic origin. Scientists working in this field must be feeling very relieved compared with their HES cell counterparts. However, it has also been proposed that ongoing HES cell research is essential for the time-being,  if only as a comparator to demonstrate the efficacy of the more ethically-acceptable adult stem cell approaches.

Confusion over government-funded human embryonic stem (HES) cell research in the U.S. has arisen after a federal judge blocked the 2009 executive order put in place by president Barack Obama (see previous news). This directive had lifted earlier restrictions on federal funding for HES cell research and stimulated a rapid expansion in the availability of stem cell lines for public sector scientists (see previous news). However, the Chief Judge of the Federal District Court for the District of Columbia found that the presidential directive contradicted a legal ban on the use of federal money for the destruction of embryos, and placed a temporary injunction to suspend it (see New York Times article).

The Dickey-Wicker law is an amendment to the annual federal financial allocation, which has been in place since 1996; previous administrations (including that of president George Bush) all chose to interpret this as meaning that federal funding of HES cell research was acceptable provided that the original creation of the HES cell lines (involving the destruction of embryos) was privately financed. However, Judge Lamberth ruled that this distinction was invalid.

The implications for such research in the U.S. public sector are not clear, although if taken to the logical conclusion it could imply that technically, no federally funded research activities that involve any HES cell lines can legally proceed. Certainly, no new funding for such research can be awarded until the issue is resolved.

Scientists have expressed dismay at the situation, but opponents of HES cell research (including the parties who brought the legal action against the executive order) were delighted, saying that forms of research that do not involve the destruction of human embryos should be favoured instead. However, the battle between opposing factions continues, as plans to launch another legal challenge in the form of an appeal against the injunction were announced by the U.S. Justice Department, which is also seeking suspension of the injunction pending the appeal process (see Wall Street Journal). Another possibility is removal of the Dickey-Wicker clause.

Comment: It may be as well if the US can move to a more transparent legal and funding situation with respect to HES cell research; certainly, politicians from different parties seem to have been somewhat disingenuous in their conclusions. The problem is that any administration has an unenviable struggle they try to balance the opposing demands for scientific and medical progress on the one hand with those for ethically acceptable practices on the other. There is one group certain to benefit, though: the lawyers.

Earlier this month the Food and Drug Administration (FDA) sought a legal injunction against a US stem cell clinic to halt their treatments – stem cells that are taken from patients and grown before administration at sites of tissue or bone injury (see Nature news).

This reportedly follows an earlier FDA finding that the Regenerative Sciences clinic treatments were drugs and biological products subject to regulatory approval. However, the clinic argues that the treatments are rather a medical procedure using a patient’s own cells, in the manner of in vitro fertilization, and therefore not a medical product - an interesting distinction.

However, they are on shakier ground when they claim that the safety and efficacy of the technique are adequate and that evidence from clinical trials as required by the FDA is not necessary. Rather, they reportedly claim that adherence to the guidelines of the International Cellular Medicine Society – of which the company chief executive is coincidentally co-founder and medical director – is sufficient.

What form and level of regulation should apply to different types of stem cell therapeutics is clearly still open to debate, but evidence of safety is crucial and any attempts by providers to evade requirements to demonstrate safety is highly questionable. Clinical efficacy is another matter – as for genetic tests, some would argue that evidence of medical benefit should be essential in all cases, whilst others may feel that the principal of caveat emptor (buyer beware) should be sufficient.

The danger is that people desperate for medical help can be misled by the claims made by providers of unproven stem cell treatments. This is potentially more serious than for typical genetic tests, which only provide information about genetic contribution to disease risk. Some stem cell treatments are marketed as potential cures for serious and at present intractable conditions such as neurodegenerative diseases or spinal cord injuries; whilst there is great hope that regenerative medicine may ultimately offer new interventions for such conditions, premature marketing of ineffective treatments is at best unhelpful and at worst, exploitative.

Regenerative Sciences’ website appears to promote treatments as an alternative to surgery for hip, knee or back conditions – so that patients might shun proven medical interventions in favour of unproven ones, which is all very well provided that their choice is a genuinely informed one. The International Society for Stem Cell Research guide for potential customers to help them assess the value of a stem cell treatment (see previous news) is therefore a useful guide.

Plans to provide free genome scans to new students at the University of California, Berkeley (see previous news) have been modified following intervention from US regulators. 

The California Department of Public Health (CDPH) reportedly found that if students received individual results from the scans, they would have to be treated as medical diagnostic tests, even though the gene variants to be analysed related to alcohol, lactose and folate metabolism as opposed to specific disease risks, and therefore must comply with state and federal regulations relating to medical diagnostics.

The university has said that it will continue with the programme, which was intended to provoke discussion, but provide collective, pooled findings as opposed to individual results, in compliance with the regulatory edict (see press release). A university facility will be used to analyse the DNA samples.

Announcing that they would comply with the CDPH ruling, programme lead and Dean of Biological Sciences Mark Schlissel nevertheless struck a defiant note, saying: "We believe this is a flawed reading of the statute that raises questions about who has control over teaching at the university, and in the broader sense, who has control over information about our own genes" (see AP news)

Others have welcomed the decision; medical anthropologist Nancy Scheper-Hughes reportedly said that the distinction between whether the testing was for educational or medical purposes had not been made sufficiently clear, with the student invitations to participate having included a ‘medical subjects’ bill of rights’ (see Nature blog).

If, however, the testing programme was conceived primarily or partly  for promotional purposes, it has been highly successful in attracting attention. 

The New South Wales Supreme Court in Sydney has ruled that a brain-damaged teenage girl with developmental delay must undergo compulsory genetic testing, against the wishes of her father (see The Australian).

This move is less draconian than it may sound, since it is intended to determine whether or not there is an underlying genetic cause for her disabilities. The girl’s father is seeking damages from the Children's Hospital at Westmead and the paediatrician involved with care of his daughter in the 1990s, claiming that her disabilities are the result of seizures that occurred during several weeks spent in hospital during infancy, prior to diagnosis of hypoglycaemia caused by congenital hyperinsulinism. The legal claim alleges that failure to diagnose the condition earlier was negligent and resulted in avoidable brain damage.

However, the Supreme Court judge supported an application made by defence lawyers for a small blood sample to be taken from the girl and analysed for other possible causes of developmental delay, such as genetic or chromosomal abnormalities, describing it as a ‘'legitimate litigious step’ (see Sydney Morning Herald).

Compulsory genetic testing – indeed any sort of diagnostic testing – of a minor with limited mental capacity, against the wishes of a parent or guardian, would under most circumstances be considered ethically unacceptable. If accurate diagnosis could make a significant difference to clinical management and outcome, there would be room for debate. In the case of a legal battle with millions of dollars potentially at stake, there is some justification for exhaustive clinical investigation. However, whether it will provide any useful evidence is less likely: congenital hyperinsulinism could most certainly have caused the girl's disabilities, but if other potential genetic causes are also identified, it is unlikely to be possible to demonstrate the relative contribution of each factor.

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The Technology Strategy Board, a UK governmental body responsible for driving technological innovation, has announced a total of £5 million funding to support feasibility research and product development for new regenerative medicine ‘products, tools and technologies’ (see press release). This is the latest in a £21.5m programme of funding for this area of research supported by the Medical Research Council (MRC), the Biotechnology and Biological Sciences Research Council (BBSRC) and the Engineering and Physical Sciences Research Council (EPSRC). Regenerative medicine is a fast-moving field, with applications moving rapidly from skin grafts grown from patients’ own cells to more elaborate tissues and organs such as tracheas (see previous news).

In the US, the government regulator the FDA has given permission for the Geron Corporation to begin the first clinical trial of human embryonic stem cells, an initial safety study of stem-cell derived glial cells as a potential therapeutic for severe spinal-cord injuries. Permission was originally granted early in 2009, but suspended a year ago due to safety concerns arising from animal trials (see Nature news).

Meanwhile, researchers have reported promising signs of spinal cord regeneration in mice with severe spinal cord injuries in Nature Neuroscience, using not stem cell transplantation but a genetic manipulation approach, blocking expression of the PTEN gene that curbs nerve growth. The study showed regenerative growth of damaged spinal cord axons (nerve cells) in mice across the injury site, as well as some growth of new axons, not previously observed in mammalian spinal cord injuries [Liu K et al. (2010) Nat. Neurosci. doi:10.1038/nn.2603]. The authors proposed that a 'rejuvenation' strategy might ultimately be of value in treating similar injuries in humans, although they have yet to demonstrate any restoration of spinal cord function so the approach is very much at the proof-of-concept stage only. 

Following a flurry of activity by American regulators, who have recently taken a keen interest in consumer genomics (see previous news), the UK Human Genetics Commission (HGC) has now launched its Common Framework of Principles for direct-to-consumer (DTC) genetic testing services.

Due to the international nature of the consumer genomics market, it is hoped that the Principles will guide the development of national codes of practice, that take account of different existing regulatory structures. The Principles were developed by an expert working group and revised following a period of public consultation (see previous news). Although they are intended to cover “all situations in which it is possible for a private consumer to purchase a genetic test without prescription by a qualified medical professional”, many of the Principles are equally applicable to other tests.

The Principles are organised in the anticipated order of relevance in the testing pathway:

There is a list of impact criteria that test providers should take into account when considering what additional support is appropriate, and certain Principles are only applicable to health-related tests (diagnostic, pre-symptomatic, carrier, prenatal, susceptibility and pharmacogenetic). Of particular note for existing consumer genomics companies is the recommendation that serious hereditary diseases (such as Huntington’s and familial breast cancer) should only be provided with the offer of pre- and post-test counselling, and genetic testing should not be offered to children or adults who are unable to consent.

The HGC intends to review the uptake and impact of these Principles in 18-24 months, and revise the content in 5 years.

Comment: Aside from the explicit exclusion of whole genome sequencing, which will no doubt be included in future revisions, the Principles provide a proportionate and comprehensive first step towards best practice in the fledgling consumer genomics industry, and responsible companies will want to sign-up. Existing regulatory mechanisms should now be strengthened – such as laboratory accreditation and consumer trading standards – to ensure that companies provide accurate information and do not make misleading claims. However, the guiding principle in this global industry should be transparency, so that consumers can make an informed choice about what they are buying.

A new paper by authors from the PHG Foundation reveals that the size of the direct-to-consumer genetic testing market may be much smaller than typically supposed. This market is of considerable interest in terms of potential impact on medical services, as well as the psychological, social and economic effects on consumers and the potential need for regulatory measures.

However, determining the actual size of the market is difficult; it is widely proclaimed to be burgeoning, but as such statements often come from providers who hope to boost sales this is not necessarily accurate. Sales figures are not publicly available. The researchers therefore set out to estimate the size of the DTC genomic testing market based on the three leading providers, restricting their analysis to disease susceptibility testing (as opposed to forensic, ancestral or paternity testing services). Analysis was based primarily on the three leading providers (23andme, Navigenics and deCODEme) for 2009, and a combination of reported customer numbers and internet traffic as a proxy for commercial activity [Wright CF, Gregory-Jones S. Genet Med. doi: 10.1097/GIM.0b013e3181ead743].

The total number of unique website visits for the three companies was just over 662,000; 23andme had the largest market share (78%) compared with 15% and 7% for Navigenics and deCODEme respectively. Assuming steady growth in sales, an estimate of 20-30,000 test purchases (equating to less than 5% of website visitors) was reached, which would equate to a commercial value of US $10–20 million. Notably, this is much lower than previous estimates of more than US $700 million.

The authors therefore conclude that current levels of consumer genomic testing for disease susceptibility are unlikely to have a major impact on health systems, although they note that emerging forms of testing such as whole genome sequencing could have a greater effect.

Comment: This analysis suggests that considerable disparity may exist between perceived and actual levels of DTC genetic testing. Market forces mean that the popularity of services are exaggerated, although in the longer-term the financial status of companies is likely to reveal a more accurate picture; deCODE filed for bankruptcy at the end of 2009 (see previous news). Considering the potential medical and social impact of new and emerging products and services will continue to be important, but attempting to verify the scale of their impact is a useful element of this process.

A study published in Nature [Kagey et al. (2010) Nature 18 Aug doi:10.1038/nature09380] has suggested the mechanism by which the different cell types in the body maintain their specific characteristics.

Different types of cell are defined by which of the genes within the genome are expressed and which are switched off. The activation of a given gene is determined by the presence of protein complexes called transcription factors at regions specific to each gene known as promoters and enhancers. The promoters and enhancers for a particular gene are not necessarily located physically close to each other on the genome, but were thought to be brought into proximity by the DNA forming loops via a poorly understood process.

This study in mice suggests the mechanism by which these loops are formed. The researchers found that the proteins Mediator and Cohesin bind simultaneously to both the promoter and enhancer of a gene that is to be activated and form a complex which brings the two separate segments of the genome physically and functionally together, causing the DNA to form a series of characteristic loops for each type of cell.

Mediator and Cohesin co-occupy different promoters and enhancers in different cells, creating specific DNA loops associated with the gene expression pattern of each type of cell. This study found that the presence of Mediator and Cohesin at particular promoters and enhancers predicted the looping that would occur, and that disruption of this loop structure caused the cell to lose its normal state and to become a different cell type.

One of the study’s authors Richard Young has been quoted as saying that this research reveals “…a surprising new understanding of the control of genes” and could provide “…a fundamental new insight into the underlying causes of several neurological and developmental diseases”.

Comment: This study has increased our understanding of how physical changes to the structure of the DNA within a cell alter gene expression, and thus which cell type it will be. It has long been known that the activation of individual genes is dependent upon promoter and enhancer regions associated with that gene, but the means by which these physically separated regions achieved this was poorly understood. Although this study was in mice and not humans, it is expected that a process as fundamental as the control of gene expression will be the same across all vertebrates.

A number of developmental disorders in humans, including FG syndrome and schizophrenia, are associated with mutations in the genes that encode Mediator and Cohesin; this study suggests that the underlying cause of these disorders might be changes to the structure of the loops in the DNA that in turn alter patterns of gene expression within certain cells. However, it could be a long time before this knowledge is able to directly inform therapies for specific disorders.

Tuberculosis (TB) is a common, often deadly infectious disease usually affecting the lungs. Approximately two million people, mostly from the developing world, died from this disease in 2008 (according to WHO). A third of the world’s population are thought to be infected with the causative bacterium, Mycobacterium tuberculosis. However, only one in ten of these carriers will develop fully blown TB over their lifetime. Current tests cannot identify which individuals will develop the disease and this means that anti-TB drugs could potentially be given to everyone who is shown to be infected with the bacterium. A study [Berry et al. (2010) Nature 19 August doi: 10.1038/nature09247] recently published in Nature reports on a relatively new and complex genomic test to investigate biological markers that have the potential for diagnosing and predicting active TB.

The researchers used a technique called ‘genomic transcription profiling’ that assesses gene activity by measuring the types and quantities of RNA cells produce. They compared the transcriptional profiles of expressed genes in blood samples from three different groups of subjects: those with active TB before treatment, those with latent TB (i.e. apparently healthy but infected carriers) and healthy controls. The aim was to identify a gene transcript pattern that was similar in people with active TB and “high risk” latent patients.

A distinctive ‘393 transcript signature’ was identified in patients with active TB, and validated in two independent cohorts from the UK and South Africa, with further testing in people with other diseases including bacterial infections. The 393-transcript signature was found to be characteristic of active TB, and returned to normal after treatment. The researchers found that 10-25% of the patients with latent TB also displayed this characteristic ‘active’ or high risk profile. The paper found that the test had a sensitivity of 62% and a specificity of 92% - that is, it would identify 38% of patients as not having active TB when they do, and detect 8% of those without TB as having the disease.

Comment: This study reports on a transcriptional signature of TB from human blood that may have important implications for better diagnosis, treatment and prevention. It may help to identify patients with active TB and thus reduce the indiscriminate use of TB medication. However, the test’s accuracy in predicting which TB patients develop the active disease needs to be measured in the general population in a prospective study having been developed and initially tested in a highly selected group.

A study published yesterday in Science [Lemmers et al. (2010) Science 19 Aug doi:10.1126/science.1189044] has uncovered the mystery cause of a form of muscular dystrophy pointing the way towards possible therapies.

Facioscapulohumeral muscular dystrophy (FSHD) is one of the more common forms of muscular dystrophy - affecting around 1 in 20,000 people - and is characterised by progressive weakening of muscles in the face, shoulders and upper arms. Its mechanism was unknown and thus no effective therapies exist.

All that was known previously was that FSHD was associated with a shortened repeating DNA sequence on chromosome 4, but that this alone was not enough to cause the disease. No direct gene association had been found. The same repeats are present on chromosome 10, but only those on chromosome 4 are associated with the disease.

Within each repeating unit is a gene called DUX4 that had been thought to be an ancient ‘dead’ gene that was no longer expressed. This study found that the gene was in fact always transcribed, but that the RNA transcripts were unstable and immediately degraded because they lacked a  poly(A) tail – a short sequence that marks an RNA transcript for expression.

This study found that the DNA adjacent to the repeat region on chromosome 4 contained the sequence ATTAAA, and that all the families with FSHD that they examined had specific SNPs causing this sequence to be appended to their DUX4 transcripts. This sequence was not found on chromosome 10. It was further found that DUX4 RNA was present in the muscle cells of people with FSHD, but not in those without the condition.  Earlier studies had already shown that DUX4 can trigger muscle cell death.

Comment: This study suggests a plausible genetic model for FSHD whereby specific polymorphisms create stable DUX4 transcripts which in turn become proteins that cause muscle damage. This points the way towards clear therapeutic targets and will undoubtedly lead to studies into methods by which the DUX4 gene or its proteins can be deactivated. Some caution should be exercised however in concluding that the mechanism of FSHD has been fully revealed, since the SNPs that the researchers identified were in a small sample size of just four families.

Parkinson’s disease is a common neurological condition that affects motor and cognitive disability with symptoms getting worse over time. According to Parkinson’s support and research charity Parkinson’s UK, around one in every 500 people has Parkinson’s, meaning around 120,000 cases in the UK alone. Over the past few years, several genome-wide association studies (GWAS) have been conducted but these studies have only really replicated known associations with the SNCA and MAPT genes with other genes slowly starting to be implicated (see previous news). A study recently published online in the journal Nature Genetics has replicated these known associations and also identified a new interesting association with the HLA region.

The study by Hamza et al. reports a GWAS involving 2,000 Parkinson’s patients and 2,000 controls of European descent with information at over 800,000 SNPs [Hamza et al. (2010) Nat Genet 15 August doi:10.1038/ng.642]. This work confirmed the known susceptibility regions at SNCA and MAPT and also uncovered a novel association located within the MHC/HLA, a region known to harbour genes involved in the immune system. Both the SNCA rs356220 SNP and the HLA-DRA rs3129882 SNP reached genome-wide significance. This HLA SNP also replicated in two independent datasets with overall associations slightly stronger in sporadic Parkinson’s patients as well as those with late-onset Parkinson’s. A previously suggested association with the GAK gene was also replicated through additional analyses. Although the researchers note that these four Parkinson’s susceptibility loci each have modest individual effects on Parkinson’s disease risk, they suggest that their cumulative effect may be quite substantial, with risk increasing up to five-fold for those individuals that carry six or more of the eight risk alleles at these four loci.

Comment: This well-conducted GWAS study identified a novel, biologically plausible candidate region involved in immunity as well as confirming previously known or suspected loci. The authors state that these results “lend strong and independent support to the involvement of neuroinflammation and humoral immunity in Parkinson’s disease pathogenesis”. There is currently no cure for Parkinson’s and so it is hoped that these insights will lead to treatments but as Parkinson’s doesn’t directly cause people to die, the development of any novel drugs to target the possible immune role in Parkinson’s may be slow.

The low success rate of in vitro fertilisation (IVF) – just over 28% for women under 35 and lower for older women in the UK (see HFEA figures) – is partly attributable to the failure of aneuploid embryos (those with an abnormal number of chromosomes) to implant properly. Most such embryos would be non-viable in any case, and even the least severe forms of aneuploidy have significant clinical effects; for example, resulting in Down Syndrome, Edwards Syndrome and Patau Syndrome.

In order to increase the chances of establishing a successful pregnancy, pre-implantation genetic screening (PGS) can be used to identify and select chromosomally normal embryos for implantation. Over recent years, techniques for embryo biopsy (see previous news) and analysis have been rapidly developing (see previous news). Although there have been reports of the success of these techniques, there are still doubts over the benefits of PGS.

In a report published in the journal Fertility and Sterility, Munne et al have reviewed the different steps that compose optimal PGS techniques to determine how effective they are at improving the success of rate of assisted reproduction [Munne et al (2010) Fertil. Steril. 94(2):408-30]. They found that there were variations between laboratories in the analytical techniques used (FISH, array CGH or embryo selection based on morphology), the cell biopsied and how it is removed and the number and types of chromosomes that are analysed. All these factors, along with the skill of the embryologist, contributed to the success the success of implantation.

Based on this review, the authors suggest that an improved implantation rate can be achieved by considering a number of factors that contribute to the success of the screening procedure. This includes using the technique with patients of appropriate maternal age, ensuring samples are handled carefully and that error rates of the technique are low. They recommend analysis of chromosomes X, Y, 13, 15, 16, 18, 21, and 22 at a minimum and using laboratories that have a less than 10% error rate.

In addition, they suggest that newer techniques such as array CGH may be more desirable over traditional techniques such as FISH, as they allow analysis of a larger number of chromosomes and can minimize embryo damage and error rates. However, they recognise that these techniques will also require appropriately trained and skilled embryologists to ensure their success.

An analysis article in the British Medical Journal discusses the importance of relating health spending to local needs in low income countries. The authors consider difficulties that low income countries face when it comes to assessing their health needs and initiatives that could help local decision and policy making [Chalkidou et al . (2010) BMJ 341:c3651].

The authors state that in many countries decisions are still driven by historical norms, priorities of foreign donors and lobbying pressures. As such many countries lack the mechanisms and capabilities for making decisions about their own health needs and developing services accordingly. This is further compounded by the lack of local data, technical expertise and institutions to contribute to needs assessments. The authors suggest that a way forward would be through an international support service involving organisations involved in decision making. They suggest that organisations such as NICE, NHS Global and the Thai Health Intervention and Technology Assessment Programme (HITAP) may be able to lend support to local decision makers by working in collaboration or sharing experiences with them.

The importance of developing services according to local needs in low and middle income countries has been recognised by the PHG Foundation, which is already engaged in a major project to tackle birth defects. This includes a newly developed toolkit to help developing countries (where this group of conditions account for a significant proportion of child deaths and ongoing disability) assess their health needs and develop basic services to prevent and care for this these conditions.

The aim is to provide governments and their health partners with the tools and data to build the evidence base and make the case for the development of services to tackle birth defects in their populations. Importantly, this includes options to take into account not only epidemiological, logistical and economic concerns but also ethical issues, which may also vary widely between different countries and regions.

The toolkit is to be piloted in different international locations over the coming two years, and the PHG Foundation is working with the World Health Organization (WHO) and other supporters to and drive forward concerted global efforts to share expertise and resources in order to reduce the suffering associated with birth defects.

In the UK, cardiovascular disease is the leading cause of death, accounting for around 1 in 3 deaths (see British Heart Foundation statistics). Of the heritable risk factors involved in cardiovascular disease, blood lipid concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) are amongst the most studied for their key roles as targets for therapeutic intervention (see previous news). To date, over 30 genetic loci have been identified, using genome-wide association studies (GWAS), that contribute to blood lipid variation, although these studies have largely been limited to the European population. 

A new study published in the journal Nature has focused on trying to answer questions about whether loci identified in European populations are also relevant in non-European populations and also how clinically and biologically relevant these identified loci are [Teslovich et al. Nature (2010) doi:10.1038/nature09270]. The study, undertaken through a large-scale collaboration by researchers based in the USA, Europe, and Asia, identified 95 loci associated with at least one of the four traits tested (TC, LDL-C, HDL-C, TG) in around 100,000 individuals of European ancestry using a meta-analytic approach. These included the 36 previously reported and 59 novel loci. Of these 59, 39 were associated with TC, 31 with HDL-C, 22 with LDL-C, and 16 with TG. Interestingly, 21 of the 36 known loci showed association with another lipid phenotype in addition to that previously reported.

Additional analyses were undertaken in populations with East Asian, South Asian, and African American ancestry using a different cohort of Europeans as a control group. The SNPs found in this control European cohort were largely replicated in the non-European populations, albeit to a lesser extent in the African American population.

In order to assess the clinical relevance of these loci, associations with coronary artery disease were assessed in 25,000 cases and 66,000 controls of European descent. Thirteen loci showed association, with most of them also being associated with LDL-C, showing consistency with LDL-C as a causal risk factor. A second clinical phenotype, hyperlipidaemia, was also assessed in a smaller study, where individuals with greater numbers of risk loci showed higher lipid levels.

Comment: An accompanying editorial commented that “Despite the outstanding power of this study to detect common variants of very small effect, the 95 loci identified explain only about 10-12% of the total variance in blood-lipid levels, which corresponds to about 25-30% of the genetic variance.” Despite the large size of this study, which allowed multiple loci with very small effect sizes to be identified due to the increased power, a large proportion of genetic variance is still unaccounted for, as is common in studies of this type (see comment in previous news).

However, this study did identify a large number of loci associated with blood lipids in both European and non-European populations, as well as providing clinical and biological evidence that increases the strength of these associations. As the editorial quite rightly points out, many clinically relevant questions must now be answered following on from this work, with translation the often ignored little brother.

Breast cancer is now the most common cancer in the UK (see CRUK website). However, thanks to extensive research and improved management, survival rates for breast cancer have been improving for thirty years. Ongoing research is aiming to identify ways of reducing the incidence of breast cancer by improved prevention, as well as to understand the complex biological disease pathways in order to develop new treatments. Sporadic breast cancer is a complex disease associated with both genetic and environmental risk factors (see previous news). There are now about 20 genetic variants known to be linked to disease susceptibility and more are being identified. Whilst the risk conferred by each is typically small, in combination there may be potential to use these markers to improve risk prediction.

A new study evaluates risk associated with 14 breast cancer risk variants (SNPs), alone or in combination, for half a dozen cancer subtypes [Reeves et al. (2010) JAMA 304(4):426-434], to look at how individual variants and polygenetic risk models correspond to breast cancer risk and subtype. This large prospective study used more than ten thousand women with breast cancer and about as many healthy controls without breast cancer. The scientists used meta-analysis of results from the study as well as of other studies. The analyses of the results suggested that SNPs in the FGFR1 and TNRC9 genes, as well as a third SNP on chromosome 2, were most closely tied to overall breast cancer risk, and that risk prediction was most reliable for oestrogen receptor (ER) positive cancers and lower grade tumours.

The researchers also developed polygenic risk models using combined data on four, seven, or 10 of the SNPs that were most strongly associated with breast cancer. They concluded that women under 70 years of age with the highest polygenic risk scores have an estimated breast cancer risk of 8.8% compared with a risk of 4.4% in women with the lowest polygenic scores. They also found that the polygenic risk score was substantially more predictive for ER-positive cancers (ranging from a high of 7.4% to a low of 3.4%) than ER-negative breast cancers (a range of just 1.4% to 1.0%).

Comment: This is an important study which evaluates the predictive value of selected genetic markers identified by different studies and finds that it varies for different tumour subtypes. However, the authors caution that whilst their findings are potentially useful for understanding disease mechanisms, they would not be useful for individual breast cancer risk prediction or population stratification as known risk factors for breast cancer such as family history are more predictive. Nevertheless, this is an interesting line of enquiry and it may be that ultimately the combination of established and novel environmental and genetic risk factors could refine risk prediction for targeted population screening.

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