News

26 January 2010 UK media coverage of plans to expand the list of conditions for which pre-natal genetic diagnosis (PGD) is permissible in the UK implies that some of the disorders are not serious.

The Human Fertilisation and Embryology Authority (HFEA), which regulates clinics providing prenatal genetic diagnosis in the UK, is reportedly in the process of considering which disorders to add to the list of permissible conditions. For a clinic to be able to offer PGD as part of in vitro fertilisation (IVF) – identifying and selecting for implantation only those embryos that do not carry a specific genetic disorder – the HFEA must agree that the condition in question is sufficiently serious. For some conditions, approval is only given on a case-by-case (as opposed to clinic-wide) basis.

In recent years, there has been some controversy over decisions by the HFEA to allow PGD for conditions that are adult onset or do not necessarily affect all those with the disease gene, such as hereditary forms of breast and colorectal cancer (see previous news), and for conditions for which there is effective treatment (see previous news). In making decisions, the HFEA takes into account factors such as the seriousness of symptoms, age of onset, variability fo symptoms between affected individuals, the availability of treatments and how invasive those treatments are.

Two major UK newspapers have now reported that clinics are ‘destroying embryos with minor genetic conditions’ (see Telegraph article) and ‘allowing doctors to screen out embryos that could lead full lives despite having a genetic condition’ (see Times article). Both pieces focus on Marfan syndrome and thalassemia as being ‘minor’ conditions, characterising Marfan syndrome as a condition ‘that can lead to abnormal growth’ and thalassaemia as one that ‘can cause mild anaemia’. They suggest that the use of PGD for such conditions is tantamount to unacceptable eugenics.

This is a serious misrepresentation of potentially very serious conditions likely to anger affected families, whether or not they themselves would wish to used PGD to avoid the birth of an affected child. For example, over one third of people with Marfan Syndrome die in early adulthood, according to the Marfan Society, whilst half of those with beta-thalassaemia die before 35 (see HFEA website).

Whilst it is true that for some genetic conditions, the severity of symptoms can vary widely between affected individuals, it is not possible to predict how badly people will be affected – which is why termination of pregnancies where the fetus is diagnosed with a potentially severe condition is permitted at any stage of pregnancy in the UK. Equally, expanding the use of PGD requires careful consideration and raises potential ethical issues, particularly if the prospect of screening prospectively for multiple different conditions (as opposed to a specific condition already known to affect the family in question) were to become closer.

However, portrayal of unambiguously serious genetic disorders as ‘minor’ is either ignorant or disingenuous. The striking similarity of the pieces, despite having different authors, suggests that this inaccuracy could have originated elsewhere, but is nevertheless disappointing.

25 January 2010The Australian National Health and Medical Research Council (NHMRC) and Office of the Privacy Commissioner last month released new guidance for health practitioners on disclosure of genetic information to patients’ relatives. 

The guidelines set out requirements that must be fulfilled to permit such disclosure to a genetic (as opposed to legal) relative of a patient; disclosure in the absence of patient consent is permissible only where it is necessary to ‘lessen or prevent a serious threat to the life, health or safety of the patient's relative’ (see press release). This is in line with recent UK guidance on the same issue (see previous news).

Before making any such disclosure, health professionals – who should understand the genetic basis of the patient’s condition and be competent to take responsibility for decision-making, as well as documenting the process - must take reasonable steps to obtain patient consent; if this is not forthcoming they must discuss the case with other health practitioners with appropriate expertise before proceeding. Genetic information disclosed without consent should be limited to the minimum necessary, avoid identifying the patient (or revealing their lack of consent to disclosure), and only be made available to genetic family members ‘no further removed than third-degree relatives’.

The Office of the Privacy Commissioner (OPC) has ruled that under such circumstances obtaining contact information for the relatives in question from the patient who has withheld consent to disclosure would be impractial, and issued a Temporary Public Interest Determination to allow this collection legally.

22 January 2010The Academy of Medical Sciences (AMS) has published a new report challenging the next government of the UK to make medical science a central tenet and make the most of the opportunities for health offered by advances in the field (see press release).

Reaping the rewards: a vision for UK medical science, which notes the abundance and world-leading excellence of biomedical research in the UK and the unique opportunities for medical research via the National Health Service (NHS), says that the UK has an ‘unparalleled competitive advantage’ for commercial medical research that could ‘improve the health of the population both here and abroad’.

However, it warns competitors such as the US, China, Singapore and Canada are actively growing their own medical research sectors and that the UK is losing out as clinical trials and research move to other countries. The report sets out seven key challenges that the AMS says must be addressed over the next five years to reverse this trend and capitalise on public sector investment in medical research:

To benefit patients the NHS must become a willing participant in health research

The regulatory environment is driving medical science abroad

Innovative incentives must firmly root the medical science industries in the UK

Publicly funded health research needs further coordination

Public health challenges must become cross-Departmental priorities

Health research should be used as a driver of foreign policy and international development

The UK must grow and sustain its world-class biomedical workforce for our knowledge economy

Broadly, the report calls for a more coordinated approach to research across the public, private and third sectors; a ‘proportionate, risk-based regulatory framework’, incentives for excellence and innovation, and the need for medical science to ‘underpin cost-effective international development measures that enable poorer countries to address their health needs’. As such it notes that health research should be central to UK foreign policy.

6 January 2010 The UK Human Tissue Authority (HTA) has recently released new information about consent and the use of DNA via its website. The HTA is a public body established under the Human Tissue Act 2004 that licenses organisations that store ands use human tissue for different purposes including research, medical treatment, post-mortem examination and education, in England, Wales and Northern Ireland.

The website brings together information on consent including the HTA Code of practice on Consent, frequently asked questions, a glossary, policy information on non-consensual DNA analysis (and how to apply for this via the HTA), and two flowcharts on Consent and the use of DNA and Qualifying consent.

The Medical Research Council (MRC) also provides an online Data and Tissues Tool Kit, developed in conjunction with the HTA and other relevant bodies, that offers help and guidance on legislative requirements and good practice with respect to the use of human tissue and personal information for healthcare research in the UK (see previous news).

With respect to broader health research, the UK Clinical Research Collaboration (UKCRC) recently released a new booklet on the changing regulatory and governance environment for clinical research, outlining new measures intedned to reduce bureaucracy and streamline research. The UKCRC is a partnership of stakeholders including academia, industry, funders, regulators, patients and the NHS established to redesign the clinical research environment with a view to improving national health and wealth.

The Health Services Research Network has also recently produced a briefing document describing changes in the research governance landscape.

4 January 2010 A new UK Stem Cell Tool Kit has been launched as a reference tool for anyone developing programmes of human (but not animal) stem cell research and manufacture for clinical applications. The hope is that this portal will help streamline and accelerate the process of clinical translation from research into healthcare practice by making the regulatory path clearer for researchers within the ‘stringent but facilitating regulatory framework for stem cell research’ in the UK.

For a given project, the Tool Kit offers graphical representations of regulatory routes, key regulatory questions and milestones, with detailed information about required steps and contacts for each stage.

The resource was developed by the Department of Health and the Medical Resaerch Council with the support of key regulatory bodies including the Gene Therapy Advisory Committee (GTAC), the Human Fertilisation and Embryology Authority (HFEA), the Human Tissue Authority (HTA) and the Medicines and Healthcare Products Regulatory Agency (MHRA), as well as other groups. It will be updated every three months.

Professor Brendon Noble of the MRC Centre for Regenerative Medicine in Edinburgh commented: “This will be an important tool in therapy development planning. It will also act as a focus for discussion over key issues and roadblocks to the development of cell based therapies” (see press release).

28 January 2010Methicillin-resistant Staphylococcus aureus (MRSA), is a bacterial strain that is resistant to a range of antibiotics including the drug of choice, methicilllin. These bacteria are easily transmissible, especially among hospital patients who are immunocompromised, and can cause mild to severe infections, including septicemia.

A proof-of-principle study in the journal Science describes the use of high-throughput sequencing to track the evolution and spread of MRSA [Harris SR et al. 2010 Jan 22; 327(5964):469-74]. By sequencing genomes of 63 MRSA ST239 isolates (43 from a global collection recovered over 20 years, and 20 collected in a single hospital in Thailand over 7 months), the team discerned relationships between isolates from different locations, tracked spread from one continent to the next, and gained a better understanding of its transmission within a single health care facility.

The advanced high-throughput form of DNA sequencing used for this research was crucial, allowing comparison of whole MRSA genomes and pinpointing subtle differences between them, including SNPs and small insertions and deletions.

The results suggest that the MRSA isolates typically cluster by geographical location, with European isolates being particularly diverse, consistent with a possible European origin for the ST239 strain. Although intercontinental transmission of seems to be rare, the researchers showed several exceptions. For example, isolates in Portuguese hospitals in the early 1990s came from a European source, but were replaced by isolates more similar to Brazilian ST239 in the late 1990s.

The researchers also found that the ST239 strain appears to be mutating faster than previously recognised, with a new mutation appearing roughly every six weeks. Such mutations frequently affect parts of the genome related to drug resistance. In the Thai hospital, the researchers found even greater genetic diversity between ST239 isolates than detected from the global samples; their results also suggested that genome sequencing could help track the course of infection outbreaks within hospitals.

Comment: The sequencing approach, relying on comparison of whole genomes instead of looking at either single loci or limited regions in the genome, should help scientists to gain insights into fundamental processes of evolution in not only S. aureus, but other clinically important pathogens of the world. It could help to locate MRSA transmission hotspots, whether as part of global surveillance strategies or to target elevated infection control strategies in local settings.

22 January 2010A paper in Nature Medicine has been has been heralded as a major advance for bone marrow transplantation, reporting a new way of manipulating cord blood stem cells to expand their numbers without causing differentiation from stem cells into normal blood cells (which are unsuitable for transplantation).

Bone marrow donations are used to treat diseases of the blood cells such as leukaemia; the patient’s own, diseased, bone marrow stem cells (which give rise to blood cells) are artificially destroyed and healthy bone marrow from a tissue-matched donor is transplanted to replace them. The procedure may still fail if the patient’s immune system rejects the transplant.

Stem cells taken from umbilical cord blood are a superior source of tissue because they are much less likely to cause immune rejection. This is why cord blood banking is an important medical advance in recent years (see previous news). However, the relatively small amount obtained from one cord is not usually enough, and patients need two different samples; even then, limited numbers of cord blood stem cells delays the process of repopulating the patient’s bone marrow and increases the risk of medical complications. 

US researchers used a Notch ligand protein to stimulate a signalling pathway that caused both mice and human bone marrow precursor cells to proliferate whilst retaining the ability to give rise to different blood cells [Delaney C et al. (2010) Nat Med. doi:10.1038/nm.2080]. They were able to generate an approximate 100-fold increase in the number of human bone marrow cells.  

To test their function in patients, the researchers gave each of ten child and adult leukaemia patients bone marrow transplants from two cord blood samples. In each case one of the two donor samples had been treated to expand the number of cells. These cells showed a faster ability to repopulate the patient bone marrow compared with the untreated ones. 

The authors conclude that Notch signalling has a key regulatory role in haematopoiesis (blood cell formation) and that Notch ligands will be useful improving culture of stem cells in the laboratory prior to cord blood transplantation.

Comment: The researchers note that the next step for this research will be studies to determine whether or not the faster engraftment observed for cord blood cells expanded using their method prior to transplantation also improves patient outcomes – fewer infections, faster recovery and improved survival. However, this initial work is very promising. Perhaps if normal cord blood transplantation from unrelated donors can be made safer and more effective, the controversial practice of private cord blood banking will become less common (see previous news).

19 January 2010On the face of it, two new papers published this week about the genetics of type 2 diabetes (T2D) seem somewhat contradictory. The first, an enormous genome-wide association study (GWAS) published in the journal Nature Genetics, has thrown up a plethora of new loci associated with fasting glucose level [Dupuis J, et al. Nature Genetics (2010) doi:10.1038/ng.520], which is itself a useful clinical predictor of the development of T2D. The Meta-Analysis of Glucose and Insulin-related traits Consortium (MAGIC) conducted meta-analyses of 21 GWAS, and followed up 25 loci in a second replication phase in order to validate 16 new loci associated with fasting glucose levels in over 120,000 non-diabetic participants. These included eight loci that have also been shown to increase the risk of developing T2D in a separate case-control studies. These loci point to numerous likely candidate genes involved in insulin production, glucose sensing and pancreatic beta-cell proliferation and development.

The second paper, published in the British Medical Journal, paints a rather less positive picture of the importance of genetics to T2D [Talmud PJ, et al. BMJ (2010) doi: 10.1136/bmj.b4838]. Using the Whitehall II prospective cohort study, with over 5,500 initially healthy people, various risk prediction models were evaluated to assess their ability to discriminate between those who developed T2D over 10 years (approximately 5% of the sample) and those who did not. Two prediction models based on traditional risk factors – such as age, sex, body mass index, family history and smoking – were compared against a model based solely on measurement of 20 single nucleotide polymorphisms (SNPs). By assessing the area under the receiver operator characteristic curve (a plot of sensitivity versus 1-specificity, where a value of 1.0 represents a perfect test and 0.5 represents a useless test), the traditional models significantly outperformed the genetic model (around 0.75 versus 0.54), and their performance was not substantially improved by the addition of genetic risk factors. This finding is consistent with other studies indicating that genetic risk factors have limited utility in the prediction of T2D (see previous news).

Comment: It is easy to be despondent about the failure of GWAS to find large genetic risk factors for common diseases and provide a perfect crystal ball for predicting disease. But this is not a good reason to abandon research into the genetic basis of common diseases. We must not lose sight of the most important finding from many GWAS – further elucidation of the underlying biological mechanisms that contribute to disease or pre-disease states. As the authors point out, these discoveries “may reveal new pathways for diabetes therapeutics”; unfortunately, however, translation of these findings into real clinical benefits for patients is likely to be a slow process.

18 January 2010The public health and economic burden of age-associated cognitive decline and dementia is set to rise as the population ages in the UK and other developed countries. In 2007, according to the Alzheimer’s Society, one in 88 people in the UK were suffering from dementia. Alzheimer’s disease (AD), the most common type of dementia, is characterised by a decline in memory, reasoning and communication skills, and a gradual loss of skills needed to carry out daily activities.

 

To date, only the APOE4 gene variant has been conclusively shown to influence AD risk. A new study published recently in JAMA has examined the association of the V405 polymorphism in the cholesteryl ester transfer protein (CETP) gene, previously linked with exceptional longevity and lower cardiovascular risk in a study of Ashkenazi Jews[Barzilai N et al. (2003) JAMA 290(15):2030-40].

 

US researchers investigating the CETP V405 polymorphism in relation to memory decline and dementia followed 523 people aged 70 and older with no signs of cognitive decline at the start of the study over fifteen years [Sanders AE et al. (2010) JAMA 303(2):150-8]. Participants underwent standard neuropsychological and neurological testing each year from 1994 to 2009 and performed tests to measure memory, attention span and the time it takes to process and react to a signal (psychomotor speed).

 

A total of 40 cases of incident dementia occurred over the course of the study, and the analyses showed that the CETP V405 gene variant was independently and significantly associated with slower memory decline and lower incident dementia and AD risk; statistical models were adjusted for sex, education, race, medical co-morbidities as well as other influencing factors to ensure that the V405 genotype was the main predictor of the outcomes. In fact, participants with two copies of the favorable CETP variant had a 70% reduction in their risk of developing AD compared with participants with none, and showed a slower rate of memory decline.

 

Comment:This is the first study to link the CETP V405 gene variant with decreased risk of dementia; recent genome-wide association studies for AD have failed to identify this variant, but this could be because a prospective study (which starts with no cases of disease and documents them as they emerge) may avoid selection bias in identifying existing cases. The author’s other point that GWAS focus generally on elevated (as opposed to reduced) disease risks is somewhat misleading, however.

 

The biological basis for the putative link between the CETP variant and reduced risk of dementia is unknown, although plausible given that other genes involved in lipid metabolism (such as APOE) are also associated with dementia.Improved understanding of underlying mechanisms of genetic susceptibility and risk may have important future public health implications, for example in developing drugs that mimic the effect of the V405 CETP variant that might retard memory decline and dementia.

15 January 2010The new study published in PLoS ONE has linked epigenetic changes with cardiomyopathy, a form of heart disease characterised by weakening of the heart or a change in muscle structure that diminishes the ability of the heart to function effectively. There are three main forms of cardiomyopathy – dilated, where the heart becomes enlarged and weakened; hypertrophic, where the heart muscle becomes thickened, forcing the heart to work harder to pump blood out of the heart; and restrictive, where the heart muscle becomes stiff and hence unable to properly fill with blood (for more information, see The Cardiomyopathy Association).   

Differences in DNA methylation are currently understood to be involved in the control of gene expression, which may in turn contribute to complex disease susceptibility or progression. Strong links have already been found between differential methylation and cancer, and there are efforts underway to examine the link with other complex diseases such as schizophrenia, diabetes and inflammatory bowel disease.

Researchers in Cambridge have found differences in DNA methylation in hearts from a small number of people with end-stage cardiomyopathy who were undergoing heart transplantation and the healthy hearts of age-matched victims of road traffic accidents [Movassagh M et al. (2010) PLoS ONE 5(1): e8564, doi:10.1371/journal.pone.0008564].The differential methylation correlated with differences in gene expression patterns between the heart failure and control groups.

They conclude that differential DNA methylation, along with other epigenetic mechanisms, may influence the development of heart failure in response to environmental factors, including dietary influences, effectively representing a ‘missing link’ between genetic and environmental causes of heart failure. The researchers also comment that, although certain genes are known to play an important role in heart failure, sometimes mutations are not found in those genes and thus it may be methylation rather than mutation that leads to disease. 

Comment: This is small study, but provides very interesting insight into a possible role for epigenetic changes in heart failure. The researchers now hope to identify ‘hotspots’ in the genome to help identify those people at greater risk of developing heart disease, and in particular those people at greatest risk of developing heart disease rapidly. This would allow treatments to be targeted to those at greatest risk, and also enable closer monitoring of those at higher risk, to help prevent and delay heart failure.

13 January 2010Creating mouse models of numerous human diseases – known as ‘knock-out’ mice – has been possible for many years, by disrupting the particular gene of interest (see previous news). However, due to numerous differences between murine and human biochemistry and physiology, in practice these models often perform poorly as models of the human disease process or as tests for novel drug action. Therefore developing models of diseases in human cells would offer considerable advantages.

 

Until now, this effort has been hampered by difficulties in isolating and culturing the relevant human cells from the many thousands of human diseases directly caused by known genetic alterations. However, a new technique for genetic manipulation using human embryonic stem cells (hESCs) may offer a solution to this problem [Song H et al. Cell Stem Cell (2010) 6:80-9]. Unlike normal cells, hESCs are able to undergo unlimited self-renewal whilst retaining the ability to differentiate into all cells types under the right conditions. By injecting standard hESCs with synthesized circles of human DNA, it is possible to substitute modified genes into the cells, thus effectively providing a method for creating ‘knock-out’ cells. Whilst only around 20% of the cells were modified using this technique, this is already a substantially higher efficiency than had previously been achieved through other methods.

 

Two genes were selected as test cases: p53, which encodes a tumour suppressor commonly mutated in cancer cells, and ATM, which encodes an enzyme mutated in the rare recessive condition Ataxia-telangiectasia. In both cases, homozygous mutant cells were generated that did not produce functional gene products. These cells could subsequently be differentiated into different cell types, in order to observe the effect of the mutation on the development and activity of diseased cells. Importantly, the technology can easily be adapted to allow different genes to be modified, thus providing a flexible system for generating hESC models of numerous human genetic diseases.

12 January 2010The December supplement of the journal Health Research Policy and Systems is dedicated to a series of articles describing a set of tools designed by the SUPporting POlicy relevant Reviews and Trials (SUPPORT) project (see news source). The tools they have produced are aimed at helping policymakers ensure that their decisions are informed by the best research evidence. SUPPORT is an international collaboration with partners in Africa, South America, Europe and North America with an objective to provide training and support to encourage researchers and policymakers in collaborative policy-relevant research.

Each article proposes a tool and addresses four broad categories:

• Supporting evidence-informed policymaking
• Identifying needs for research evidence in relation to three steps in policymaking processes, namely problem clarification, options framing, and implementation planning
• Finding and assessing both systematic reviews and other types of evidence to inform these steps.
• Going from research evidence to decisions

Typical scenarios have been designed and presented in each article to encourage readers to use the tools described and to help them to decide on the relevant level of detail they require. The authors state that many of the issues and opportunities encountered are similar across setting, thus the tools can be used in a range of settings from low to high income countries. Some of these tools have already been used extensively in the field and have been developed further based on these experiences. Although the tools have been targeted at policy makers and those who support them, they may also be relevant to others such as non-governmental organisations and civil societies.

11 January 2010Cancer cell genomes are known to contain a variety of structural rearrangements that are thought to play a role in the development of cancer. The involvement of structural changes in driving tumour formation has long been recognised, at scales ranging from whole chromosome translocations (such as the Philadelphia translocation associated with chronic myelogenous leukemia), down to much smaller-scale rearrangements. However, much remains unknown about the nature and role of these changes in driving cancer.

Now, a new paper reports high resolution mapping of the chromosome rearrangements in human breast cancer cells. In all, 24 different breast cancers were examined for the number, position and nature of these structural changes [Stephens PJ et al. (2009) Nature 462(7276):1005-10]. Most rearrangements occurred within chromosomes (as opposed to between different chromosomes) and the most common type were tandem duplications; the authors propose that this may due to a specific (unknown) defect in DNA maintenance in breast cancer cells that generates - or fails to correct - this type of rearrangement.

The researchers also observed correlation between the chromosomal rearrangements and different sub-types of breast cancer; for example, oestrogen- and progesterone-receptor negative, basal-like tumours typically had many tandem duplications, whereas oestrogen-receptor positive luminal type tumours had fewer rearrangements and mostly within repeat regions of the genome.

In many cases rearrangements affected genes and resulted in altered or novel gene products, but none of these were recurrent, suggesting that many different, individually rare mutations may be active in breast cancer cells. However, the authors themselves note that much larger numbers of tumours need to be studied before conclusions may be drawn.

Comment: The observation that breast cancer cell genomes, even from a small sample, show a higher diversity and number of structural rearrangements than expected suggests the need for major new research into how different genomic changes are involved in cancer. It will be interesting to see how far genomic features mirror other characteristics by which tumours are classified into these sub-classes; it may also help to identify key targets for new therapeutics common to some tumour sub-groups, improving prospects for more personalised treatment of breast cancer.

8 January 2010Leprosy is a progressive disease that when left untreated can irreversibly damage the skin, eyes and nerves; the associated loss of sensation can also result in injuries and chronic disability. Although it has been largely eliminated in developed countries, leprosy is still a major public health problem and an important preventable cause of disability in many poorer countries. According to the latest report of the World Health Organization (WHO), at the beginning of 2008, the registered prevalence of leprosy globally was 212, 802.

 

Although technically an infectious disease, host genetic factors have been implicated in susceptibility to both infection and disease progression. The clinical course of disease can vary considerably but genetic variation in the causative agent, Mycobacterium leprae, is limited. Recently, the first genome-wide association study (GWAS) of leprosy, one of the largest GWAS on infectious diseases to date, was carried out by scientists at the Genome Institute of Singapore (GIS) who collaborated with 26 institutes in China for the study [Fu-Ren Zhang (2009) N Engl J Med.Dec 31;361(27):2609-18].

 

The GWAS of leprosy analysed half a million single-nucleotide polymorphism (SNPs) in a ‘discovery’ set of 706 affected patients and 1225 unaffected controls, all of whom were Han Chinese from Eastern China. The 93 SNPs showing the strongest association were examined further in three independent groups totalling 3,254 patients and 5,955 controls who were from Han Chinese or from non-Han ethnic groups from Southern China.

 

The researchers found that SNPs from six genes (CCDC122, C13orf31, NOD2, TNFSF15, HLA-DR and RIPK2) were significantly associated with leprosy, four with a particular form of the disease called lepromatous or multibacillary leprosy. Variants of genes present at the NOD2 gene locus, which is involved in regulation of innate (non-specific) immune responses, were found to be associated with susceptibility to infection. Moreover, a network analysis suggested a functional relationship between five of the susceptibility genes, suggesting that they may relate to the same biological pathway.

 

Comment: Since M. leprae cannot be cultured in the laboratory and because it only infects humans and the armadillo, research and consequently the biological understanding of leprosy have been very limited. Thanks to this GWAS, the variants of genes encoding proteins involved in the innate immune response as risk factors for developing leprosy have been highlighted, which should guide further research into the mechanism of leprosy development.

 

5 January 2010 Variant Creutzfeldt-Jakob disease or vCJD is a fatal progressive neurodegenerative condition, the human version of Bovine Spongiform Encephalopathy (BSE), also known as ‘mad-cow disease’. Both these conditions are forms of Transmissible Spongiform Encephalopathy (TSE) or prion diseases; prions are abnormal versions of normal brain proteins that can be transmitted and induce normal proteins to convert to the same abnormally folded form. There is currently no treatment for prion diseases, and recent research has also suggested that prions may be able to effectively mutate and develop resistance to prospective therapeutics (see BBC news).

vCDJ, as opposed to classical CJD (another rare disease, mostly sporadic but with some familial cases), is associated with consumption of beef from cows infected with BSE. The original UK outbreak of vCJD caused major concern about the possible extent of cases, given the large numbers potentially exposed, but over time fears have been somewhat allayed by relatively low numbers of cases, though the incubation period can be very long.

To date there have been fewer than 200 cases of vCJD in the UK, and notably all have been in individuals with a particular variant of the human prion protein PRNP gene, being homozygous for methionine at position 129 in the gene. This genotype, common to about one third of the UK population, is associated with susceptibility to vCJD.

Now a new paper in the Lancet reports the first apparent instance of vCJD in an individual heterozygous (methionine / valine) at this position [Kaski D et al. (2009) Lancet 374: 2128]. The affected man was diagnosed in 2008 and died early in 2009. The authors note the possibility that individuals with the heterozygous genotypes (almost 50% of the UK population) may in fact be as susceptible to infection, but display longer incubation periods before the disease becomes clinically apparent. If this is so, then further cases among this group are likely. However, the authors also note that both susceptibility to infection and disease incubation period may be subject to other genetic influences as yet undiscovered.

A Department of Health spokesperson commented: "The Spongiform Encephalopathy Advisory Committee (SEAC) have noted this finding, which confirms the need for ongoing vigilance and robust surveillance of CJD… We are continuing to provide resources for CJD surveillance and research, and the development of a test for vCJD remains a priority" (see BBC news). Of note, at present definitive diagnosis of vCJD is only possible on the basis of post-mortem examination of the brain, which was not done in the case of this patient; rather, diagnosis was made on the basis of clinical features and brain scans.

Comment: The total number of cases of vCJD expected to emerge in coming years is predicted to be relatively small, in the hundreds; although cases among heterozygotes could boost numbers somewhat, they would be unlikely to make a major difference, particularly if the incubation periods are long. However, there is undoubtedly a gap in current understanding of genetic influences on this and other forms of prion disease that should be addressed by ongoing research.

3 January 2010Evaluation of genetic tests for susceptibility to common complex diseases: why, when and how?
Wright CF, Kroese M. Hum Genet. 2009 Nov 20.

Direct-to-consumer genetics and health policy: a worst-case scenario?
Caulfield T. Am J Bioeth. 2009;9(6-7):48-50.

Direct-to-consumer genetic testing: good, bad or benign?
Caulfield T, Ries NM, Ray PN, Shuman C, Wilson B. Clin Genet. 2009 Nov 21.

Human genomics: The genome finishers.
Dolgin E. Nature. 2009 Dec 17;462(7275):843-5.

How many genetic variants remain to be discovered?
Pawitan Y, Seng KC, Magnusson PK. PLoS One. 2009 Dec 2;4(12):e7969.

Exome sequencing makes medical genomics a reality.
Biesecker LG. Nat Genet. 2010 Jan;42(1):13-4.

Sequencing technologies - the next generation.
Metzker ML. Nat Rev Genet. 2010 Jan;11(1):31-46

Carrier screening, incidence of cystic fibrosis, and difficult decisions.
Liou TG, Rubenstein RC. JAMA. 2009 Dec 16;302(23):2595-6.

Enzyme therapy for Fabry's disease: registered for success?
Knebelmann B, Kurschat C, Thadhani R. Lancet. 2009 Dec 12;374(9706):1950-1.

Lung function and airway diseases.
Weiss ST. Nat Genet. 2010 Jan;42(1):14-6.

Acting like a prion isn't always bad.
Miller G. Science. 2009 Dec 4;326(5958):1338.

Could they all be prion diseases?
Miller G. Science 2009 Dec 4;326(5958):1337-9.

Genomic microarrays in mental retardation: from CNV to gene, from research to diagnosis.
Vissers LE, de Vries BB, Veltman JA. J Med Genet. 2009 Nov 30.

Medicine. A reinnervating microRNA.
Brown RH. Science. 2009 Dec 11;326(5959):1494-5.

Kinase mutations in human disease: interpreting genotype-phenotype relationships.
Lahiry P, Torkamani A, Schork NJ, Hegele RA. Nat Rev Genet. 2010 Jan;11(1):60-74.

Getting connected in the globin interactome.
Ragoczy T, Groudine M. Nat Genet. 2010 Jan;42(1):16-7.

Use of genetics in the clinical evaluation of cardiomyopathy.
Judge DP. JAMA. 2009 Dec 9;302(22):2471-6.

read more ...