In the news

UK Public Health Minister Dawn Primarolo and Science and Innovation Minister Lord Drayson have announced new appointments to the Human Genetics Commission (see HGC press release). The HGC is a twenty-one strong panel that advises the Government on human genetics and particularly associated social, ethical and legal issues. 

Professor Jonathan Montgomery (Professor of Health Care Law at the University of Southampton and Chair of Hampshire Primary Care Trust) will become Chair with effect from 1st February 2009. Professor Montgomery commended the work of his predecessors in the post, Baroness Helena Kennedy and Sir John Sulston, and said: "I am delighted to take up the Chair of the Human Genetics Commission at a time when our understanding of the human genome is beginning to deliver real benefits to individuals and society” (see Department of Health press release).

Other new HGC members are Professor Tim Aitman, Professsor Tom Baldwin, Mrs Nicola Drury; Professor Anneke Lucassen and Dr Duncan McHale; these are all professionals from the health service (including genetics services), academia and the biopharmaceutical industry. Mr Alastair Kent, who is Director of the Genetic Interest Group (GIG), was reappointed for another term.

The first pregnancy following the use of a new prenatal genetic screening technique has been announced by the CARE Fertility Group in Nottingham (see press release). The new technique involves using array comparative genomic hybridisation (array CGH) to screen chromosomes biopsied from the polar body of a fertilised egg following in vitro fertilisation (IVF).

A polar body is the small cell resulting from meiosis during gamete formation, which contains a complementary number of chromosomes to the gamete itself. Two polar bodies are produced – one (entirely maternal in origin) from the egg prior to fertilisation, and one following penetration of the egg by the sperm. These have no known function, and are generally regarded as ‘by-products’ of meiosis. However, by testing both the first and second polar bodies, the chromosomal content of the resultant embryo can be inferred. Even though the majority of aneuploidies are incompatible with fetal development, up to half of eggs in younger women, and up to 75% in women approaching 40, are chromosomally abnormal. Therefore, this technique allows the identification of the most viable embryos for transfer, thereby significantly increasing the chances of a successful pregnancy.

To date, analysis of genetic material in polar bodies has been used for purposes of prenatal genetic diagnosis (PGD) of monogenic diseases (through detection of the disease causing mutation in the polar body, and hence its exclusion from the embryo itself) as well as some aneuploidies of maternal origin. Techniques for pre-implantation genetic screening (PGD) have been developing rapidly in recent times and they have all been based on the use of array CGH (see previous news). However, the disadvantage of these techniques is that they involved the removal of a single cell from the embryo and its freezing during the analysis procedure, which may be detrimental. The improved technique developed by the CARE Group has the advantage that it can be carried out within 24-48 hours negating the need for embryos to be frozen prior to transfer. In addition, analysis of chromosomes in the polar body is performed at an early stage of development and precludes the need for removal of a cell from the embryo.

Although the Human Embryology and Fertility Authority (HFEA) have agreed that the Care Group may offer the treatment to their patients, it is unlikely to become widely available in the NHS for some years, as further research is required to ascertain its benefits, efficacy and safety.

The US National Human Genome Research Institute (NHGRI) has announced new funding for the creation of transdisciplinary research specifically for the study of the ethical, legal, and social implications (ELSI) of emerging genome technologies and the growing proliferation of genomic information. These Centers for Excellence in Ethical, Legal and Social Implications Research, or CEERs, are to seek to integrate basic genomics with clinical and health policy research, ethics, law and the humanities, and to make ELSI findings available to policymakers. Their research teams are to “have the expertise and flexibility to anticipate, conduct research on, and respond rapidly to a range of ELSI issues” (see call for proposals).

The research agenda of the CEERs should focus on a single issue or a set of related issues relevant to the NHGRI's large-scale scientific research initiatives, including the Cancer Genome Atlas (see previous news), Human Microbiome Project (see previous news) and 1000 Genomes Project (see previous news).

A total of almost US $4 million will be made available to fund a total of up to three specialised centres and three exploratory research projects for five years from 2010. Two CEERs at the University of North Carolina-Chapel Hill and the University of Pennsylvania in Philadelphia were previously created as part of an earlier funding round (see previous news).

Controversy continues in the US over stem-cell research, and in particular the use of human embryos to create stem cell lines. New president Barack Obama has previously said he will rescind a previous directive imposed by former president George Bush, which drastically limits federal funding for stem cell research; Bush also used his presidential veto to block moves by the US government to ease these restrictions (see previous news). Obama has also called on Congress to introduce legislation lifting current restrictions, as an alternative to making an executive order to achieve this (see Yahoo news).

In the UK, the Independent newspaper has reported that two of the three current holders of Human Fertilisation and Embryology Authority (HFEA) licences permitting research involving the creation of human-animal hybrid embryos (see previous news) “have been denied research funds needed to continue the work” (see Independent article). The piece suggests that the decision not to fund projects by the Medical Research Council (MRC) and the Biotechnology and Biological Sciences Research Council (BBSRC) may have been due to moral objections to the work by members of the relevant funding committees. However, the MRC has refuted this allegation with a statement from Chief Executive Sir Leszek Borysiewicz, who said: “The suggestion made in the Independent that stem cell research is under threat or that funding has halted is erroneous and misleading. Stem cell research holds great promise and is receiving more funding than ever before from the Medical Research Council”, adding that the system used for decisions on which research proposals received funding could not be influences by a personal moral view (see MRC statement).

While argument continues on both sides of the Atlantic, some new stem cell therapeutics are entering clinical trials. In Scotland recently, two new small-scale trials have been reported; stem cells derived from dead adult donors are to be used as a potential new therapy for corneal blindness (see BBC news), and another trial will assess the suitability of stem cells as a potential treatment for stroke in patients who have not responded well to conventional therapy (see BBC news). The UK Medicines and Healthcare products Regulatory Agency (MHRA) has given permission for this Reneuron trial to proceed (see press release), although the company has faced opposition to its use of stem cells derived from human embryos. The US Food and Drug Administration (FDA) has previously withheld consent to Reneuron stem cell therapy trials, but recently gave clearance for what has been claimed to be “the world’s first human clinical trial of embryonic stem cell-based therapy” for acute spinal cord injury (see press release).

Last month the American College of Medical Genetics (ACMG) announced that genetic carrier screening for the inherited condition spinal muscular atrophy (SMA) should be made available to all US couples. The most common and severest form of this autosomal recessive genetic disease, SMA type 1, is caused by mutations in the SMN1 gene (see previous news); it causes progressive neurodegeneration and paralysis, with death by the age of two.

SMA affects as many as 1 in 6,000 newborns in the US (see Families of SMA website), and the population carrier frequency for disease-associated SMN1 mutations is estimated to be as high as one in 40. Previously, carrier testing has only been made available to couples with a family history of the disorder, but new guidance from the Professional Practice and Guidelines Committee of the ACMG says this should be extended because the disease meets established criteria for population-based genetic screening. Statement author Dr Thomas Prior said: "Because SMA is a common genetic disorder in all populations, carrier testing should be offered to all couples regardless of race or ethnicity" (see press release).

Pre-conceptual or prenatal carrier screening of couples cystic fibrosis (CF) is already available in the US, although for both CF and SMA, only the most common mutations would be detected by the corresponding genetic tests, and hence most (but not all) carriers would be detected through screening.

US health-care provider Kaiser Permanente is to run a new biobank with specimens from patients enrolled in their health care programme (see Nature news article). The respositary reportedly contains 200,000 samples already, with plans to increase this to 500,000 by 2012 thanks to a grant of US $8.6 million from the philanthropic Robert Wood Johnson Foundation. DNA samples will be linked to electronic medical records and information about environmental exposures, which are to include measures of factors such as air quality, exposure to toxins and features of the social / physical environment such as the presence of parks or pavements near to housing. Data is to be made available to researchers around the world.

The venture is part of Kaiser Permanente's Research Program on Genes, Environment and Health, which seeks to examine the genetic and environmental factors that influence common diseases by creating a large population-based database “with enough statistical power to identify even subtle effects of environmental and genetic factors in less common health conditions such as mental health disorders or autoimmune diseases” (see press release).

Assuming it achieves the planned numbers, the resource will not only become the largest biobank in the US, but will also be on a scale to rival the largest such facilities already in development, such as the UK Biobank. In the UK, the Guardian newspaper has claimed that concerns about privacy are preventing individuals invited to participate in UK Biobank from joining the venture. However, chief executive of the project Professor Rory Collins said that data security was not a major issue, with lack of time being the main reason given by those who chose not to participate (see Guardian news article).

Following Royal Assent of the Human Embryology and Fertilisation Act 2008 in November, the Department of Health (DH) is currently conducting a three month consultation on draft regulations to implement the Act. Regulations and proposals have been made which fall into four broad categories:

• The statutory storage period for embryos and gametes: regulations set out the circumstances in which embryos and gametes can be stored beyond the statutory period of 10 years. Amendments include providing for a maximum storage period (of 55 years) rather than imposing a limit of 55 years on the age of patients eligible for treatment.
• The procedure for revocation, variation or refusal of licences: regulations set out the process for considering licence applications when the HFEA is minded to refuse, impose a variation to, or revoke a licence.
• Appeals regulation: regulations set out the membership of, and procedures for, the Appeals Committee to reconsider licensing decisions made by the HFEA.
• The disclosure of information for research purposes: regulations set out the procedure for applying for authorisation for the disclosure by the HFEA of identifying information to researchers. This includes creating an authorisation process by which identifying information can be accessed (and appropriate fee levied by the HFEA) where consent cannot be obtained from donors for the release of that information.

The consultation is aimed at gathering views on key principles of each set of regulations and the draft regulations themselves. The DH is aiming to bring most of the provisions of the Act into force by October 2009 following consideration of the any relevant regulations by Parliament in the summer. However, the provisions of the Act relating to parenthood will come into force earlier, in April whilst those relating to parental orders will commence in April 2010.

The British Fertility Society (BFS), along with a multidisciplinary working group, has also released new UK guidelines relating to laboratory procedure in the screening of sperm, egg and embryo donors in the UK (see press release). The recommendations update and combine in a single document guidelines that had previously been published by the British Andrology Society for sperm donors and the BFS for egg and embryo donors. They are aimed at protecting recipients of donor material as well as any donor conceived people from acquiring infections or serious heritable disorders from the donor. Along with the recommendation that donors should be assessed/screened for infectious diseases and inherited conditions, a new recommendation is the requirement to assess risk of prion-related diseases and the recommendation to screen for human lymphotropic viruses (HTLV) 1 and 2.

To receive our monthly round-up by email please register here (also gives you access to our Resources section).

Go to monthly round-up

The Life and Medical Sciences unit of the European Science Foundation (ESF) has released a science policy briefing on systems biology (see press release). The briefing: Advancing Systems Biology for Medical Applications, provides a detailed strategy for the application of systems biology to medical research. Systems biology is a dynamic, interdisciplinary field that combines mathematical and computational modelling techniques together with experimental data from a variety of sources (e.g. genomics, proteomics, metabolomics etc.) in order to gain a better understanding of biological phenomena. This field can contribute to our understanding of complex diseases by shedding light on how various biological pathways interact.

The document produced by the ESF gives a background to how systems biology is contributing to our knowledge of disease and provides recommendations and steps needed for the integration of systems biology into different areas of medical research. In particular, recommendations have been made relating to research in the fields of cancer, diabetes, inflammatory disease and central nervous system disorders. The authors identify specific areas where a systems biology approach could be applied in each field. For example, in the field of cancer research, the authors recommend that studies should be carried out on well-characterised and important cancers such as colorectal cancer; they also recommend the funding of projects that incorporate data from animal and cell models of disease as well as human samples. In addition, recommendations have been made on how data can be generated for advanced modelling in systems biology and the how dynamic modelling can be facilitated through standardisation and cooperative research. This is an important aspect if systems biology is to advance, as the production of mathematical models requires high quality data as well as the development of appropriate tools for their generation. 

The recommendations are aimed at providing more specific and practical guides to achieving breakthroughs in biomedical systems biology. The authors believe that if they are implemented it will “will help systems biology to fulfil its promise in making a reality of personalized medicine, combinatorial therapy, shortened drug discovery and development, better targeted clinical trials, reduced and even alternatives to animal testing.” and call for a co-ordinated strategy towards systems biology across Europe.

 

 

The UK media have widely reported on the birth of the first baby following screening by preimplantation genetic diagnosis (PGD) to identify embryos carrying an inherited BRCA gene mutation. The Human Fertilisation and Embryology Authority (HFEA) decided in 2006 that PGD inherited predisposition to breast, ovarian and bowel cancers would be permitted (see previous news), despite their relatively low penetrance – meaning that the probability of individuals who inherit the mutation developing a related cancer during their lifetime is relatively low compared with many genetic diseases; in the case of the BRCA gene mutations, up to 80% for breast cancer and 50% for ovarian cancer. The first licence application to perform PGD for BRCA1-linked hereditary breast and ovarian cancer was made in 2007 (see previous news).

Now a baby girl has been born free from the BRCA1 mutation that was present in three generations of women from her father’s family who developed breast cancer. The doctor who performed PGD for the couple commented: "This little girl will not face the spectre of developing this genetic form of breast cancer or ovarian cancer in her adult life…The lasting legacy is the eradication of the transmission of this form of cancer that has blighted these families for generations" (see BBC news).

The news has provoked some ethical discussion around the topic of whether any form of genetic screening is acceptable, despite wide public acceptance in the UK of current antenatal screening programmes such as that for Down Syndrome. There has been speculation as to whether the next step from selecting embryos free from harmful traits will be selecting embryos for the possession of beneficial traits to create so-called ‘designer babies’. Not all these discussions center on scientifically plausible scenarios. The HFEA has taken the step of issuing a press release countering inaccurate media reports prior to the birth of the child in question, clarifying that the embryos produced by IVF were then screened to identify those with the mutation, and these embryos were excluded from implantation; they state that: “The embryo which was chosen was not genetically manipulated or programmed. The cancer causing gene was not removed from the embryo”.

Therapeutics derived from stem cells are considered to hold significant promise as potential interventions against a range of serious forms of injury and disease; however, as yet there are few clinically proven stem-cell treatments. The International Society for Stem Cell Research (ISSCR) released new guidance late last year aimed to ensure that appropriate consideration of relevant scientific, clinical, regulatory, ethical and societal issues is maintained in clinical development and translation. The new document, Guidelines for the Clinical Translation of Stem Cells, looks at steps that need to be completed in order to move from current areas of research to effective therapeutics, and call for rigor and transparency with respect to scientific findings, oversight and consent to participate in clinical trials. The ISSCR specifically criticises clinics that presently “exploit patients’ hopes by offering unproven stem cell therapies, typically for large sums of money and without credible scientific rationale, oversight or patient protections” (see press release) and propose that the new guidance will equip patients and their doctors with the information they need to make informed decisions about whether or not to consider participation in stem cell research trials. An investigation of websites that already offer stem cell therapies for serious diseases has found that most make unproven claims of therapeutic benefits, in countries where provision of such treatments is not strictly regulated such as China and Russia (see Times article); the ISSCR has urged all countries to develop appropriate regulatory systems.

The Roman Catholic Church has released a position statement on human stem cell research; the document Dignitas Personae opposes the use of stem cells derived from aborted human fetuses or embryos created by cloning, but finds the use of stem cells derived from adults, umbilical cords or human fetuses that died naturally acceptable (see press release).

In a significant ruling, the Enlarged Board of Appeal (EBoA) of the European Patent Office (EPO) has ruled against an application from the Wisconsin Alumni Research Foundation for a method of deriving stem cells from human embryos; although the US Patent and Trademark Office granted the patent, the EPO has finally rejected it on the basis that commercial exploitation of the patent would be "contrary to public order or morality" and hence not permissible according to their own convention (see Nature news article). The EBoA stressed that this decision “does not concern the general question of human stem cell patentability” (see press release), and many companies are likely to get round this issue by filing patents for individual countries rather than European-wide patents (see Guardian news article). Had the patent had been upheld, however, it would potentially have covered virtually any application relating to the use of human embryonic stem cells, so that any companies or hospitals using such applications  in Europe could have been compelled to pay licensing fees.

Cardiomyopathy (deterioration of the heart muscle) is a frequent cause of heart failure, and mutations in genes encoding sarcomeric proteins have been associated with heritable forms of this condition. One such gene is MYCBP3, which encodes cardiac myosin binding protein C (cMyBP-C). A recent paper in Nature Genetics describes the identification of a common MYBPC3 variant, which may be associated with increased risk of cardiomypathy in South Asian populations, and a possible mechanism by which it contributes to disease pathogenesis [Dhandapany et al. (2009), Nat. Genet. Jan. 18 doi:10.1038/ng.309].

The variant, a 25 base pair (bp) deletion mutation was initially identified in a previous study of South Asian individuals with inherited hypercardiomyopathy (HCM); however, the study concluded that its relation to hypercardiomyopathy was unequivocal. In order to investigate its relation to disease further, Dhandapany et al. undertook a case-control study of 800 cardiomypathy cases (comprising hypertrophic cardiomyopathy, restrictive cardiomyopathy, and dilated cardiomyopathy cases) and 699 healthy controls in two groups. They found a statistically significant number of cardiomyopathy cases were either heterozygous or homozygous for the 25bp deletion. A much smaller proportion of the controls were  heterozygous, but none were homozygous for the deletion mutation. The group also analysed the frequency of the mutation in India, through screening 6273 individuals in different geographical locations. This showed that although the deletion was found in all major Indian populations, the frequency was higher in southern and western states. In addition, preliminary studies also seemed to indicate that this mutation is present more in South and South East Asia compared to other regions of the world.

The authors suggest that possession of the MYBPC3 variant, may increase risk of cardiomyopathy due to production of an altered protein leading to minor defects in the heart muscle. Furthermore, they suggest that late-onset cardiomyopathy is initiated by accumulation of this protein; however, there may also be other factors that contribute to increased risk, since this variant does not explain all cases of cardiomyopathy and some individuals who are heterozygous for the mutation do not develop the condition. Although the screening for this variant may allow identification of some South Asians at increased risk of cardiomyopathy, it is thought that it only accounts for around 4% of all cases of cardiomyopathy in South Asians. Moreover, the identification of this mutation in South Asian individuals through screening, would currently not alter the medical advice given, nor will it allow identification of those at risk of heart failure, which can have many other causes. More than 200 rare disease-associated mutations affecting 20 different genes have already been identified, highlighting the complex nature of cardiomyopathy.

The limitation of using genetic factors for risk prediction in cardiovascular disease is also high-lighted in a recent paper in the Annals of Internal Medicine. Paynter et al have examined the use of a polymorphism in chromosome 9p21.3 in predicting risk of cardiovascular disease [Paynter et al (2009) Annals of Internal Medicine 150 (2): 65-72]. The authors evaluated the use of conventional risk factors (e.g. blood pressures, smoking, cholesterol levels) and genetic factors in clinical classification of risk for cardiovascular disease, in 22129 white female health professionals. The women had no chronic disease when they joined the study and were followed over a 10 year period. The researchers found that measurement of a single polymorphism in chromosome 9p21.3 location did not improve global risk prediction, when traditional risk factors were known. An earlier study investigating risk prediction of diabetes also demonstrated the limitations of the inclusion of genetic factors (see previous news). However, the results of the present study are perhaps not that surprising, considering that only the contribution of a single polymorphism was evaluated. Risk prediction based on genetic factors is a complex process requiring knowledge based on the cumulative effects of multiple common risk variants (see previous news). In addition to associations between genetic factors and risk, knowledge about the mechanisms by which they contribute to risk is also needed both for better stratification and, more importantly, for the development of novel treatments.

Epilepsy is a neurological condition where individuals are affected by recurrent seizures that correlate with periods of abnormal brain activity. There are various known causes of epilepsy, such as brain damage or a brain tumour, and these are termed symptomatic epilepsy; however, the majority of cases are termed idiopathic epilepsy, having no known root cause. The idiopathic generalized epilepsies (IGE) account for up to a third of all epilepsies, and epidemiological evidence has suggested that they involve complex genetic contributions (see previous news). Now a new paper in the journal Nature Genetics reports an association between microdeletions in a region on chromosome 15 and IGE.

Previous research has suggested that the 15q13-q14 region of chromosome 15 may be involved in epilepsy; susceptibility loci for common IGE syndromes have been mapped to the region, and deletions have been associated with various neuropsychiatric conditions, including epilepsy, autism and schizophrenia. The authors of this new study tested the 15q13.3 region in two independent groups of individuals with IGE and matched controls. The research project was part of EPICURE, an international collaborative research project to study the genomics and neurobiology of epilepsy, with a view to developing novel therapeutic interventions

Together, more than 1,200 individuals with IGE and over 3,600 matched controls were screened. A total of 12 IGE patients were found to have microdeletions in the 15q13.3 region, but none of the controls. This deletion was calculated to be around around fifty times more frequent in IGE than in the general population,

This finding strengthens previous observations of a link between microdeletions in this region of chromosome 15 and idiopathic epilepsy; however, there was not the same association with other neuropsychiatric symptoms previously documented. The phenotype of individuals with the microdeletion varied; a variable degree of intellectual disability was observed in three, but the other nine had neither intellectual disability nor dysmorphic features, and none had any history of psychosis. In addition to identifying the most prevalent genetic risk factor for IGE thus far, the authors also conclude that their findings “imply that shared mechanisms are involved in the pathogenesis of a spectrum of seemingly unrelated neuropsychiatric disorders, and argue for a new framework for understanding complex genetic diseases” [Helbig I et al. (2009) Nat Genet. Jan 11, Epub ahead of print].

Comment: The chromosome 15 region linked with a common, complex form of epilepsy differs from previous genetic susceptibility regions, which have been associated with rare, inherited forms of epilepsy. The implication of structural variants (in this case, microdeletions) as opposed to sequence variants with a complex form of disease is of particular interest. However, the interplay of genetic factors in determining the phenotype of epilepsy, learning disability and neuropsychiatric conditions is likely to prove extremely difficult to decipher.

Evidence-based recommendations produced by the US Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG) on the clinical validity and utility of three genetic tests currently in use in the US have been published in January’s issue of Genetics in Medicine (see press release).  EGAPP’s function is to evaluate genomic tests and applications that are moving from research towards practice in a systematic, evidence-based manner. The group has previously recommended against the use of cytochrome P450 (CYP450) genetic testing as a prelude to the treatment of adults with depression with selective serotonin reuptake inhibitor drugs (see previous news).

New recommendations were made regarding UGTA1A1 genotyping in patients with metastatic colorectal cancer (CRC) treated with irinotecan [EGAPP (2009) Genet Med. 11(1):15-20]; the use of testing strategies to identify Lynch Syndrome among newly diagnosed cases of colorectal cancer [EGAPP (2009) Genet Med. 11(1):35-41]; and the use of three specific tumour gene expression profiling tests in women with breast cancer [EGAPP (2009) Genet. Med. 11(1):66-73]. Summaries of the evidence leading to the recommendations, as well as an article describing the methods and process used by the EWG in collecting, analysing and grading evidence, are also available in this issue of the journal.

In formulating their recommendations, EGAPP begin by addressing a specific clinical scenario (since a single test may be used in different clinical scenarios). An analytic framework and key questions are formulated based upon this clinical scenario, allowing explicit literature searches to be carried out. Evidence in relation to the analytical and clinical validity and clinical utility of a genetic test is gathered along with a consideration of contextual issues in relation to the implementation of testing. Along with assessing the available evidence, this process also identifies gaps in research and the EWG as part of their assessment also describes studies which can contribute to the evidence-base.

The Working Group concluded that there was insufficient evidence for or against the routine use of UGTA1A1 genotyping in patients with metastatic CRC and the use of gene profiling tests in women with breast cancer. However, they felt that there was sufficient evidence to recommend offering genetic testing for Lynch Syndrome in those diagnosed with CRC. The lack of evidence on the clinical utility of UGTA1A1 genotyping and contextual issues demonstrating both benefits and harms of testing, meant that firm recommendations in favour or against this test could not be made. Insufficient evidence to balance the benefits and harms of tumour profiling in breast cancer also precluded a firm decision in relation to this test. In the case of testing for Lynch Syndrome, adequate evidence was available on the analytical and clinical validity as well as clinical utility.

Genetic tests can have a broad public health impact; however, with the increasing development of tests, policy makers need to consider their potential harms and benefits through an evidence-based mechanism prior to their use in clinical practice. This evaluation process requires information on analytical and clinical validity as well as clinical utility. However, due to the absence of a requirement for the formal evaluation of clinical utility, often this information is difficult to obtain. The lack of information on clinical utility has been highlighted many times by both EGAPP and the United Kingdom Genetic Testing Network (UKGTN). The requirement for formal evaluation of clinical utility in order to address this gap in knowledge has been highlighted by a PHG Foundation report on the evaluation of genetic tests and molecular biomarkers. The PHG Foundation has taken specific interest in the policy issues concerned with the evaluation and regulation of genetic tests, and has been closely involved in developing processes for so doing within the UKGTN.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by distinctive beta-amyloid protein plaques and neurofibrillary tangles in the brain, associated with progressive dementia. In the UK, Alzheimer’s disease affects around 417,000 people (according to the Alzheimer’s Society website) and is the leading cause of dementia in the elderly. Late onset Alzheimer's disease or LOAD (with an age of onset of greater than 65) is the main form of this disease, accounting for more than 90% of all cases. The public health burden of LOAD or sporadic AD in developed nations is generally increasing as the population ages.

Although mutations in key genes have been associated with the very rare, familial forms of early onset AD, only one genetic variant (APOE4) has been reliably associated with susceptibility to the common form of disease, although recent research has suggested that a variant of the CALHM1gene may also confer increased risk of LOAD (see previous news). Now new research has identified a new putative susceptibility variant in a gene on the X-chromosome, PCDH11X [Carrasquillo MM et al. (2009) Nat Genet. Jan 11 (Epub ahead of print)].

Writing in the journal Nature Genetics, the US researchers report the findings from a genome-wide association (GWA) study of around 2400 individuals with LOAD and a similar number of controls, all from the US and of European descent. The PCDH11X gene is expressed primarily in the brain and has been suggested to encode a form of neural receptor, making it a plausible candidate for involvement in the pathology of LOAD. Significantly increased disease risk was observed in women homozygous (having two copies) for the gene variant; the association was marginal in women with only one copy of the variant, and not statistically significant in men with a copy. The effect of this variant therefore appears to be gender-specific, since men have only one X chromosome and hence a maximum of one copy of the genetic factor in question. This is the first genetic susceptibility factor for LOAD identified that affects women, but not men, although the greater disease prevalence in women is attributed primarily to their increased longevity following diagnosis.

Comment: Lead researcher Dr Steven Younkin said: "It is exciting to find a new gene for Alzheimer's, particularly the first that has a gender-specific effect, but we have a lot more work to do to resolve the complex genetics of the disease" (see BBC news). Of note, LOAD is a multifactorial disease, thought to arise due to a combination of multiple genetic and environmental factors; each genetic variant linked to the condition is likely to be associated with relatively small effects in terms of disease risk. However, every new factor linked to the disease provides an opportunity for improved understanding of the disease process and possible interventions to prevent or limit pathology, as well as contributing to the overall picture of genetic susceptibility. Whether the reported new association will be reproducible, particularly in different ethnic populations, remains to be determined.

Prion diseases are progressive neurodenegerative conditions that can be transmitted in a manner akin to infectious diseases, although the ‘infectious agent’ is not a living organism but rather a prion protein (PrP) that stimulates the autocatalytic misfolding of other PrPs in the host. Such diseases can affect both animals and humans, for example scrapie in sheep, and kuru in humans. Perhaps best known is bovine spongiform encephalopathy (BSE) in cattle, and epidemic of which in the UK and other countries exposed much of the human population to abnormal PrPs via the consumption of animal products. Subsequently, a new form of prion disease, variant Creutzfeldt-Jakob disease (vCJD), was identified in young adults and found to be caused by BSE-like prions.

It is not known how many millions of individuals were exposed to the BSE prions, but a very low number of cases of vCJD have been diagnosed to date, less than two hundred. However, since the incubation period for the disease can be extremely long, it is not known how many more cases may yet appear, and there is significant interest in the genetic basis of susceptibility and resistance to infection. The best known genetic variant involved is a common single nucleotide polymorphism (SNP) in the PRNP gene that encodes the human form of PrP. All patients with clinical vCJD who have been genotyped are homozygous for methionine at position 129 in the PRNP gene; however, since around a third of the UK population share this genotype, there are presumed to be other genetic factors involved in susceptibility.

A paper in the journal Lancet Neurology reports the findings from a genome-wide association (GWA) study that compared samples from 119 vCJD patients with several hundred controls from the Wellcome Trust Case-Control Consortium (see previous news). The researchers also compared the strongest SNP associations with several hundred samples from patients with other forms of prion disease, including iatrogenic CJD (iCJD), sporadic CJD (sCJD), and kuru [Mead S et al. (2009) Lancet Neurol. 8(1):57-66]. Several variants within the PRNP gene locus were found to be strongly associated with prion disease risk; the previously identified codon 129 showed the greatest contribution to disease risk, but a new SNP from the region was also found to be involved. Another variant upstream of the RARB (retinoic acid receptor beta) gene showed weaker association with vCJD and also with iCJD. Yet another variant in a region upstream of the STMN2 gene was associated with prion disease more generally, including resistance to vCJD and kuru, and age of onset of sCJD. The STMN2 gene encodes a protein called SCG10, which regulates microtubule stability in neuronal cells.

The researchers conclude that their study confirms the primary importance of the PRNP codon 129 SNP as the outstanding genetic risk factor in human prion disease. The new associations identified were less robust, but still significant taking into account the inherent limitations of a study with so few case samples. They therefore propose that the genes closest to the three candidate SNPs (PRNP, STMN2 and RARB) warrant further investigation as potentially being involved in prion pathology, and postulate that susceptibility conferred by these variants may also contribute to vCJD cases

Comment: This research presents the first GWA to look for associations with susceptibility to prion disease in humans, although the small number of cases of vCJD at the present time has limited the strength and reliability of the findings. However, the results may nevertheless lead to further useful investigations. Better understanding of the genetic factors involved in susceptibility to BSE infection in humans may not only allow estimation of the probable scale of public health problem likely to emerge in coming years as a result of sub-clinical vCJD infections becoming symptomatic, but also contribute towards elucidation of the mechanisms by which the disease becomes established and progresses – and hence towards efforts to devise a therapy.

Influenza or flu is a highly infectious viral disease; seasonal epidemics occur due to minor genetic variation in the viral particles that allow them to evade the human immune system. Occasionally, a human flu virus may acquire a whole new segment of genetic material from another flu virus, such as a strain that normally infects birds or pigs. A virus that can infect humans, but which is genetically very different from previous strains, can cause a pandemic (world-wide epidemic), because humans have no resistance to the new strain. Pandemic flu not only causes a massive increase in infections, but may also have severe effects in unexpected groups; whilst epidemic flu is generally only serious in the very old, very young, or ill, previous pandemics have caused high mortality in otherwise fit young adults.

Based on previous experience, a new flu pandemic is in many ways overdue: there have been pandemics in 1918, 1957 and 1968, and the World Health Organization (WHO) is concerned that conditions “favouring the emergence of a pandemic virus are…well known, and are increasingly being met” (see WHO report) and that there is a significant risk of another pandemic within the next few years. This is obviously a major public health concern, and substantial research efforts are going into developing candidate vaccines and treatments, and systems to deliver them should the need arise.

New genetic research has revealed the sequences of three key genes from the influenza H1N1 variant strain that caused the 1918 Spanish flu pandemic, which resulted in up to 50 million deaths. It was already known that the virulence of this strain was linked to its unusual capacity to invade the lungs and cause severe pneumonia; now a paper in the journal Proceedings of the National Academy of Sciences (PNAS) identifies three key genes that allowed the virus to do so.

The Japanese-American team generated 1918 pandemic viruses using DNA taken from lung tissue that came from victims of the pandemic. They then created viruses from a combination of the 1918 strain and a modern, low-virulence H1N1 virus, and assessed their virulence in ferrets, which are apparently a fairly good animal model of the human disease [Watanabe T et al. (2008) Proc Natl Acad Sci U S A. Dec 29, Epub ahead of print]. Most of the new recombinant strains showed only normal patterns of infection and spread, but one that produced the 1918 viral RNA polymerase complex and nucleoprotein showed virulence much more like that of the 1918 pandemic strain, including spread to the lower respiratory tract and lungs.

A reassortant virus containing the 1918 viral RNA polymerase complex genes (PA, PB1, and PB2) and nucleoprotein (NP) gene showed virulence properties in the upper and lower respiratory tracts of ferrets that closely resembled those of wild-type 1918 virus. The authors conclude that their findings “strongly implicate the viral RNA polymerase complex as a major determinant of the pathogenicity of the 1918 pandemic virus”. The 1918 RNA polymerase complex may be involved in generally increased viral replication capacity, or in tissue-specific increased replication capacity; for example, modulating interactions with a cellular factor that is present in the lower respiratory tract

Comment: Although not in every respect as exciting as it sounds, given that genetic virulence factors and an unusual propensity to colonise the lungs were already known for the 1918 influenza virus, the findings of this research are nevertheless important since they link the key genetic virulence factors from the 1918 flu virus with lung spread and invasion. This sort of information will inform ongoing monitoring of emerging viral strains to identify potentially dangerous ones, as well as contributing to research into new forms of anti-viral drugs to combat the most serious effects of a pandemic strain. Intervention to avoid spread of the virus to the lungs during an infection could prevent many deaths.

A paper in Nature reports on the creation of an in vitro model of the genetic disease spinal muscular atrophy (SMA) using skin cells from an affected child (see also BBC news). SMA is an autosomal recessive genetic disorder caused by mutations in the SMN1 or SMN2 (survival motor neuron 1 or 2) genes, which leads to degeneration of specific motor neurons and progressive paralysis. Patients with SMA 1 typically die by age 2; SMA2 is generally less severe as low levels of functional SMN2 protein are still produced. A team of American researchers sought to create a human cell-based system to study the mechanisms by which motor neurons degenerate and how the SMN proteins function [Ebert AD et al. (2008) Nature doi:10.1038/nature07677].

Using fibroblast cells from an SMA1 patient and his unaffected mother, they generated induced pluripotent stem cells (iPS cells) using vectors based on lentiviruses to introduce the necessary genes OCT4, SOX2, NANOG and LIN28. Both wild-type and SMA cell-lines were established, and showed normal replication and growth. Analysis of RNA from the original fibroblast and iPS cells showed that intact (full-length) SMN1 transcripts were present in both forms of wild-type cells, but neither the original nor the induced pluripotent SMA cells.

The researchers next generated neurons and astrocytes from the iPS-SMA and iPS-WT cells; 4 weeks after differentiation was induced, both types of cell-lines had given rise to similar numbers of neurons, including motor neurons. However, 6 weeks after differentiation, the number and size of motor neurons was significantly reduced in the iPS-SMA cells compared with the iPS-WT cells, although the overall growth of other neuronal cells was not affected. This suggests that the disease-phenotype of the iPS-SMA initially allowed normal growth and differentiation of neuronal cells, but later shows selective loss of motor neurons compared with the wild-type cells.

Finally, treatment of the iPS cells with compounds known to increase production of SMN protein from the functional SMN2 gene showed evidence of increased SMN production similar to that observed in fibroblasts, suggesting that the system could be suitable for screening potential drugs to ameliorate the disease. Referring to the development, research lead Clive Svendsen of the University of Wisconsin-Madison commented: "Now you can replay the human disease over and over in the dish and ask what are the very early steps that began the process. It's an incredibly powerful new tool" (see press release).

Comment: Previous research created patient-specific induced pluripotent stem cells from individuals with different genetic diseases (see previous news); this paper is new not only with respect to the disease studied, but also in demonstrating disease-specific loss of cell function and survival when compared with equivalent cells from a healthy patient, lending weight to the assertion that iPS cells can reproduce elements of pathology. Although further investigation will be required to determine whether or not the cell-based system is definitely reproducing the actual disease processes (as opposed to some effect arising from the processes used to induce pluripotency and neuronal differentiation leading to loss of motor neurons), it is likely to prove valuable both for further investigation of disease processes, and for in vitro screening of potential therapeutics. It is sad to think that the trial subject is unlikely to benefit directly from the research, given the typically rapid progression of disease, but shows how families affected by serious diseases may chose to participate in clinical trials in the hope that others may benefit in the future.

Helsinki discords: FDA, ethics, and international drug trials.
Kimmelman J, Weijer C, Meslin EM. Lancet 2009 Jan 3; doi: 10.1016/s01406736(08)61936-4.

A favourable (molecular) signal for personalised medicine.

Lancet 2009 Jan 3; doi: 10.1016/S0140-6736(08)61934-0

Genotype-phenotype databases: challenges and solutions for the post-genomic era.
Thorisson GA, Muilu J, Brookes AJ. Nat Rev Genet. 2009 Jan;10(1):9-18.

Integrative biology - a strategy for systems biomedicine.
Liu ET. Nat Rev Genet. 2009 Jan;10(1):64-8.

A scientific approach to policy.
Alberts B.Science. 2008 Dec 5;322(5907):1435.

Is the grass greener? From health statistics to policy decisions.
Crook ED, Hundley TJ. Lancet. 2009 Dec 20;372(9656):2090-2. Epub 2008 Nov 17.

Progress and challenges in genome-wide association studies in humans.
Donnelly P.Nature. 2008 Dec 11;456(7223):728-31.

Cohort studies and the genetics of complex disease.
Manolio TA. Nat Genet. 2009 Jan;41(1):5-6.

Detecting shared pathogenesis from the shared genetics of immune-related diseases.
Zhernakova A, van Diemen CC, Wijmenga C. Nat Rev Genet. 2009 Jan;10(1):43-55.

Breast cancer susceptibility: current knowledge and implications for genetic counselling.
Ripperger T, Gadzicki D, Meindl A, Schlegelberger B. Eur J Hum Genet. 2008 Dec 17.

Legal update: living with the Genetic Information Nondiscrimination Act.
Erwin C. Genet Med. 2008 Dec;10(12):869-73.

Prostate cancer genomics: towards a new understanding.
Witte JS. Nat Rev Genet. 2008 Dec 23.

Molecular diagnosis of Fragile X syndrome.
Sofocleous C, Kolialexi A, Mavrou A. Expert Rev Mol Diagn. 2009 Jan;9(1):23-30.

Regeneration games.
Watts G. BMJ. 2008 Dec 3;337:a1321. doi: 10.1136/bmj.a1321.

Obama transition. A fresh start for embryonic stem cells.
Holden C. Science. 2008 Dec 12;322(5908):1619.

 

Quantitative genetics.
Gunter C. Nature. 2008 Dec 11;456(7223):719.

Is obesity our genetic legacy?
Blakemore AI, Froguel P. J Clin Endocrinol Metab. 2008 Nov;93(11 Suppl 1):S51-6.

Celebrating a year of Science.
Alberts B. Science. 2008 Dec 19;322(5909):1757.

Analysis: Secretary's Advisory Committee on Genetics, Health, and Society Report falls short.
Klein RD. Hum Pathol. 2008 Dec 10.

Shared Genetic Risk Factors for Type 1 Diabetes and Celiac Disease.
Plenge RM. N Engl J Med. 2008 Dec 25;359(26):2837-8.

 

Searching for targets of viral microRNAs.
Whitby D. Nat Genet. 2009 Jan;41(1):7-8.

 

Evaluating signatures of sex-specific processes in the human genome.
Bustamante CD, Ramachandran S. Nat Genet. 2009 Jan;41(1):8-10.

 

Protein demethylation required for DNA methylation.
Hotz HR, Peters AH. Nat Genet. 2009 Jan;41(1):10-1.

 

The many roles of histone deacetylases in development and physiology: implications for disease and therapy.
Haberland M, Montgomery RL, Olson EN. Nat Rev Genet. 2009 Jan;10(1):32-42.

RNA Seq: a revolutionary tool for transcriptomics.
Wang Z, Gerstein M, Snyder M. Nat Rev Genet. 2009 Jan;10(1):57-63

In tough times, personalized medicine needs specific partners.
Ballantyne C. Nat Med. 2008 Dec;14(12):1294.

read more ...