News

27 February 2009A new report from the March of Dimes says that almost all newborns in the US now receive recommended newborn screening for serious genetic diseases; in previous years there has been major variation in practice across different states, so that the geographical location at which a child was born had a significant influence over which conditions they would be screened for. All 50 states and the District of Columbia reportedly now require that newborns are screened for at least 21 of the 29 ‘core’ genetic diseases on the panel recommended by the American College of Medical Genetics (see previous news), although Pennsylvania and West Virginia had still to implement their newly expanded screening programmes as of the end of December 2008. 

Screening for a larger number of diseases has become possible in recent years due to the development of a technique called advanced tandem mass spectrometry (MS/MS). Early identification of babies affected by metabolic and other disorders can allow prompt treatment to minimize or even avert the effects of disease. Implementation of the expanded ACMG panel of 29 disorders began in 2006, although it has been noted that clinical management of rare disorders identified via expanded newborn screening programmes can pose a problem (see previous news). Not only is appropriate clinical expertise required, but in some cases the only effective interventions are extremely expensive.

In general, expansion of newborn screening programmes can allow early detection and treatment of serious diseases; however, in some cases diagnosis is possible for disorders for which there are as yet no effective treatments, and inclusion of such diseases in newborn screening panels is more controversial, with practice varying around the world. There is also debate over whether early diagnosis confers genuine clinical benefit for some conditions (see previous news).

Referring to the latest findings and commending the increasing equity of access to expanded newborn screening, March of Dimes president Dr Jennifer Howse commented: “With the help of volunteers, parents and our partners, we have nearly erased the cruel injustice that sentenced babies to an undetected but treatable metabolic or functional condition based on their birth state.  This is a success story” (see press release).

23 February 2009Seven high-profile biomedical journals have this month published recommendations for the reporting of genetic association studies framed within a statement and checklist. Entitled STrengthening the REporting of Genetic Association studies, STREGA is an extension of the STROBE statement (STrengthening the REporting of OBservational studies in Epidemiology) published back in 2007 [Von Elm et al. (2007) PLoS Med 4(10):e296 ; Vandenbroucke et al. (2007) PLoS Med 2007 4(10):e297].

A tremendous increase in the volume of published literature addressing gene-disease associations over the past decade - along with inadequate reporting of study methods and results - has led to increasing difficulties in assessing the strengths and weaknesses of this rapidly evolving evidence base. This in turn has hampered researchers in their attempts to identify methodological biases in these studies and their synthesis together with existing research and the interpretation of this knowledge. Motivated by these difficulties, a multidisciplinary workshop took place in Ottawa, Canada in June 2006 using the experiences of the human genome epidemiology network (HuGENet) and the work conducted by the working group on STROBE. This workshop brought together approximately thirty epidemiologists, geneticists, statisticians and journal editors with the objective of providing guidance built on the STROBE statement for reporting the results of studies of gene-disease associations.

Using the same outline as the STROBE report, STREGA introduces concepts that are of particular interest in genetic association studies such as genotyping error, population stratification, modelling haplotype variation, Hardy-Weinberg equilibrium, and replication. Additional items also include information on the selection of participants, the rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods used, relatedness of study participants, reporting of descriptive and outcome data, and the volume of data. The STREGA report also presents evidence-based rationale for the inclusion of these topics into the guidelines along with specific suggestions for reporting. It is hoped that these recommendations will encourage greater transparency in the reporting of genetic association studies which will lead to greater facilitation of evidence synthesis leading to greater understanding of the role of genetic factors in disease causation. The STREGA workshop report and recommendations are available at www.strega-statement.org.

STREGA co-author Dr Julian Higgins of the MRC Biostatistics Unit in Cambridge commented, “The simultaneous publication of the STREGA recommendations by seven diverse journals highlights the recognised need for improved reporting of genetic association studies. By encouraging authors to think about how to report what they have done, we hope ultimately to ensure that the underlying research is performed to the highest epidemiological and genetic standards”.

List of Journals co-publishing the STREGA report:

• Annals of Internal Medicine
• European Journal of Epidemiology
• European Journal of Clinical Investigation
• Genetic Epidemiology
• Human Genetics
• Journal of Clinical Epidemiology
• PLoS Medicine

18 February 2009The UK Clinical Molecular Genetics Society (CMGS) has recently completed the latest annual audit of National Health Service genetics laboratories. The 2007-8 figures show a significant rise in the total number of samples processed for NHS services (as opposed to research), increasing by 40% to a total of 152,593 for the 26 out of a total of 28 laboratories that provided audit data.

For postnatal reports there was a 20% increase on the previous year to more than 99,000 in total (excluding leukaemia and DNA storage samples), and a 15% increase in single gene disorder reports. The most frequently performed tests were for cystic fibrosis (12%), Fragile X syndrome (11.6%) and familial cancer BRCA gene mutations (10%). This order is the same as for 2005-6 (see previous news), but the proportion of cystic fibrosis and Fragile X tests has fallen and that of BRCA tests increased since then. The fourth most common category of postnatal reports was for DNA bank samples (6.2%), ahead of hereditary haemochromatosis HFE gene mutations (5.7%). Factor V Leiden mutation testing has fallen from 3.6% of all postnatal reports in 2005-6, to 1.1% for 2007-8. In all, more than 400 different categories of postnatal report were recorded.

The total number of prenatal reports was similar to the previous year at more than 7500; the majority of these were for common aneuploidies (79%). The total for indications other than aneuploidy testing was 11% higher than the previous year at 1347; of these, the most common category was cystic fibrosis tests (27%), followed by cell-free fetal DNA samples for analysis (11%) – see previous news for more information about this emerging form of early non-invasive prenatal diagnosis, which may account for much of the total rise in test numbers. Sickle-cell anaemia was the third most common test indication (10%).

Numbers of predictive and confirmatory tests are now being assessed for the Genetics and Insurance Committee (GIAC) report, with a similar total number of tests recorded as for the previous year (5874). The most common test was for BRCA 1/2 mutations associated with familial breast and ovarian cancer (more than 2000 in total), followed by the most common forms of familial colorectal cancer, HNPCC (~750) and FAP (~250). Huntington’s disease, Marfan syndrome, long QT syndrome and familial hypercholersterolaemia each accounted for around 250 tests.

17 February 2009 The US Genetics and Public Policy Centre (GPPC) has released a report outlining its findings from a public consultation project aimed at gathering information about the public’s attitude and willingness to participate in a proposed large cohort study (see press release). The project was initiated following interest by federal agencies such as the US National Institute of Health (NIH) in conducting a large cohort study that would gather information on participants’ genes, environment and health and follow them over the course of 10 years in order to better understand the interaction between these factors. It is hoped that the findings from the pilot consultation study conducted by the GPPC will help inform the design and implementation of the proposed biobank as well as further public consultation exercises associated with such ventures.

The GPPC gathered information on public attitudes through conducting a series of sixteen focus groups in six locations across the US, individual interviews with community leaders, a national survey and Town Hall meetings. Meetings were conducted in order to gather further feedback from the public and attempts were made to ensure that these sessions represented the demographics of each location. Attendees were asked to consider and give their views on issues such as the benefits and burdens of the proposed study, acceptable and unacceptable types of research and policy needs amongst others.

The report concluded that most people who attended the sessions agreed with the proposed biobank venture, even though some of those who agreed with the proposal would not participate in the actual venture. Although the sessions were viewed favourably and were thought to be an effective means of gathering public views, the authors of the report felt that it had its limitations in terms of representing the community. Most people who attended the session were more highly educated than the general populace and more efforts need to be made in order to increase attendance by all segments of the community.

Comment: Biobank ventures are becoming increasing important as researchers try to understand how interactions between genes and the environment influence health, requiring studies to examine genetic factors, environmental exposures and health outcomes in large population groups over extended periods. However, their success depends on ensuring acceptance and participation from members of the general public. Many issues and concerns such as privacy, return of results and regulation of such studies may deter people from participating or contributing to such ventures, and there have been various initiatives to assess these concerns and consider how to address them (see previous news). Public engagement activities are necessary to understand public attitudes to such research and ensure that their concerns are adequately addressed.

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12 February 2009The use of fetal nucleic acids (primarily DNA at present, but also RNA) from a sample of maternal blood taken early in pregnancy is an exciting new technique with potential to improve various forms of antenatal testing by allowing earlier diagnosis without the risk associated with current invasive techniques. A new report from the PHG Foundation in Cambridge, Cell-free fetal nucleic acids for non-invasive prenatal diagnosis, sets out the findings of a UK Working Group of technical experts, National Health Service (NHS) providers and wider stakeholders for the Joint Committee on Medical Genetics (JCMG) of the Royal College of Physicians.

Funded and led by the PHG Foundation, this group was convened to assess the prospects for this technique in the UK and implications for the NHS. Bodies represented include the Royal College of Obstetricians and Gynaecologists, the Royal College of Midwives, the British Maternal & Fetal Medicine Society, the UK National Screening Committee, the Human Genetics Commission and the Genetic Interest Group and Antenatal Results and Choices charities, as well as expert scientists and clinicians, NHS managers and policy makers, and experts in law and ethics. Conclusions and recommendations include:

• Reliable non-invasive prenatal diagnosis using fetal DNA is already possible for some applications and likely to become available for others within the next 3-5 years.
• The NHS should take steps now to ensure that it is able to respond in a timely and appropriate manner as the technology develops. This includes formal evaluation for different purposes, development of specified care pathways and national best practice guidelines, and oversight from the appropriate authorities.
• Both public engagement efforts and health professional education about the potential and limitations of the technique are urgently needed.
• The technique should only be used according to standardized protocols within agreed clinical pathways, with formal audit and monitoring processes, and quality assurance frameworks. This will ensure appropriate use and accurate, reliable results.
• Non-invasive prenatal diagnosis is already available privately on a direct-to-consumer basis, and may have an increasing impact on NHS primary care and antenatal services. A voluntary code of conduct should be supported to help ensure the quality of private services.
• Ethical and social issues associated with some of the broader implications of non-invasive prenatal diagnosis using fetal DNA warrant further consideration and research.

JCMG chair Professor Trevor Cole commented: "The PHG Foundation has led a large multidisciplinary expert group to produce this timely appraisal of non-invasive prenatal diagnosis. The report provides an authoritative account of the technologies and their current and possible future uses in clinical care and sets out clearly the many issues that will need to be addressed. Organisations and individuals with an interest in this area should use it as a valuable source of information about the technology and its wider implications, and as a starting point for further work” (see press release), adding that the “excitement and opportunities of technology…need to be balanced against the necessity of properly validated techniques, effective and patient centred clinical services and responsible actions of society".

10 February 2009 The US National Human Genome Research Institute (NHGRI) has been releasing a series of white papers as part of its long range planning process on the future of human genome research (see press release). Although termed white papers, these documents in fact pose a series of questions relating to different aspects of human genome research with the aim of stimulating discussion and identifying how the NHGRI can contribute to advances in genomic research. Community members have been asked to comment and review the questions in each document, so that the NHGRI can identify topics for further planning activities and workshops.

The first two documents contain questions pertinent to applying genomics to clinical problems and have been further divided into questions pertaining to diagnostics, preventive medicine, and pharmacogenomics and those pertaining to therapeutics. The questions raised include addressing how genetically-based diagnostic or risk assessment strategies add to existing medical technologies and what information and decisions support mechanisms will convince and aid physicians to employ such strategies. In terms of therapeutics, the NHGRI feel that it can contribute by considering such things as what the critical gaps in infrastructure are and how efforts to define the mechanistic underpinnings of disease predisposition, initiation, and/or progression can be improved.

The third paper relates to education and community engagement and raises questions relating to health professional education as well as public education and community engagement. The final paper on the future of human genome sequencing contains a series of poses a number of questions raised by the emergence of next-generation and third generation sequencing technologies, such as their consequences for biomedical research and the value of continued development in these technologies.

The NHGRI will receive comments on the questions posed in these white papers till the end of February and based upon these responses a mature set of questions will be established and open for comment from mid-March. The institute’s previous planning process resulted in the publication of an article in Nature in which leading figures from the NHGRI outlined their vision for the future of human genomics (see previous news).

5 February 2009In the US, a federal court is considering whether or not the nucleotide sequence of a gene is ‘obvious’ or not; if so, it cannot be patented. There are four key criteria by which patent applications are weighed: whether the invention described is novel, useful, non-obvious, and described in sufficient detail to allow another expert to reproduce or use it for the described purpose.

Prior to May 2007, finding the sequence of a gene encoding a protein that was already known to science was considered a patentable discovery in the US, and millions of gene sequence patents have been filed. However, a final ruling in the current case relating to a patent application filed by Kubin could be pivotal. The Kubin patent claims the nucleotide sequence encoding a protein at least 80% similar to the cell surface Natural Killer (NK) Cell Activation Inducing Ligand (NAIL) protein; however, the US Patent and Trademark Office (USPTO) rejected the application in early 2007 on the grounds that, since the protein had previously been isolated and the essential techniques used to determine the genetic sequence had previously been described, obtaining the nucleotide sequence required only routine biotechnological skills and was therefore an obvious step according to 35 U.S.C. § 103 [Kintisch E (2009) Science. 323(5913): 452-3].

Kubin appealed against the patent examiner’s decision to the Board of Patent Appeals and Interferences (BPAI), but the BPAI issued a precedential decision affirming the patent examiner’s rejection in May 2007. The current case is another appeal by Kubin to the Federal Circuit Court of Appeals; meanwhile, the legal status of gene sequence claims in the US remains uncertain (see PharmExec article). Depending on how this is eventually resolved, the way in which researchers seek to patent their work in order to allow commercial exploitation may have to change, especially for diagnostic applications.

3 February 2009 The Molecular Oncology Task force of Cancer Care Ontario has released a report on laboratory testing and clinical genetic services in Ontario (see press release). Cancer Care Ontario is the agency responsible for the improvement of cancer services in the province of Ontario and advices the government on these issues. The report has identified areas to be addressed if genetic testing in Ontario is to keep pace with advances in this field and makes recommendations aimed at ensuring Ontarians have access to high quality services.

The report's authors state that although there is a strong licensing and quality assurance programme in place in this region, this has not kept up with the rapid pace in the development and availability of predictive genetic tests. In addition, there are no effective mechanisms to evaluate the clinical and analytical validity, clinical utility and cost-effectiveness of new tests. In order to combat this gap, the Task Force recommends the implementation of an oversight body which will be responsible for a test approval process following evaluation of the evidence base. They also recommend implementation of a mandatory approval process for each genetic test performed by laboratories and a process by which patients and providers can be educated about the tests. The Task Force warns that “Not addressing these issues will result in insufficient infrastructure to meet growing demands and an inability to implement and fund new tests.”

Although these recommendations have been made with the view of improving genetic testing services in the field of cancer, they also apply to many other fields of medicine. The system suggested by the Task Force is very similar to that in place in the UK. Here, the UK Genetic Testing Network functions as an oversight body that evaluates new tests for inherited disorders and acts as an advisory body to the NHS. It works with laboratories, commissioners, clinical genetic teams and patient support groups. However, many new biomedical tools and interventions are emerging, and the PHG Foundation considers the evaluation of such tools to be of importance. Our work stream on the Evaluation and regulation of genetic tests is focused on working with national and international bodies to achieve appropriate levels of assessment and oversight for genetic tests and biomarkers.

25 February 2009It has been estimated that around 15% of cancer cases worldwide are linked to viral infections, accounting for 1.5 million cases and 1 million deaths per annum. Particularly well studied oncogenic viruses include the human papilloma virus (HPV) linked with cervical cancer, the hepatitis B virus (HBV) linked with liver cancer, and the Epstein-Barr virus (EBV) linked with lymphomas and nasopharyngeal tumours. All these viruses have long latent periods of inactivity, and only a small minority of those infected will go on to develop cancer. The reasons why this infection is either controlled or progresses are largely unknown.

 

New research from the Cancer Epigenetics Group in Spain sheds some light on this question, by looking at patterns of DNA methylation of viral genomes [Fernandez et al. (2009) Genom Res, doi:10.1101/gr.083550.108]. Methylation of DNA is a well studied phenomenon that occurs throughout the genome to alter gene expression in a heritable fashion, so that silencing or activation of a specific gene can be passed on to future generations of cells. It has previously been strongly linked to cancer, through methylation and silencing of tumour suppressor genes (so-called ‘epimutations’).

 

Researchers examined the methylation status of HPV, HBV and EBV genomes in a range of individuals, from asymptomatic healthy carriers, through those with chronically infected tissues and premalignant legions, to those with full-blown invasive tumours. In all cases, they observed that the viral genomes became increasingly methylated as the cancers progressed, leading the authors to suggest that DNA methylation might be a strategy for camouflaging the virus from the human immune system. This has ramifications for the use of DNA demethylating agents in chemotherapy (both approved and in development), which in addition to reactivating tumour suppression genes that have been silenced by methylation, might also reactivate the virus and thereby potentially enhance the therapeutic benefits by increasing the natural immune response.

 

Comment: the finding that viral genomes become increasingly methylated in association with the progression of cancer is perhaps somewhat surprising, given that methylation is usually associated with silencing rather than activation. It therefore suggests a novel mechanism by which the virus exerts its oncogenic effects, and highlights the complex interplay between the host immune system and the viral genome. Regardless of the mechanism, the discovery could have major public health implications in the future for both diagnosis and early treatment of viral cancers.

24 February 2009 Accurate prognosis of colorectal cancer is dependent upon assessment of the growth and spread of tumour cells. The current method for detecting spread of colorectal cancer to lymph nodes involves histological examination of samples of lymph node tissue in order to identify tumour cells. If tumour cells are detected, patients receive adjuvant chemotherapy in order to reduce the chances of the tumour recurring. However, as this method only examines samples of lymph node tissue, there is a possibility that occult (hidden) metastases may be present, resulting in disease recurrence in some patients whose histology results are negative for tumour cells.

Recently, a study by researchers at Thomas Jefferson University have shown that a molecular test may be a more sensitive means of identifying patients who have occult metastases (see press release). The test is based on examining the expression of a biomarker - guanylyl cyclase 2C (GUCY2C), an enzyme receptor that is selectively expressed by intestinal epithelial cells and over expressed by tumour cells. A previous study has shown an association between GUCY2C levels and colorectal cancer recurrence, suggesting it is a good biomarker [Cagir B et al. (1999) Ann. Intern. Med. 131(11):805-812].

In a new study, Waldman et al. examined the expression of GUCY2C in lymph node tissue of colorectal cancer patients in whom tumour cells were not identified by histopathology [Waldman SA et al. (2009) JAMA 301(7): 745-752]. They examined the levels of GUCY2C messenger RNA using reverse transcription PCR in samples from 227 patients and followed them over the course of approximately two years in order to assess disease recurrence. They found that 87.5% of these patients were positive for GUCY2C expression in at least one lymph node and follow-up indicated that 20.9% of those whose lymph nodes were positive for GUCY2C expression had disease recurrence in comparison with 6.3% who were negative for expression. In addition, in those who expressed GUCY2C, disease recurred after a shorter time and disease free-survival was also shorter. This prospective study corroborates the findings of the previous retrospective study, indicating a link between GUCY2C and disease recurrence. Furthermore, the study results suggest that monitoring GUCY2C expression may be a more sensitive means of detecting occult metastases and may aid in identifying those who might benefit from adjuvant chemotherapy, which is usually given to those who have metastases detected in lymph nodes by histopathology.

Comment: Methods to accurately assess tumour spread are important in determining the precise stage of the disease which in turn influences management of the condition. Molecular methods can be more sensitive than histopathological methods, having the capacity to detect one cancer cell in a million normal cells as opposed to one cancer cell for every two hundred normal cells. Molecular analysis requires the identification of suitable biomarkers and their validation. This study highlights a promising method to better stratify those with colorectal cancer and target treatment strategies. However, this test will have to be validated in a larger study in order to see if it truly does aid prognosis. In addition, only a small proportion of those expressed GUCY2C (20.9%) had recurrence of disease, suggesting that other factors may also influence disease recurrence.

19 February 2009Stem cell transplantation is considered by many to hold great hope as a potential treatment for all sorts of serious diseases and injuries. However, concerns have previously been confessed about safety, which is why trials of therapeutic transplantation are carefully regulated in many countries including the UK (but currently to a far lesser degree in countries such as Russia and China – see previous news), and why no technique is yet considered proven as both effective and safe.

One major concern has been that stem cells, by their very nature in having the capacity to proliferate, and to variable extents differentiate into different specialized cell types, might also give rise to tumours. Tumours arise from a single cell in which a series of mutations have arisen that deregulate the normal precise control over cellular growth and proliferation; loss of control leads to inappropriate or uncontrolled growth.

A new article published in the open access journal PLoS Medicine reports the case of a boy with ataxia telangiectasia who received three courses of injections to deliver fetal neural stem cells to his brain and stem cells from 2001 in a Russian hospital.  Ataxia telangiectasia is a very rare recessively inherited genetic disease caused by the presence of mutations in the ATM gene, which cause damage to parts of the nervous system and result in progressively severe disability from early childhood onwards.

Two benign tumours subsequently developed in the boy’s brain and spinal cord. Surgical removal of the spinal cord growth in 2006 and genetic analysis by Israeli doctors revealed that it was derived from transplanted cells, containing two normal copies of the ATM gene, and including both male and female cells, having XY and XX chromosomes, respectively. HLA typing confirmed that the tumour included cells from at least two distinct (fetal) donors [Amariglio N et al. (2009) PLoS Med. 6(2) : e29]. This is the first example of tumours arising from transplanted donor stem cells, other than leukaemia in patients who have received hematopoietic stem cells, especially cells derived from umbilical cord blood as opposed to bone marrow  [Greaves MF (2006) Leukemia 20(9):1633-4].

The spinal cord tumour had not recurred at the time of reporting, but the brain tumour has continued to show slow growth; although it has not been biopsied (a tissue sample removed), the researchers suggest that the tumours probably arose independently from transplanted cells injected at different sites, concluding that “the concerns raised regarding the risk of tumor development resulting from therapeutic transplantation of neural stem/precursor cells were not unfounded” and calling for more research into safety, in order to minimize the risks of stem cell therapeutics.

Comment: This finding is significant, supporting fears that stem cell therapeutics may retain the capacity to form tumour cells, and underlines the importance of properly regulated trials (including long-term patient follow-up) of novel treatments. However, all is not necessarily lost for stem cell transplantation. In the case of very serious debilitating diseases and injuries, a degree of risk (whilst strongly undesirable) may be tolerated by patients when weighed against the potential advantages of an otherwise efficacious treatment. The other potential mitigating factor is the nature of the disease in question; ataxia telangiectasia often results in a weakened immune system (see AT Society website), and this in itself could increase their propensity to develop tumours. The findings are therefore not necessarily directly applicable to other conditions for which stem cell transplantation has been used or suggested. Clearly, ongoing scrutiny will be required to assess the wider risk of tumours as the result of donor stem-cell transplantation.

13 February 2009Prostate cancer is the most common cancer in men, with around 35,000 new cases diagnosed every year in the UK according to CRUK. However, calls for a national screening programme have been rejected due in part to the lack of a non-invasive test to distinguish between clinically benign prostate cancer and life-threatening metastatic disease. In the UK, around 10,000 men die each year from prostate cancer, and it is commonly said that more men die with prostate cancer, than of it.

 

Currently, prostate cancer is diagnosed and monitored by testing for high concentrations of prostate-specific antigen (PSA) in the urine, which is followed by a direct biopsy. However, new research into the prostate cancer metabolome could provide a new non-invasive test to determine whether the cancer is aggressive or slow-growing [Sreekumar A et al. (2009) Nature 457:910-914].

 

Metabolomics is the study of the small molecules that are created by specific metabolic processed occurring inside cells. Different cells or cell types have substantially different metabolomes (the total content of these small molecules present). By using high-throughput techniques such as mass spectrometry, the researchers were able to examine 1,126 metabolites across 262 clinical samples (including tissue, urine and plasma), and compare the metabolomes of different sub-types of prostate cancer. As a result, they identified 87 differential metabolites that distinguish between aggressive and benign prostate cancer. One of the most promising is sarcosine, a derivative of the smallest amino acid glycine, which is detectable in urine and is significantly elevated in metastatic disease, pointing to a potential role in cell invasion and migration.

 

Comment: Although numerous studies of the genetic susceptibility to prostate cancer have been published, the utility of using these markers for risk prediction (see previous news) has always been hampered by an inability to distinguish those at risk of the aggressive form of the disease, who are most in need of treatment. This study not only offers a potential solution to this problem, but also shows the power of a metabolomic approach for novel biomarker discovery. Nonetheless, the development of a clinical test based on these results is likely to be years away, and require extensive clinical evaluation and validation before it could be used routinely.

9 February 2009Cochrane reviews are systematic reviews of published literature that assess the available evidence for and against the effectiveness and appropriateness of healthcare interventions in specific circumstances. A new Cochrane review looks at newborn screening for cystic fibrosis (CF) [Southern KW et al. (2009) Cochrane Database Syst Rev. (1):CD001402], an autosomal recessive genetic disease that causes excess mucus production and salt loss via sweat. This results in potentially severe respiratory and gastrointestinal effects, with a current average life expectancy of 31 (see Cystic Fibrosis Trust website); lung disease and damage cause the most serious pathology, and appear to begin very early in life.

 

One in 25 Caucasians carry mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene associated with the disease, and around one in every 2500 newborns has CF [Ratjen F, Döring G(2003) Lancet 361(9358):681-9]. Newborn screening for CF is common in developed countries with significant Caucasian populations; for example, all newborns in England are screened as part of the Cystic Fibrosis Screening Programme (see UK Newborn Screening Programme for more information about newborn screening).

The review addresses the question of whether or not newborn screening CF improves clinical outcomes, quality of life or survival when compared with symptomatic clinical diagnosis, and without serious adverse effects. These might include the effects of false-positive and false-negative results, and of diagnosis of rarer individuals in whom the disease is relatively mild.Two eligible randomised controlled trials of neonatal screening for CF among more than one million newborns were identified, but data from only one study was included in the analysis.

The review authors found that severe malnutrition was less common among screened participants; improved nutrition resulted in better growth, and potentially in improved cognitive function. They found possible benefits in terms of reduced lung disease and damage in the short-term following newborn diagnosis, but not in the longer term. This was attributed to multiple confounding factors that also influenced long-term lung outcomes, such as different CTFR mutations and lung colonization by Pseudomonas aeruginosa bacteria. However, screening costs were found to be lower than for traditional diagnosis. It is worth noting that the trials under review took place 15-25 years ago; since then, the treatment of CF has improved significantly, which would affect how much of an impact earlier diagnosis may have.

Comment: The suggestion that identification of newborns with CF had clinical benefits for the child (as opposed to merely avoiding unnecessary clinical investigations and providing optimal reproductive choice for the parents of an affected child) was originally a contentious one. The first evidence was that early diagnosis improved nutritional outcomes, if not necessarily pulmonary outcomes [Farrell PM et al. (2001) Pediatrics. 107(1):1-13], and this new review supports that finding, which isn’t surprising because it analysed data from the same trial. Perhaps the key point of note from this review is the difficulty of demonstrating or quantifying the effectiveness of particular interventions without the most rigorously designed clinical trials.

6 February 2009 Multiple sclerosis (MS) is a complex neurological autoimmune disease caused by inflammatory damage of the myelin sheath that surrounds nerve fibres (demyelination). This damage results in impaired neurotransmission, and can lead to progressive disability. Both genetic and environmental factors are thought to play a significant effect in the pathogenesis of MS. The strongest genetic association has been identified for the HLA-DRB1 locus, which encodes a human leukocyte antigen (HLA) protein, part of the major histocompatibility complex (MHC) that is a key mediator of immune recognition; the DRB1*15 haplotype increases risk of MS by 3-fold.

Environmental factors are known to be important due to the striking geographical distribution of disease; MS affects predominantly temperate regions, with prevalence rates much higher in countries closer to the poles than the equator. For example, the paper cites a 5-fold difference in MS risk between Tasmania in the south and Queensland in the north of Australia. This has led to the suggestion that sunlight and vitamin D may play a key role in susceptibility to MS; vitamin D is a hormone synthesised in the skin, with additional (but less significant) dietary intake. A new paper in the open access journal PLoS Genetics reports on the findings from research intended to identify any links between vitamin D and HLA-DRB1 [Ramagopalan SV et al. (2009) PLoS Genet 5(2), doi:10.1371].

The researchers from the UK and Canada (two countries with particularly high disease prevalence) used computer programs to search for possible Vitamin-D responsive regulatory elements close to the HLA-DRB1, HLA-DQA1 and HLA-DQB1 genomic regions. Sequence analysis identified a single MHC vitamin D response element (VDRE) in the promoter region of HLA-DRB1. This putative VDRE sequence was sequenced in hundreds of individuals homozygous for the HLA-DRB1*15 MS risk allele, and found to be identical. However, sequencing in individuals homozygous for other HLA-DRB1 alleles revealed various sequence variations.

The authors next used molecular biological experiments to demonstrate that the VDRE specifically bound to vitamin D receptor in vitro, and that the HLA-DRB1*15 promoter sequence mediated vitamin D inducible gene expression. Deletion of the VDRE, or substitution of non–MS-associated HLA-DRB1 alleles removed this effect. Finally, the cell surface expression of the HLA-DRB1 protein subunit was shown to increase on the addition of vitamin D to HLA-DRB1*15 lymphoblastoid cells, but not to cells expressing other HLA-DRB1 alleles.

The conclusion of the paper is that vitamin D specifically interacts with the promoter region of HLA-DRB1*1501 to influence its expression, providing a functional link between observed genetic and environmental epidemiological data. They propose that dietary vitamin D supplementation at critical time periods may be important for disease prevention. Lead researcher Dr Sreeram Ramagopalan said that the study "implies that taking vitamin D supplements during pregnancy and the early years may reduce the risk of a child developing MS in later life" (see BBC news report), although it is likely that vitamin deficiency at these periods may influence risk to all kinds of disease.

Comment: The authors postulate that insufficient vitamin D in early childhood or before birth might affect expression of in HLA-DRB1*15 in the thymus, interfering with the normal process of thymic deletion (whereby autoreactive, ‘self’-recognising T-cells are removed from the immature immune system) and increasing the risk of autoimmunity and MS. The evidence thus far certainly supports a specific interaction with an influence on susceptibility to MS; however, there are other genetic and environmental factors that will play a role in the disease, and further research will be necessary to understand them better. Meanwhile, this latest finding may aid studies into the pathogenesis of MS.

2 February 2009Challenges and opportunities for evidence-based genetics practice.
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Radical treatments for difficult times
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Prostate cancer genomics: towards a new understanding.
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