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Germany has passed a new law significantly limiting the use of genetic tests, according to recent reports in the media (see Deutsche Welle and Associated Press).

 

Under this new legislation, genetic tests can only be carried out by a licensed doctor following the patient’s consent, making it an offence to conduct direct-to-consumer (DTC) genetic tests. Additionally, paternity tests will only be legal if both the man and woman agree, and individuals risk a fine of 5,000 Euros for carrying out tests in secret. Moreover, the law limits the use of genetic tests on fetuses to purely medical purposes (see recent work) , and specifically prohibits the use of genetic testing of fetuses for indications of a predisposition to illnesses that appear only later in life.

 

Following ongoing controversy regarding the obligatory use of genetic tests as a condition for employment in Germany (see previous news), the legislation also address discrimination using genetic information, preventing employers and insurance companies from demanding genetic tests in a similar manner to the Genetic Non-discrimination Act recently passed in the US (see previous news).

 

The law has been welcomed by Health Minister Ulla Schmidt who sees it as “a crucial step in protecting the rights of patients” and “prevent[ing] the abuse of sensitive personal data”. However, the German Medical Association has warned that the law might lead to “medical tourism”, with people trying to get genetic testing done abroad.

 

Comment: This law represents essentially a complete ban on DTC genetic tests, a regressive and paternalistic approach that takes genetic exceptionalism to an extreme not seen in other jurisdictions. It is unclear upon what grounds this special treatment of genetic tests is justified, or indeed what exactly constitutes a ‘genetic test’ – if it is simply a test that uses DNA (or RNA) as the analyte, there can be no rational case made for treating it any differently from measurement of any other biomarker. On the other hand, if the definition relates specifically to a test for inherited monogenic disorders, where a case for special treatment is often made, then the legislation seems to have significantly overshot its remit, since the majority of genetic tests available DTC are for common complex diseases.

 

There is still extensive ongoing debate regarding the appropriate level of regulation of DTC genetic tests – see, for example, two recent contrasting articles in the European Journal of Human Genetics [Guwitz D & Bregman-Eschet Y (2009) Eur J Hum Genet doi: 10.1038/ejhg.2008.254, and Patch C et al. (2009) Eur J Hum Genet doi: 10.1038/ejhg.2008.246] – and differing approaches are being considered across numerous countries. Moderate steps to protect the consumer from DTC genetic are being developed in the UK by the Human Genetics Commission (HGC). Outlined in two reports – Genes Direct in 2003 and the follow-up More Genes Direct in 2008 – its recommendations fall substantially short of an outright ban on DTC genetic tests (see previous news). Working with a small group of experts, the HGC is currently drafting a ‘Common Framework of Principles’, applicable to all jurisdictions, to which companies wishing to supply DTC genetic tests will be encouraged to sign up. These are expected include consideration of the clinical validity and utility of different tests, the level of information provided to consumers, quality assurance, data protection and consent.

The Nuffield Council on Bioethics, an independent UK body that examines ethical issues arising from advances in biology and medicine, has launched a public consultation examining the ethics of health-related services and technologies that are available direct-to-consumers, as opposed to via primary care practitioners such as GPs. The consultation has a major focus on commercial genetic testing, but also looks at private and online providers of health services and medical profiles, and online pharmaceutical sales; it forms part of a larger study (see previous news).

Although there are potential benefits from this type of health service, for example convenience and accessibility, there are also concerns; for example, that consumers may receive results that are difficult to interpret or misleading, and which may cause inappropriate worry. Study chair Professor Christopher Hood commented: “…there is not much regulation of these new services and we may be getting information that causes more harm than good” (see press release). Private health services can also increase the burden on National Health Service (NHS) providers; for example, if consumers are prompted to visit their GPs with unfounded health worries, or as a result of adverse reactions to inappropriate medication purchased online. Nuffield director Hugh Whittal said: "There is a range of benefits to be had, but it is only right some questions are asked about risks, the quality of information, equity of access and the impact on the NHS" (see BBC news report).

The consultation document, Medical profiling and online medicine: the ethics of ‘personalised’ healthcare in a consumer age sets out the issues of interest, with separate sections examining electronic health records, online health information, online drug purchases, telemedicine, body imaging and DNA profiling. An additional section considered cross-cutting issues pertinent to both body imaging and DNA profiling.

The section on DNA profiling explains briefly how the UK Genetic Testing Network evaluates genetic tests for NHS purposes, considering the analytical and clinical validity, clinical utility, and the ethical, legal, and social implications of each. With respect to commercial services, concerns about the lack of regulation in this area are noted; some have called for statutory regulation and others (such as the PHG Foundation) for further consideration of how these tests should be regulated ; the document refers to the 2008 report in this area produced by the PHG Foundation and the UK Royal College of Pathologists, The Evaluation of Diagnostic Laboratory Tests and Complex Biomarkers. The document also mentions  ‘recreational genetics’ services, for example offering genealogy searches, or genetic analysis purported to aid the identification of suitable partners. The following section raises the question of what information should be provided to customers by private DNA profiling companies, and potential issues such as the testing of children and the difficulty of effective legislation or governance of an international market.

The Council is requesting contributions and views from current and potential consumers and providers of such services, researchers, academics, regulators, policy makers and other interested parties. A report detailing the findings of the consultation will be produced in 2010.

Researchers at the University of Queensland in Australia have launched a major new study to investigate genetic factors involved in Attention Deficit Hyperactivity Disorder (ADHD). ADHD is a complex condition with a neurobiological basis, influenced by multiple genetic and environmental factors; there is strong epidemiological evidence to support significant involvement of genetic factors in susceptibility to ADHD. It is typified by inappropriate hyperactivity, impulsivity and lack of attention in children and adolescents, and is one of the most common psychiatric disorders, affecting between 3-9% of school-aged children and young people (see NHS Choices website)

The new study is intended to elucidate possible links between genetic factors, cognitive difficulties (commonly associated with ADHD) and brain function in children. Lead researcher Mark Bellgrove said: "By documenting cognitive ability in children with ADHD, researchers hope to determine genetic differences between those children with and without cognitive problems" (see press release).

The study is funded by the National Health and Medical Research Council (NMRC) of Australia and will be carried out by researchers at the Queensland Brain Institute (QBI) and the Mater Children's Hospital in Brisbane, the Royal Children's Hospital in Melbourne and Curtin University of Technology in Perth. Researchers hope to recruit more than 600 families for the ADHD study. The ultimate aim would be to improve diagnosis and targeting of treatment for the condition, for which effective drugs are already available.

Conventionally, a majority of drug development is conducted in the adult population and data is extrapolated from these studies in order to guide treatment in children and pregnant women. However, due to physiological changes, drug metabolism in children and pregnant women can differ to that in the general adult population leading to incomplete knowledge about their effects. Technical, ethical, legal and financial factors tend to hinder the conduct of drug development research in children and pregnant women, leading to a lack of information on the efficiency, dosage and safety of drugs in this population. In order to improve knowledge about drug metabolism and tailor treatment in these populations, the US National Institutes of Health have announced a new programme that will fund research into improving existing drugs and developing new drugs specifically for paediatric and obstetric populations (reported by Genome Web).

Three grants are available in the Translational Research in Paediatric and Obstetric Pharmacology programme that will be issued by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The grants will support basic, translational and clinical studies and those using genomic, epigenomic, proteomic and systems biology will be encouraged. The goals of these grants are to support pharmacological studies addressing the special differences of drug actions and responses among children at various developmental stages, between children and adults, and between pregnant and non-pregnant women; development of new drug targeting children and pregnant women and multidisciplinary collaborations between basic and physician scientists to improve the use of therapeutics in obstetrics and paediatrics.

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The Genetics and Public Policy Center (GPPC) at Johns Hopkins University has reportedly produced a document setting out proposals for the implementation of a compulsory web-based registry of genetic tests in the US, as proposed by the Secretary’s Advisory Committee on Genetics, Health and Society (SACGHS) to the US Department of Health and Human Services (HHS) last year (see previous news). Speaking at the American College of Medical Genetics' Annual Clinical Genetics Meeting in March, GPPC deputy director Joan Scott said that the paper, which had been accepted for publication, was intended to stimulate discussion about the best way to implement the resource (see Pharmacogenetics Reporter article).

The document proposes a national web-based registry combining information from existing resources such as the GeneTests website with data from genetic testing laboratories, to include information on the purpose, analytical validity, clinical utility and validity of each test. Oversight of the registry would be crucial, with the GPPC proposing that the HHS has the legal authority to oversee its implementation, or to devolve that authority to another agency.

However, whereas the original SACGHS recommendations were for a mandatory registry to include all laboratory tests, the GPPC proposes that only genetic tests should be included, although the definition of a genetic test is not clarified (for example, whether this would include non-DNA based tests that indirectly reveal information about a genetic condition).

An ambitious new UK biobanking initiative is reportedly being planned for the study of genetic and environmental factors in disease and behaviour; a database of 300,000 pairs of twins with linked biological samples has been proposed by researchers at King's College London, according to the Times newspaper. There are an estimated 640,000 sets of twins in Britain. The TwinBank project at the KCL Department of Twin Research & Genetic Epidemiology would be ten times larger than the current largest resource, allowing researchers to study not only very common condition but also rarer forms complex diseases such as leukaemia and motor neuron disease that affect fewer than 1 in 100 individuals.

TwinBank would include both identical and non-identical (fraternal) twin pairs, with samples linked to NHS medical records. A pilot study is underway whilst applications for the estimated £6-20 million required in funding are proceed (see Times report). Professor of Behavioural Genetics Robert Plomin commented: “TwinBank would give us unprecedented opportunities to study the genetic and environmental factors that influence human health and behaviour. It would be a dream resource” (see press release).

 

The UK charity Wellbeing of Women, which works to support medical research and provision in the areas of reproductive and gynaecological health, also announced plans for a new biobank project last month. This will be a data bank to support research into genetic factors in different complications of pregnancy such as pre-eclampsia, intra-uterine growth retardation (IUGR) and recurrent miscarriage. A variable degree of inherited susceptibility to some complications of pregnancy is known or suspected. For example, pre-eclampsia has a significant genetic component (see previous news) and is the subject of ongoing genetic research (including by the GOPEC consortium). The Baby Bio Bank will store cord blood and placenta samples along with blood samples and medical histories from the parents of each baby, with collection expected to begin from June 2009 for up to five years. Project lead Lesley Regan said that it would be “an international resource for obstetricians and scientists" (see press release).

A number of central databases holding information on various aspects of life including health have been built by the government in recent years. Recently there have been some concerns about these databases following the loss of data from Her Majesty’s Revenues and Customs (HMRC) and the European Court of Human Rights ruling that the UK National DNA Database was in breach of human rights law (see previous news). As a result, the Joseph Rowntree Reform Trust commissioned the Foundation for Information and Policy Research (FIPR) to carry out an in-depth study of public sector databases resulting in the publication of a report charting these databases (reported by the Guardian).

The scope of the report - Database State included systems that will at some time or another, hold identifiable personal information on a significant minority of citizens, including existing systems as well as those which have not been built yet such as the National Identity Registry. In all, the report assessed 46 databases across major government departments and described their purpose, methods by which they share data and the potential risks they pose. The databases were given an overall ranking (green, amber or red) following an assessment of aspects such as impact on privacy, utility and effectiveness. In addition, the report makes policy recommendations as to how data should be held, managed and collected by the government.

Nine databases were assessed within the Department of Health. Of these, seven were coded as amber signifying that they demonstrated “significant, worrying failings, and may fall foul of a legal challenge” and two as red suggesting that they do not conform to EU human rights or data protection laws. The Secondary Uses Service (SUS) processes patient identifiable data from a variety of sources, for the primary purpose of administration and in order to support secondary uses such as medical research. This service was assessed as 'red' on the basis that there is no provision for individuals to exert a right of opt-out. The Detailed Care Record aims to electronically link together information from GPs, hospitals and clinics, and was also assessed as ‘red’. This was because the system lacked a curator who would maintain and be responsible for the quality of the data, and it was felt that this would result in rapid deterioration of the records held in the system. In addition, the authors felt that increasing the number and types of users to whom information would be made available under the proposed scheme was likely to compromise privacy as well as precluding more detailed consideration of the context for the proposed information sharing.

As part of their recommendations, the authors suggest that systems coded as amber should be independently reviewed and changes made such as giving individuals the right to opt-out and those coded red should be scrapped or substantially redesigned. The report also recommends that government should compel the provision or sharing of sensitive personal data only for strictly defined purposes, and in almost all cases, sensitive data should be kept on local rather than national systems. In addition, it suggests that more effective IT systems could be built by subjecting new database systems to greater public scrutiny and openness and recruitment of civil servants able to manage complex systems.

Comment: The report is predicated upon a presumption that public interests in privacy and confidentiality outweigh other public interests such as having a sound understanding of health and disease through epidemiological or secondary medical research. The legal requirement for interventions to be 'necessary and proportionate' arguably allows such tradeoffs to be accounted for and reports from other groups have shown that a universal requirement for consent may result in vulnerable groups being unrepresented or produce biased research. It is also arguable that that the central tenet of this report is misguided in that it does not seek to take account of national law. The UK Data Protection Act provides for a more inclusive interpretation of medical purposes than the EU Data Processing Directive, thus establishing a statutory basis for sharing identifiable medical data for the purpose of medical research. Member states are permitted to derogate from the principles set out in European law, although the extent to which UK data protection law could and should lawfully derogate from European law continues to be a source of academic debate.

It is also somewhat ironic that the Secondary Uses Service has been so roundly criticised,  given that it has in the past been characterised as a means of protecting and safeguarding patient identity through the provision of a more systematic and robust means of de-identifying patient data (following the 2007 Report of the Care Record Development Board Working Group on the Secondary Uses of Patient Information). 

 

 

Bev Rowbotham, president of the Royal College of Pathologists of Australasia (RCPA), has said that genetic testing services in Australia are "unco-ordinated, inequitable and inefficient" (see Sydney Morning Herald report). There are concerns that some patients are missing out on clinically valuable testing, whilst others may be receiving inappropriate tests.

The first survey of academic, public and private laboratories providing genetic testing services in Australia was intended to provide essential information to support the development of policy and resource allocation for future testing. The survey was funded by the Australian Department of Health and Ageing, and performed in collaboration with the Human Genetics Society of Australasia. Launched in March, the Report of the Australian Genetic Testing Survey 2006 found that in 2006 a total of more than 160,000 tests were performed for a total of 437 different indications; figures for the following year were reportedly even higher. However, there was huge geographical variation in access to (and state funding for) testing; the Medicare Benefits Scheme (MBS) funds only a handful of approved tests (five in 2006).

Graeme Suthers, who chairs the RCPA Genetics Advisory Committee, said that it was uncertain how much doctors in different states knew about the availability or appropriateness of different tests, commenting: “While we expected some level of divergence between the frequency of tests performed across the range available, the survey demonstrated a gap to the magnitude of thousands to tens of thousands-fold between the numbers of certain genetic tests being performed, with some being performed more than 10,000 times, while others were performed once or twice, if at all, in 2006” (see press release).

The RCPA has reiterated calls for a National Genetics Framework to provide equitable access to testing, as well as addressing a serious shortage of clinical and laboratory staff for genetic counselling and testing. They also provide a web-based resource tool intended to assist both referring clinicians and testing laboratories.

Regulation of biomedical research is important in ensuring progress in research whilst minimising potential harms. However, this is often a complex process involving a number of stakeholders and the formulation of appropriate regulations that are understood by all those involved. In spring last year, the MRC and Wellcome Trust held a workshop which bought together representatives from academia (including scientists and lawyers), government, UK and overseas regulators and industry to discuss biomedical regulation, the problems associated with it and how these could be resolved. The proceedings of this workshop have now been published in a report (see press release).

The workshop was informed by a literature review of regulation and its aim was “to consider ways in which the regulation of research involving human participants might be simplified, while retaining the confidence of the public” (MRC/Wellcome Trust workshop: Regulation and biomedical research) The report summarises perspectives different stakeholders have of regulation as well as providing UK and international examples of regulatory processes. In addition, views from other sectors such as the Food Standards Agency and the Office of Rail Regulation were also given in order to identify aspects which could be adopted for biomedical regulation.

The report concluded that although biomedical regulation is necessary in order to protect consumers, research participants and researchers, in the UK the current process is overly complex. A number of recommendations were made in order to improve the process, such as asking governments to involve stakeholders earlier as well as improving communications between regulators. In addition, the workshop highlighted difficulties non-lawyers had in understanding legislation and suggested Bills and Acts should be formulated in such a way as to be comprehensible by everyone. However, the report recognises that regulation of biomedical research is an inherently complex process due to the competing objectives of facilitating research whilst safe-guarding public interests. They recognise that in the short-term the regulatory environment in the UK cannot be changed radically but that there may be scope for change in the way rules are applied.

Autism spectrum disorders (ASDs) are a group of related neurodevelopmental and neuropsychiatric disorders, including autism and Asperger’s syndrome, which become apparent in childhood and involve impaired verbal communication and social interaction along with repetitive behaviours. ASD has complex, multifactorial origins, but genetic factors are believed to be significant as the conditions show a high degree of heritability. A new paper in Nature reports the results of genome-wide association studies (GWAs) in more than 4300 affected individuals and their families, and almost 6500 controls, of European ancestry. The work was led by researchers from the University of Pennsylvania School of Medicine in the US, using DNA samples from the Autism Genetic Resource Exchange (see previous news).

The initial GWA study performed did not identify any variants as being significantly associated with ASD, nor did a series of further GWAs in independent data sets. However, combined analysis of the data revealed a single significant association with a single-nucleotide polymorphism (SNP) on chromosome 5. Five further SNPs from the same 5p14.1 region showed possible association, although this was not statistically significant. The region on chromosome 5 where the key variant was located is between two genes encoding neuronal cell-adhesion molecules cadherin 10 and 9 (CDH10 and CDH9) [Wang K et al. (2009) Nature doi:10.1038]. These cadherins are part of a group of molecules known to be involved not only in cellular adhesion in the brain, but also in the generation of synaptic complexity in the developing brain.

Although none of the SNPs identified in this study as potentially linked with ASD showed any association with expression levels of the cadherin 9 or 10 proteins, the authors postulate that elements in this region of the genome might regulate gene expression in the developing brain; physiological research has previously suggested that abnormal brain development (specifically, a lack or normal connectivity between neurons) may underlie ASD. The authors therefore propose that the genetic variants identified by their GWA study could indicate a genetic link to the underlying pathology of autism and related conditions, increasing the risk of ASD by affecting the normal expression of key cadherin proteins.

A second publication in Annals of Human Genetics also reports a link between ASD and genetic variation near the CDH10 and CHD9 genes [Ma D et al. (2009) Ann. Hum. Gen. 73 (3) 263-273]. An additional publication in Nature will reportedly present results identifying gene duplications and deletions more common among individuals affected with ASD, including further cell adhesion molecule genes and some involved with the ubiquitin system that may regulate turnover of cell adhesion molecules (see NIH press release).

Comment: Earlier research has linked rare genetic variants with ASD, particularly copy number and structural variants (see previous news), and suggested that the genetic contributions to both sporadic and apparently inherited forms of autism and related conditions are highly complex (see previous news). This latest research is the first example of common genetic variants to be associated with increased susceptibility to ASD. The authors correctly observe that their findings are merely “part of a larger effort to interrogate the complex genetic architecture of ASDs”. Lead researcher Dr Hakon Hakonarson was careful to underline this fact, saying: "There are going to be many genes involved in causing autism…In most cases, it's likely that each gene contributes a small amount of risk, and interacts with other genes and environmental factors to trigger the onset of disease" (see BBC news).

Changes in chromosomal structure such as copy number variations (CNVs) in certain regions can be associated with a wide range of developmental disorders including forms of learning disability (LD). Clinical diagnosis can be supported by investigation of chromosomal abnormalities. Technologies such as array comparative genomic hybridisation (array-CGH) can assist in accurate diagnosis by rapid detection of copy number changes across the whole genome. However, along with identifying variations associated with particular phenotypes, this technology can also identify new variations of unknown significance, which may or may not be involved in the developmental disorder. The determination of the pathogenicity of these variants is complicated by the rarity or novel nature of many of the associated mutations, making correlations between observed variations with specific disease phenotypes difficult.

In order to facilitate the diagnosis of developmental disorders, an interactive web-based database was initiated in 2004 at the Wellcome Trust Sanger Centre - DECIPHER (Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources). This tool allows clinicians from around the world to maintain and share records of phenotype and chromosome rearrangements (with informed consent). A recent report in the American Journal of Human Genetics outlines DECIPHER’s role in clinical practice and genetic research and how it has benefited patients, clinicians and researchers [Firth H et al (2009) Am J Hum Genet. 84(4) 524-33]. The report describes the analysis tools available to those who use DECIPHER, as well giving examples of how it has been used through case studies. In addition, the report also describes its utility in the clinical evaluation of novel changes as well as it role in investigating gene function.

The database contains clinical information about chromosomal changes such as deletions, insertions, inversions and translocations from particular cases and displays this information on the human genome map. This allows identification of cases which share phenotypic and chromosomal characteristics, thereby leading to a greater understanding disorders and their underlying genetic cause. Currently, the database contains information on over 2000 cases from 100 centres. In addition, the database also catalogues chromosomal rearrangements identified in healthy individuals; excluding these non-pathological rearrangements aids identification of chromosomal changes genuinely associated with disease phenotypes. Along with aiming to increase medical and scientific knowledge about these chromosomal changes, the database also aims to improve medical care and genetic advice for individuals/families and facilitate research into the study of genes which affect human development and health.

Comment: A genetic diagnosis can be of great value to individuals and families for many reasons including optimal clinical management of the condition, genetic counselling and access to special needs services (see our website sections on Learning Disability: the interface with genetics and Evaluation of array-CGH for chromosomal abnormalities in clinical practice). The DECIPHER database, by facilitating information sharing among clinicians, is helping to improve medical understanding of and clinical support for individuals affected by developmental disorders arising from chromosomal abnormalities.

It has been known for more than a decade that variants in the apolipoprotein E (APOE) gene significantly affect an individual’s susceptibility to late-onset Alzheimer’s disease. In particular, a single copy of the e4 variant increases the risk by around 4-fold, whilst two copies increase the risk by around 12-fold. Even in the wake of the plethora of genome-wide association studies, this remains one of the highest risks associated with susceptibility to a common complex disease. However, despite these large relative risks, the variant is not a clinically useful predictor of who will develop the disease – many people with the e4 variant will not develop Alzheimer’s disease, and many of those with the disease do not possess the variant.

 

New research published in the Proceedings of the National Academy of Science into the role of the APOE e4 variant in cognitively normal adults has helped to illuminate the molecular basis for this genetic risk for Alzheimer’s disease. In one study, functional MRI was used to investigate brain activity in e4-carriers versus matched non-carriers, ranging from 20-35 years of age [Filippini M et al. PNAS (2009) doi: 10.1073/pnas.0811879106]. Even at this young age, decades before any degenerative processes are postulated to have occurred, researchers were able to detect a statistically significant difference in brain activity between the two groups, with e4-carriers showing more activity in the hippocampal regions primarily responsible for memory. This difference could be interpreted as “reflecting a greater cognitive ‘effort’ by e4-carriers to obtain the same level of performance as their non-carrier counterparts”, and that the memory part of the brain becomes exhausted from “overwork”, contributing to Alzheimer’s disease.

 

In a separate study, PET scanning was used to characterise the relationship between APOE and the presence of fibrillar protein deposits (‘amyloid plaques’) in the brains of cognitively normal individuals, ranging from 57-72 years of age [Reiman EM et al. PNAS (2009) 106: 6820-6825]. Although deposition of amyloid-beta (Ab) protein is one of the cardinal features of Alzheimer’s disease, and is still used as the gold standard for post-mortem diagnosis, these deposits are also found in the brains of many cognitively normal older people. Using a compound that binds specifically to fibrillar Ab, researchers found that the amount of Ab deposition throughout the brain increased significantly with the APOE e4 dosage (0, 1 or 2 copies of the variant), although remained lower than that of individuals already diagnosed with Alzheimer’s disease.

 

Comment: Although both these studies are small (involving fewer than 40 participants each), they offer a tantalising insight into the potential lifelong effect of APOE in the brain. Exciting as these results may be for our understanding of basic neurophysiology and the underlying aetiology of Alzheimer’s disease, suggestions that the work may lead to an early screening test for the disease are premature and unwarranted. Aside from the uncertain clinical validity of offering a highly imperfect predictive test for a disease many decades before it’s putative onset, as well as the lack of clinical utility of a offering a test for a disease that has no cure or preventative treatment, such a test would also raise significant and fundamental ethical questions for society.

Changes in the length of the QT interval, a feature of the electrocardiogram that reflects repolarisation of the heart muscle, are known to be associated with heart rhythm defects and risk of sudden cardiac death. Long QT and Short QT syndromes are rare, heritable conditions in which the QT interval is either markedly prolonged or shortened, respectively. The conditions are highly genetically heterogeneous, with large numbers of pathogenic mutations identified in several different genes. Less dramatic changes in the QT interval, thought to be due to more common genetic variants of weaker effect, are known to be associated with increased cardiovascular mortality in the general population. Two recently published papers report success in identifying some of these common variants by genome-wide association studies (GWAS).

Pfeufer et al.conducted GWAS in five population-based cohorts (15,842 individuals) from Europe and the US [Pfeufer A et al. (2009) Nat Genet. 41(4), 407-14], while Newton-Cheh et al.carried out a meta-analysis of three GWAS on 13,685 individuals of European ancestry from the Framingham Health Study, the Rotterdam Study and the Cardiovascular Health Study [Newton-Cheh C et al. (2009) Nat Genet 41(4), 399-406]. Both studies found common variants that affected the QT interval in three genes (KCNQ1, KCNH2 and SCN5A) known to be associated with Long QT syndrome. Significant association with prolongation of the QT interval was also confirmed, by both studies, for variants in the NOS1AP gene involved in the nitric oxide synthase pathway. Importantly, all but one of the ‘top ten’ associations observed by Newton-Cheh et al. were confirmed by the study of Pfeufer et al. Each study also found associations with additional genes that showed significant, but weaker, association in the other study. Collectively, the gene variants identified by these studies account for approximately 3.5-6.5% of the population variance in QT interval, a higher proportion than any other known covariate (excluding heart rate).

Comment: Both groups of investigators used their results to devise a QT ‘score’ by assessing the cumulative affect of one or more of the risk-associated variants. The highest QT scores were associated with odds ratios of 2.5-3 for a degree of QT interval prolongation that is known to be clinically important as a risk factor for sudden cardiac death. This suggests that it may, in the future, be possible to stratify the population according to their risk genotype and perhaps to offer risk-reducing interventions to those at the highest risk. However, much work remains to be done to assess the clinical validity and utility of such a test. It is likely that, as is already clear for the monogenic arrhythmia syndromes, risk assessment will be a complex process in which genetic test results must be considered together with cardiological evaluation and factors such as age and sex.

A new PHG Foundation report, the findings of our needs assessment and review of services for Inherited Cardiovascular Conditions (ICC) in the UK, will be available from our website in June. This will set out our findings with respect to the many rare inherited conditions associated with cardiac problems (such as Long QT Syndrome) and how advances in the understanding of the genetic and physiological basis of these conditions are challenging health services to provide more specialist clinical care for affected individuals and their families.

Human genetic variation and its contribution to complex traits.

Frazer KA, Murray SS, Schork NJ, Topol EJ. Nat Rev Genet. 2009 Apr;10(4):241-51.

Beyond odds ratios - communicating disease risk based on genetic profiles.

Kraft P, Wacholder S, Cornelis MC, Hu FB, Hayes RB, Thomas G, Hoover R, Hunter DJ, Chanock S. Nat Rev Genet. 2009 Apr;10(4):264-9.

Property rights.

Nature. 2009 Mar 26;458(7237):385.

The phantom menace of gene patents.

Gaisser S, Hopkins MM, Liddell K, Zika E, Ibarreta D. Nature. 2009 Mar 26;458(7237):407-8.

Ownership of medical information.

Hall MA, Schulman KA. JAMA. 2009 Mar 25;301(12):1282-4.

The beginning of the end of the embryo wars.

Caplan AL, Patrizio P. Lancet. 2009 Mar 28;373(9669):1074-5.

Embryonic education.

Nature. 2009 Mar 26;458(7237):385.

Personal genomics services: whose genomes?

Gurwitz D, Bregman-Eschet Y. Eur J Hum Genet. 2009 Mar 4.

Amendments to the coroners and justice bill.

Nathanson V. BMJ. 2009 Mar 3;338:b895. doi: 10.1136/bmj.b895.

Stem-cell experts raise concerns about medical tourism.

Barclay E. Lancet. 2009 Mar 14;373(9667):883-4.

Monitoring and regulating offshore stem cell clinics.

Kiatpongsan S, Sipp D. Science. 2009 Mar 20;323(5921):1564-5.

By common consent.

Nature. 2009 Mar 12;458(7235):125.

New insights into the genetics of addiction.

Li MD, Burmeister M. Nat Rev Genet. 2009 Apr;10(4):225-31.

Ethical implications of epigenetics research.

Rothstein MA, Cai Y, Marchant GE. Nat Rev Genet. 2009 Apr;10(4):224.

Motor-neuron disease: Rogue gene in the family.

Sleegers K, Van Broeckhoven C. Nature. 2009 Mar 26;458(7237):415-7.

Opening up public health: a strategy of information and communication technology to support population health.

Reidpath DD, Allotey P. Lancet. 2009 Mar 21;373(9668):1050-1.

What is health? The ability to adapt.

Lancet. 2009 Mar 7;373(9666):781.

The value of Academic Health Science Centres for UK medicine

Smith S. Lancet. 2009 Mar 28;373(9669):1056-8.

Somatic and germline genetics at the JAK2 locus.

Campbell PJ. Nat Genet. 2009 Apr;41(4):385-6.

Genetics of cardiac repolarization.

Shah SH, Pitt GS. Nat Genet. 2009 Apr;41(4):388-9.

Replication timing and epigenetic reprogramming of gene expression: a two-way relationship?

Göndör A, Ohlsson R. Nat Rev Genet. 2009 Apr;10(4):269-76.

Dynamic DNA methylation.

Law JA, Jacobsen SE. Science. 2009 Mar 20;323(5921):1568-9.

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