In the news

  • Newsletter Edition
The PHG Foundation monthly newsletter features news and views about genetics and genetics research, from a public health perspective. The newsletter is written by staff of the PHG Foundation.

In the news

News story   |   By Dr Alison Stewart   |   Published 31 May 2007

The independent Council that oversees the ethics and governance arrangements for UK Biobank has published its annual review for 2006. The UK Biobank Ethics and Governance Council’s (EGC) report outlines the key principles of Biobank’s Ethics and Governance Framework and summarises the advice it gave to UK Biobank during 2006 on several issues, including the information given to prospective participants and the procedure for the enrolment interview and taking of samples.

Suggestions for improving the enrolment procedure were based on observation of the pilot phase conducted during 2006, and involvement in developing the Standard Operating Procedures for managing the enrolment process. They included paying greater attention to the privacy of participants during the enrolment interview, and suggesting the need for the procedures to cover how Biobank staff would manage any incidental findings arising from the initial medical examination.

The EGC advised Biobank that prospective participants should be told more explicitly that their consent entailed allowing access to their full past and future medical record, that commercial companies are expected to apply for access to the Biobank resource, and that participants will not benefit financially from taking part in Biobank.  Biobank has accepted these recommendations.

The report also outlines the EGC’s efforts to achieve transparency and public engagement in its work, and its programme of commissioned research. The latter includes a literature survey of published research regarding public attitudes to Biobank, and research on the concepts of ‘public interest’ and the ‘public good’.

The EGC recognises that it is operating in a dynamic environment of changing legal requirements and social attitudes, as well as the need to adjust the parameters of the Biobank project itself in the light of experience. It states its intention to maintain active communication with the Biobank executive and, as an example of this communication, an agreement to establish a procedure through which the EGC will be involved in monitoring any complaints received by Biobank.

The EGC is holding a public presentation and discussion of its work in Manchester on 11 June 2007.

News story   |   By Dr Philippa Brice   |   Published 25 May 2007

In a collaborative effort, the US National Center for Biotechnology Information (NCBI) and the Genetic Alliance recently launched a new web-based portal to improve access to information on genetic disorders for health professionals, patients and carers. The portal is intended to serve the needs of a broad spectrum of users, by providing information suitable for the general public as well as experts, and allowing users to track emerging information over time. The Disease InfoSearch option allows users to specify the genetic disorder of interest, then links to pages of relevant resources, including information on diagnosis and treatment, genetics and genetic testing, clinical trials and PubMed-linked scientific research. NCBI Director David Lipman commented: "Genetic Alliance is dedicated to improving the lives of those with genetic disorders, and we share their goal of improving public access to information" (see press release).

Another subsidiary of the US National Institutes of Health (NIH), the Office of Rare Diseases (ORD) has released its first newsletter this month; Focus on Rare Diseases is to be produced quarterly. The ORD website also features the Genetic and Rare Diseases Information Center (GARD), and links to other sources of genetics information.

News story   |   By Dr Philippa Brice   |   Published 24 May 2007

The UK National Institute for Health and Clinical Excellence (NICE) has released the report from its citizen’s council (a group of 30 members of the public selected as representative of the UK population). NICE provides national guidance on promoting good health and preventing and treating ill health; the council met in January 2007 to consider the question:In what circumstances is it justified for NICE to recommend that an intervention is used only in the context of research?

The report, which is available for public comment before it is presented to the NICE Board in July 2007, lists circumstances that should be taken into account when NICE is deciding whether or not to make an “only in research” (OIR) recommendation. Many of these are practical; for example, a study must be: feasible; already completed, in progress or due to start soon; represent good value for money; and likely to answer well defined, unresolved questions NICE has about the intervention in question. The report notes that OIR recommendations “should not be used as a way of ducking the need to say “no” to interventions that are excessively costly”, but also says that NICE “should resist the attempts of patient groups, the media and other bodies that may wish to pressurise it into choosing an OIR decision when a “no” decision is the more appropriate response”.

News story   |   By Dr Alison Stewart   |   Published 16 May 2007

The US National Human Genome Research Institute (NHGRI) and National Cancer Institute are teaming with healthcare organisations in the state of Michiganto carry out a research study on how young adults react to DNA test information indicating their genetic risk of common diseases.

The Multiplex Initiative, led by NHGRI behavioural scientist Colleen McBridge, will contact 1000 young people aged 25 to 40 and offer them a free ‘mulitplex’ test for variants in 15 different genes thought to be associated with type 2 diabetes, coronary heart disease, high blood cholesterol, hypertension, osteoporosis, lung cancer, colorectal cancer and malignant melanoma. Those who respond will be given web-based information to help them decide whether to accept the test offer; if they accept, they will have a personal meeting with an ‘educator’ who will provide more information about risks and benefits and obtain the individual’s informed consent if they wish to go ahead and provide a blood sample for testing.

Participants will receive test results by mail. Follow-up phone calls and interviews will provide help in interpreting results and assess each participant’s response to their genetic risk information. Test results will not become part of the participants’ health care records but they will be free to share their results with their health care provider if they choose to do so.

According to Colleen McBride, “the Multiplex Initiative will inform the field about how to communicate genetic risk to patient populations and will establish an infrastructure for additional research studies aiming to answer social and behavioral questions important for the genome era”. Behavoural responses to genetic test information will be an important part of evaluating the clinical utility of tests.

News story   |   By Dr Alison Stewart   |   Published 11 May 2007

According to the UK’s Sunday Times and Daily Telegraph newspapers, The Bridge Centre in London has been granted a licence by the Human Fertilisation and Embryology Authority to use preimplantation genetic diagnosis (PGD) to test the embryos of a couple at risk of having a child with a genetic eye condition called congenital fibrosis of the extraocular muscles (CFEOM).

CFEOM is an extremely rare autosomal dominant congenital condition that causes inability to move the eyes (see GeneReviews summary for further information). Individuals with this condition are unable to raise their eyes above the horizontal, may have droopy eyelids and mis-aligned eyes (appearing ‘cross-eyed’), and lack binocular vision. Horizontal movement of the eyes may also be restricted. Surgery to the eye muscles may improve some aspects of the condition but results are limited and variable. The condition can cause severe distress to those affected but is not progressive or life-threatening. Molecular genetic testing is available for the most common type of CFEOM, Type 1, which is caused by mutations in the KIF21A gene.

In the case of the couple whose treatment has been licensed by the HFEA, the male partner is affected by the condition, as is his father. Without PGD, there is a 50% risk that the couple would have an affected baby. The couple say they want to spare their children from the disfiguring nature of the condition and from the need for potentially dangerous surgery. Critics claim that PGD should not be licensed for conditions they describe as ‘cosmetic’.          

News story   |   By Dr Alison Stewart   |   Published 10 May 2007

Over the last two years, the European Commission (the executive body of the European Union) has been working to develop a regulation creating a centralised market-authorisation procedure for “advanced therapy medicinal products”, including both gene therapy and cell therapies. A draft regulation, published in late 2005 (see previous newsletter article), provided for the creation of a new expert Committee for Advanced Therapies within the European Medicines Agency (EMEA) and for the specification of technical requirements to ensure the quality, safety and efficacy of advanced therapy products. It also set out risk management and traceability requirements, and measures to provide incentives for small and medium-sized enterprises in the field.

As part of the EU’s co-decision process, the regulation (which, once passed, must be adopted directly into national legislation) must also be approved by the European Parliament and Council. This hurdle was cleared on 25 April when the European Parliament voted to approve the regulation. The approval by a plenary session of the Parliament followed an extensive process of review by parliamentary committees and negotiation with the Commission and Council (see the Parliament’s legislative observatory for details of this process).

The Parliament rejected a package of amendments that would have introduced a variety of contentious ethical considerations into the regulation, for example by excluding products derived from embryonic stem cells from its remit. If these amendments had been passed, they would probably have scuppered the regulation, as the Council had already indicated that it could not support any provisions that undermined the right of individual member states to set their own policies on these issues. The general ethical principles set out in the original draft regulation remain unchanged: donation of cells and tissues must be voluntary and unpaid, and anonymity of donors and recipients must be guaranteed.

The new Advanced Therapies regulation will apply in all countries of the EU one year after entry into force; in practice, this will mean mid-2008.

News story   |   By Dr Philippa Brice   |   Published 9 May 2007

The Upper House of the state Parliament of Victoria, Australia, has voted 23 to 16 in favour of permitting therapeutic cloning for the creation of stem cells for medical research (see Infertility Treatment Amendment Bill 2007). Therapeutic cloning refers to the creation of a human embryo by somatic cell nuclear transfer, whereby an enucleated human oocyte (egg cell) is fused with a nucleus taken from an adult human cell. Human reproductive cloning will remain illegal.


This move followed a decision in December 2006 by the Australian federal government House of Representatives to amend earlier legislation preventing the cloning of human embryos for stem cell research (see further information on this Stem Cell Research Bill). The new law will only come into effect when each state has ratified it. Victoria is the first state to pass equivalent legislation on therapeutic cloning, but decisions from the states of New South Wales and Queensland are expected to follow soon. If all the states ratify the new law, Australia will have legislation comparable to that of the UK and other countries where therapeutic cloning is permitted, such as China, Japan and South Korea. Many European countries have more restrictive laws, as does the US.

News story   |   By Dr Philippa Brice   |   Published 9 May 2007

Controversy has been sparked in the UK media by the launch of a private fetal gender testing service from the sixth week of pregnancy. International company DNA Worldwide offers analysis of free fetal DNA from a finger-prick sample of the mother’s blood. If Y-chromosomes are detected, it is assumed that the fetus is male; if they are not, the fetus is assumed to be female. A kit that includes materials to take a blood test at home and send to the laboratories costs from £189.95, and parents can check for the results of their test online. 99% accuracy is claimed for the ‘Pink and Blue Early Gender Test’, which has been available in the US since 2006.

The use of free fetal DNA in the maternal bloodstream for early and non-invasive genetic testing is not new; in recent years there has been significant progress towards using the technique for prenatal diagnosis of genetic diseases and chromosomal disorders such as Down’s Syndrome (see previous journal club item). Last year the UK Institute of Child Health has reported results where free fetal DNA was used to identify the gender of fetuses from as early as seven weeks, although this was in the context of an inherited condition that affects girls; early identification of female fetuses permitted prompt prenatal treatment (see previous news story). There are a significant number of genetic disorders that are sex-linked, for example conditions affecting predominantly males such as Duchenne muscular dystrophy and Fragile X syndrome. A non-invasive means of obtaining fetal DNA for genetic testing in such cases avoids the small risk of miscarriage associated with current invasive techniques (amniocentesis and chorionic villus sampling), and is considered a very desirable approach in such circumstances.

However, early gender testing for non-medical (social) reasons is less popular. A statement from the Royal College of Obstetricians and Gynaecologists, whilst acknowledging that finding out the sex of an unborn baby can be exciting for parents, says that sex selection for non-medial reasons is inappropriate, saying: It is to be hoped that the birth of every baby will be a special moment for the parents, regardless of whether it is a boy or a girl. Focus should remain firmly on the health and care of the mother and developing baby, rather than gender”.

Some fear that parents might use the private testing service to allow the selective abortion of fetuses of the ‘wrong’ gender. The company says instead that customers want more time to plan for their baby, although their director did caution that parents who wish to know their child’s gender for medical reasons should seek the help of clinicians, because the company does not provide the counselling that forms an important part of the decision to have prenatal genetic testing for an inherited disease (see BBC news).

News story   |   By Dr Alison Stewart   |   Published 8 May 2007

During the last few years the US National Institutes of Health has been considering the pros and cons of initiating a large, longitudinal population study to investigate the influence of genetic and environmental factors on common complex diseases. Similar initiatives are already underway in some other countries including the UK (Biobank), Iceland, Estonia and Japan.

In response to a request by NIH Director Elias Zerhouni, the Secretary’s Advisory Committee on Genetics Health and Society (SACGHS) undertook to review the policy issues raised by such an endeavour and to recommend ways of addressing them. Its report, Policy issues associated with undertaking a new, large US population cohort study of genes, environment and disease, was published in March 2007, following consultation on a draft version issued in June 2006 (see previous newsletter article). SACGHS concludes in the report that “a new large population study could lead to improved diagnostics, treatments, and preventive measures for common diseases such as cardiovascular disease, diabetes, and cancer”. However, it identifies several important gaps in current knowledge about the public acceptability of such a project in the US, and its feasibility from a scientific, social, economic and ethical standpoint.

SACGHS recommendations on research policy issues stress the need to establish a collaborative model for project leadership, including key stakeholders in the public and private sectors, and representation from the behavioural, social, public health and population science disciplines in addition to biologists and epidemiologists. Consultation with the scientific community should be undertaken to gauge views on the validity of the project, the level of resources that should be committed to it, and provisions for fair access to resources and data associated with the project. There should be regular assessment of the outcomes from the project as they accrue, in order to ensure that population health benefits promised by the project are realised, and any adverse social consequences are avoided.

In a section of the report on ‘research logistics’, SACGHS expresses particular concern about the feasibility of enrolling participants in the numbers required, and ensuring adequate representation of population subgroups. It recommends that, in advance of any funding decision, there should be a thorough assessment of the public’s willingness to participate. Procedures for collecting, storing, tracking and centralising accurate clinical information over the lifetime of the project also need careful consideration; ways of assessing environmental exposures must be refined.

One of four recommendations on regulation and ethics is for the establishment of an independent ethics committee to protect the interests of participants and the public. Prospective participants should also be informed clearly about policy for use of data and specimens, and there should be avenues for regular consultation with study subjects in order to detect and address any emerging concerns.

The SACGHS report complements an earlier technical report by the National Human Genome Research Institute: Design considerations for a potential United States population-based cohort to determine the relationships among genes, environment and health

News story   |   By Dr Alison Stewart   |   Published 4 May 2007

The US Secretary’s Advisory Committee on Genetics Health and Society (SACGHS), which advises the Secretary for Health and Human Services, is seeking comments on its draft report Realising the promise of pharmacogenomics: opportunities and challenges.

The aim of the report is “to provide timely, policy-relevant information about pharmacogenomics to help frame recommendations for the Secretary and other policy-makers and stakeholders”. The report identifies a number of challenges for the development of pharmacogenomics and its effective integration into health care practice, including the need to improve the health-information infrastructure, to provide education and training for practitioners, and to maintain the confidence of all stakeholders by effectively addressing ethical, legal and social issues arising from pharmacogenomics. The SACGHS believes that the task of developing appropriate regulatory policies for pharmacogenomic tests entering the market mandates new approaches that are challenging the framework and capacity of the main regulatory agency, the Food and Drug Administration.

The report makes a range of recommendations, including provision of increased resources for both basic and translational research. It makes the point that ‘translation’ must encompass not only clinical trials, but also the “translation of clinical research findings into clinical and public health practice and policy” – a key aim of public health genetics. The principles of public health genetics are also evident in a carefully considered discussion of the evaluation of pharmacogenomic tests for their analytical validity, clinical validity, clinical utility and cost-effectiveness. The report recommends development of better tools for test evaluation, including improved methodologies for observational studies, and empirical research on the types and levels of evidence required for making decisions on the use of tests for different purposes. Evaluation should be continuing process, with support for the conduct of systematic reviews and technology assessments to summarise the evidence as it accrues.

Other recommendations include the development of interoperable databases and better systems for data sharing (together with measures to protect the privacy and confidentiality of personal data), development of clear clinical guidance and decision support tools for the use of pharmacogenomic tests in practice, support for initiatives in public education and engagement, and research on the value and opportunity costs of investment in pharmacogenomics.

SACGHS is requesting comments on the accuracy and coverage of the report, whether the recommendations are appropriate, and how the recommendations should be prioritised. The closing date for comments is 1 June.


News story   |   By Dr Alison Stewart   |   Published 2 May 2007

EuroGentest is a European network of excellence that aims to improve and harmonise standards for laboratory genetic testing services in Europe. The network’s six major units of work cover quality management, information databases, public health, ethical and legal aspects, new technologies and education. 

As part of its remit “to improve the quality of genetic counselling services associated with genetic testing across Europe”, a public health unit working party recently issued a set of Draft recommendations of the minimal criteria for geneic counselling related to genetic testing. The draft recommendations have been circulated to European clinical geneticists and genetic counsellors for discussion and improvement.

The recommendations define both genetic counselling and genetic testing; they note that the latter is generally taken to mean cytogenetic, molecular genetic and biochemical tests carried out in genetic testing laboratories as part of genetic services. However, they acknowledge that a need for counselling may also arise in the context of other types of test (histological, radiological etc) for highly-penetrant monogenic diseases. The recommendations distinguish testing from population screening, and categorise five types of genetic testing: diagnostic, prenatal, preimplantation, predictive, susceptibility and carrier testing.

An important feature of the draft recommendations is that they suggest that, while specialist genetic counselling is vital in the context of, for example, prenatal or predictive (presymptomatic) testing for monogenic disease, it will generally not be necessary for susceptibility tests indicating an increased or decreased risk of a multifactorial condition, or for pharmacogenetic tests. This recommendation differs from those of several other international bodies, including the Council of Europe in its European Convention on Human Rights and Biomedicine, which mandate genetic counselling for all uses of genetic tests.

In an associated project to inform its recommendations, the public health unit working party commissioned a survey of the Regulation and practices related to genetic counselling in 38 European countries. The survey found that although most European countries do not have specific legislation on genetic testing, many have professional guidelines for genetic counselling, and other general legislation covering issues such as informed consent, data protection and confidentiality. Most respondents predicted a trend towards increasing regulation. Two-thirds of countries considered their genetic counselling services to be of high quality and well-organised but the remaining 13 were concerned by problems of poor training, lack of specialists, poor coordination and lack of formal recognition of the field.

News story   |   By Dr Philippa Brice   |   Published 1 May 2007

Gene therapy had been used in an attempt to treat a genetic sight disorder. In the first clinical trial of its kind in humans, a team of clinicians from London's Moorfields Eye Hospital and University College London have introduced functional copies of the RPE65 gene to the retina of a man with Leber's congenital amaurosis, a form of inherited childhood blindness caused by mutations in RPE65 (see press release). This gene encodes an enzyme expressed in the retinal pigment epithelium (RPE), which has an essential role in vision; the mutation in RPE65 gene prevents the normal retinal function in detecting light.

It will take months before it is possible to determine whether the gene therapy has been successful in restoring some degree of sight, as has already been demonstrated in canine models, to any of the twelve trial participants. The best results are expected to be from the treatment of younger patients. Experts hope that the eye will prove to be a tractable target for gene therapy because it is a relatively simple and accessible organ; if so, gene therapy could potentially be used for other genetic visual defects.
Keywords : syndromesGene Therapy

Research articles

Research article   |   By Dr Philippa Brice   |   Published 30 May 2007

A new study published in Nature identifies four new genes associated with increased susceptibility to breast cancer. The normal lifetime risk of developing breast cancer for women in the UK is estimated to be 1 in 9 (11%). In individuals with inherited forms of increased susceptibility to breast cancer, lifetime risk can be much higher; women with inherited mutations in the BRCA1 or BRCA2 genes have a lifetime risk of as much as 85%. However, mutations in genes known to be linked with breast cancer such as the BRCA genes cannot be identified in the majority of families with a significant history of breast cancer. It has previously been presumed that these forms of familial breast cancer are the result of multiple contributory genetic susceptibility factors. Individually, each of these gene variants confers only a modestly increased risk, and hence have been impossible to identify by standard genetic association studies.

However, a new international collaborative study led by researchers at the University of Cambridge has performed a highly powered, three-stage genome-wide association study which has identified four new susceptibility genes: FGFR2, TNRC9, MAP3K1 and LSP1 [Easton DF et al. (2007) Nature Epub ahead of print, doi:10.1038/nature05887]. The researchers first analysed more than a quarter of a million single nucleotide polymorphisms (SNPs) in nearly four hundred each of breast cancer cases and controls. More than 10,000 SNPs selected because they were significantly more frequent in the breast cancer cases were then analysed in more than four thousand each of breast cancer cases and controls. Finally, the thirty SNPS most strongly associated with breast cancer were analysed for a total of around 22,000 breast cancer cases and controls, leading to selection of four genes as the most plausible candidate breast cancer susceptibility genes.

The FGFR2 gene showed the strongest association with breast cancer, increasing the risk of disease by around 60% for individuals with two copies of the variant form of the gene. The researchers also report that their analysis suggests the existence of multiple additional candidate susceptibility genes, some conferring a degree of increased risk comparable with that associated with the FGFR2 and TNRC9 genes.

Two additional papers published in Nature Genetics from US and Icelandic-led teams also link mutations in the FGFR2 gene with increased risk of sporadic post-menopausal breast cancer [Hunter DJ et al. (2007) Nat Genet. Epub ahead of print], and in the TNRC9 gene with increased risk of estrogen receptor–positive breast cancer, respectively [Stacey SN et al. (2007) Nat Genet. Epub ahead of print].

Comment: Together, these new susceptibility genes increase the proportion of familial breast cancer predisposition for which genes are known from around 25% to around 29%; although this is in many ways a relatively modest contribution to knowledge of genetic susceptibility to the disease, the findings are important because they demonstrate that using sufficiently large and highly powered genome-wide association studies can reveal the existence of multiple alleles that make individually moderate contributions to genetic risk. This suggests that the years ahead may generate significant information about the genetics of different forms of cancer, and of other polygenic diseases.

Research article   |   By Dr Philippa Brice   |   Published 24 May 2007

Human pathogens transmitted by mosquitoes represent a major global health problem. An international research effort led by The Institute for Genomic Research (TIGR) has sequenced the Aedes aegypti mosquito genome, with the first draft published in Science Express this month [Nene V. et al. (2007) Science May 17; DOI: 10.1126/science.1138878].

In the same way that the 2002 release of the genome sequence of the Anopheles gambiae mosquito, the major insect vector for malaria, was an important step towards new approaches to control of malaria, the much larger A.aegypti genome is expected to be valuable in developing strategies against the human diseases yellow fever and dengue fever. In particular, researchers hope to learn more about the interactions between the mosquito vectors and the pathogenic viruses they carry, and looking for opportunities to engineer virus-resistant mosquitoes. Lead investigator Dr Nene commented: With more than half a million cases of dengue fever which is endemic in at least 100 countries and more than 30,000 deaths from yellow fever each year, clearly understanding the biology of the vector for these two worldwide killers is essential to eradicating these diseases” (see press release).

Research article   |   By Dr Alison Stewart   |   Published 18 May 2007

Fragile X syndrome is an inherited form of learning disability caused by expansion of a tract of CGG repeats on the X chromosome that leads to methylation and decreased expression of the FMR1 gene. The condition is estimated to affect between 1/4000 and 1/8000 males.  Normal individuals have fewer than 45 repeats of the CGG sequence, while affected individuals have more than 200 repeats. Alleles with 55-200 repeats are classed as ‘pre-mutation’ alleles that may expand during female meiosis, so that a woman with a pre-mutation, although herself not usually affected by significant learning disability, is at risk of transmitting a full mutation to her offspring. Males with Fragile X syndrome are generally more severely affected than females. The carrier frequency of Fragile X syndrome in the population is thought to be about 1/100.

Molecular diagnosis of Fragile X carrier status is laborious because techniques based on use of the polymerase chain reaction (PCR) do not work with large tracts of repeated sequence. Researchers at Quest Diagnostics in California have developed a new technique, capillary Southern analysis (CSA), that they claim is rapid, high-throughput, amenable to automation and suitable for use as an initial screening test [Strom CM et al (2007) Genet Med 9, 199-207]. Alleles identified as pre- or full mutations by CSA analysis can be subjected to detailed analysis by Southern blotting to confirm the nature of the mutation and the methylation status of the FMR1 gene. The researchers claim that their protocol detects female carriers with 100% sensitivity and at least 95% specificity, and suggest that the use of CSA as a screening test should enable introduction of a population carrier screening programme for Fragile X syndrome.

Comment: The CSA technique seems likely to be a welcome innovation in the diagnosis of Fragile X carrier status. However, the existence of a rapid screening test is only one of many criteria for a population screening programme, and the issue of antenatal carrier screening for Fragile X is controversial. Although some analyses have found that antenatal carrier screening would be ‘cost-effective’, there are many questions still to be answered. The consequences for a woman of testing positive for a pre-mutation are of particular concern, as the chances of expansion to a full mutation may be as low as 10% in women with no family history of the condition.

Research article   |   By Dr Alison Stewart   |   Published 14 May 2007

The number of reasonably firm gene-disease associations for Type 2 diabetes is now at least 9, according to results from four large genome-wide association studies accepted for publication in the journals Science and Nature Genetics [Saxena R et al. Science advance online publication DOI: 10.1126/science.1142358 (abstract); Zeggini E et al. Science advance online publication DOI: 10.1126/science.1142364 (abstract); Scott L et al. Science advance online publiceation DOI: 10.1126/science.1142382 (abstract); Steinthorsdottir V et al. Nature Genetics advance online publication doi:10.1038/ng2043 (abstract)].

Altogether, the studies scanned DNA from about 50,000 cases and controls from several different populations world-wide. Previously published associations with Type 2 diabetes were confirmed for several common single-nucleotide polymorphisms (SNPs) including variants in or near the HHEX, SLC30A8, FTO, PPARG, KCNJ11 and TCF7L2 genes. New associations found independently by two or more of the studies were in a non-coding DNA region near the CDKN2A and CDKN2B genes, and in introns of the IGF2BP2 and CDKAL1 genes. Each individual variant increased risk for Type 2 diabetes by between 10% and 40%; in some cases, the risk varied in different populations.

Comment: These reports are an example of the spectacular power of genome-wide association studies and of the benefits of large-scale world-wide collaborations. It is hoped that further research to characterise the genetic changes responsible for increasing risk, and the biological functions of the genes involved, will shed light on how the insulin resistance and reduced insulin production that are characteristic or Type 2 diabetes develop.

Research article   |   By Dr Alison Stewart   |   Published 10 May 2007

Two papers in press in Science magazine report results of genome-wide association studies which have revealed that a common DNA sequence variant on human chromosome 9 is significantly associated with risk of heart attack [(Helgadottir A et al. Science advance online publication DOI: 10.1126/science.1142842 (abstract); McPherson R et al. Science advance online publication DOI: 10.1126/science.1142447 (abstract)]. The independent reports come from two large consortia involving scientists from Iceland’s deCODE Genetics Inc and researchers from universities in the US, Canada and Denmark. Together, the populations studied by the two consortia totalled more than 40,000 individuals.

The consortium led by deCODE reports that individuals homozygous for the variant (21% of the population) have a 60% greater risk of suffering a myocardial infarction (heart attack) than non-carriers. The relative risk for early heart attack is said to be 2-fold. The population attributable risk conferred by the variant is calculated to be 21% overall, and 31% for early onset disease. The other consortium quotes a 30-40% increased risk of coronary heart disease in Caucasian homozygotes.

Interestingly, the sequence variant, which involves a single nucleotide change, is in a region of chromosome 9 that contains no previously-characterised genes, and does not appear to be associated with known risk factors for coronary heart disease such as hypertension or diabetes.

Comment: The reported association appears to be highly significant and is strengthened by the fact that it has been independently confirmed in two very large studies. This is one of the strongest risk factors for a common disease to be discovered to date. As usual, the immediate assumption has been that a genetic test should be used to identify individuals at increased risk; indeed, deCODE chief Kari Steffansson has been reported by the news media as saying that the company is already developing such a test.

However, caution is required. As Janssens et al have pointed out in a recent commentary about similar calls for a ‘predictive’ test for a gene variant implicated in risk for Type 2 diabetes, “a risk ratio or population attributable risk alone cannot predict the potential usefulness of genetic testing[Janssens ACJW et al. (2006) BMJ 333, 509-10]. Full evaluation is needed, including such factors as sensitivity and specificity, positive and negative predictive values, and false-positive and false-negative rates.

The clinical utility of any test must also be carefully investigated: will it lead to improved health outcomes? It is assumed that high-risk individuals will alter their lifestyle to lower their risk. The lifetime risk for coronary heart disease in the general population is high (about 50% at age 40) yet progress in persuading people to adopt healthy behaviour has been limited. Further research is needed to find out whether knowledge of an increased genetic risk significantly increases motivation for behavioural change.

In summary, this discovery is exciting and may in time lead to important clinical benefits, for example through improved understanding of the pathological mechanisms underlying coronary heart disease. However, full and critical evaluation is essential before any test is implemented.  

Research article   |   By Dr Alison Stewart   |   Published 1 May 2007

The field of genetic epidemiology has been plagued by the difficulty of achieving independent replication of proposed associations between genetic variants and common, multifactorial diseases. A new study published in JAMA highlights this problem by reporting failure to replicate significant associations for any of 85 different variants in 70 genes that have been previously reported as susceptibility factors for atherosclerosis or for acute coronary syndromes including unstable angina and myocardial infarction [Morgan TM et al. (2007) JAMA 297, 1551-61].

The variants were tested in 811 white patients of European ancestry who presented with these conditions at two US university-affiliated hospitals, and in 650 age- and sex-matched controls. Only one variant, in the control region of the beta-fibrinogen gene, was found to be significantly associated with acute coronary syndromes at the P<0.05 level, but the significance level was marginal (P=0.03). A supplementary analysis to look specifically for weak associations found that only about half of the 85 variants were even marginally more frequent in cases than in controls.

Comment: The negative results from this study do not necessarily mean that positive results from previous studies were wrong. As the authors mention, a recent meta-analysis of 14 of the variants included in their study found odds ratios of 1.10 to 1.73 for risk of myocardial infarction, suggesting that any elevated risk, if present, is likely to be small and may not show up clearly in any but the very largest studies [Cascas JP et al. (2006) Ann Hum Genet 70, 145-69]. It is also possible that discrepancies between the new study and previous reports may be explained by differences between the study populations. Although the negative results from the work of Morgan et al should not necessarily be regarded as definitive, they do at least suggest that caution is needed and that any clinical use of reported associations to assess risk is premature.

New reviews and commentaries

Selected new reviews and commentaries, 10th May 2007

Reviews & commentaries : by Dr Philippa Brice

Environmental biology and human disease. Schwartz D, Collins F (2007) Science 316(5825):695-6. Policy forum article on the complex interactions between genetic and environmental factors in disease aetiology, and promoting the US Genes, Environment, and Health Initiative (PubMed).

When Bad Genes Look Good - APOE*E4, Cognitive Decline, and Diagnostic Thresholds. Glymour MM (2007) Am J Epidemiol. Apr 12; [Epub ahead of print]. Commentary on the types of bias that can affect studies of the influence of genetic factors on disease onset and progression, focusing on ApoE4 (PubMed).

Cytochrome P450 genotyping and antidepressants. Perlis RH (2007) BMJ 334(7597):759. Editorial considering the current lack of evidence for the clinical efficacy of pharmacogenetic testing to predict the efficacy of antidepressant drugs (PubMed).

The essential role of genetic counseling in inherited thrombophilia. Lochhead P, Miedzybrodzka Z (2007) Semin Hematol. 44(2):126-9. Discussion of genetic testing, and concomitant genetic counselling, for mutations associated with inherited forms of thrombophilia (PubMed).

Insights on Pathogenesis of Type 2 Diabetes from MODY Genetics. Weedon MN, Frayling TM (2007). Curr Diab Rep. 7(2):131-8. Review of the effect of polymorphisms in the genes associated with juvenile-onset diabetes on predisposition towards type 2 (adult-onset) diabetes (PubMed).

The Genetics of Anorexia Nervosa. Bulik CM, Slof-Op't Landt MC, van Furth EF, Sullivan PF (2007) Annu Rev Nutr. Apr 12; [Epub ahead of print]. Review of current knowledge on molecular genetic aspects of anorexia (PubMed).

Genotype-Phenotype Correlations in Autosomal Dominant and Autosomal Recessive Polycystic Kidney Disease. Rossetti S, Harris PC (2007) J Am Soc Nephrol. Apr 11; [Epub ahead of print]. Review on the influence of mutations in the PKD1, PKD2 and modifer genes on inherited forms of polycystic kidney disease (PubMed).

Inherited cancer susceptibility syndromes in paediatric practice. Field M, Shanley S, Kirk J (2007) J Paediatr Child Health43(4):219-29. Clinical review on the role of genetic testing for rare tumour susceptibilities in children, with examples (PubMed).

Toward understanding the genetic basis of neural tube defects. Kibar Z, Capra V, Gros P (2007) Clin Genet71(4):295-310. Review of the role of genetic factors in complex congenital neural tube defects, including important insights from the study of animal models (PubMed).

Racialized genetics and the study of complex diseases: the thrifty genotype revisited. ParadiesYC, Montoya MJ, Fullerton SM (2007) Perspect Biol Med 50(2):203-27. Critique of the thrifty genotype hypothesis of complex disease causation, calling for a robust interdisciplinary approach to genetic epidemiological research to generate useful results (PubMed).

Recent advances in newborn screening. Wilcken B (2007) J Inherit Metab Dis30(2):129-33. Review of the impact of tandem mass spectrometry in newborn screening for metabolic disorders, prospects for newborn screening for lysosomal storage disorders, and the need for more information on the impact of early detection on outcomes for such disorders (PubMed).

Genetic determinants of cancer metastasis. Nguyen DX, Massagué J (2007) Nat Rev Genet. 8(5):341-52. Review looking at the specific genetic and epigenetic changes that underlie metastasis (PubMed).

Animal models of human disease: zebrafish swim into view. Lieschke GJ, Currie PD Nat Rev Genet. 8(5):353-67. Review of the achievements and potential of zebrafish for modelling human diseases and for drug discovery and development (PubMed).

Inherited Thrombophilia: Key Points for Genetic Counseling. Varga E (2007) J Genet Couns.  May 1; [Epub ahead of print]. Review (PubMed).

Information Processing in the Context of Genetic Risk: Implications for Genetic-Risk Communication. Etchegary H, Perrier C (2007) J Genet Couns.  May 1; [Epub ahead of print]. Review of information processing models, with implications for clinical practice (PubMed).

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