News

25 March 2008The rising incidence of obesity presents one of the most disturbing and widespread public health problems for many societies. In the UK the rate of obesity has roughly doubled since the 1980s, with approx 17% of men and 21% of women now classed as obese and so at increased risk of diabetes, strokes, heart disease and cancer.

Earlier studies show that genetic predisposition is the major factor in determining whether a person becomes overweight as it accounts for 70-80% of the risk, with lifestyle playing a far smaller role. As with many other common complex conditions however, obesity doesn’t result from changes in just one gene, rather it is caused by changes in a whole series of genes, the combined effect of which is the propensity to gain weight.

In 2007 researchers scanned the genome of thousands of diabetic and obese individuals in a genome-wide association study that identified a gene called FTO, showing that individuals who possess a particular sequence variation in FTO are, on average, 3 kg heavier than those who don’t (see previous news).

However, obesity results from the interaction of many different genes in combination with different environmental effects. This complexity makes identification of each individual gene challenging using conventional techniques. In light of this, two studies published in the journal Nature have taken a different line – rather than attempting to identify individual genes, they measured gene expression levels (a measure of how much protein-coding sequence is produced by each gene) to identify networks of genes that are associated with obesity (see Reuters report).

In one study, the team measured the expression of nearly 24 000 known genes in blood and fat samples from hundreds of Icelanders in the database of the genetics company deCODE. This identified characteristic gene expression patterns in fat that correlate with body mass index (BMI, a measurement of obesity). The team used the data to identify ‘networks’ of hundreds of interacting genes that are regulated together and associated with obesity. A related study in mice indicates that many of these genes are associated with inflammation, so confirming the known link between obesity and the immune system. Furthermore, individual sub-networks associated with diabetes and atherosclerosis can be identified.

Although these reports do not necessarily identify which genes in the network are the root cause of obesity and which become altered as a consequence, they do highlight potential areas for intervention. As one author says: “We’re not just looking at one gene, that may or may not be druggable...We’re looking at what are the best nodes, or information control points. What’s the best light switch to affect the network maximally?” With this in mind, it should be noted that most genes (and the proteins they encode) might be involved in several unrelated pathways so that manipulating the ‘obesity’ network might cause harmful changes in other unrelated networks. 

Such work highlights the extraordinary complexity that lies behind genetic susceptibility to common multifactorial conditions such as obesity and associated metabolic diseases such as diabetes. The identification of individual contributory genetic factors involved adds to knowledge and understanding, and could even prove useful for the creation of therapeutic interventions to aid weight loss, ultimately, as one author states: “good diet and exercise is still probably the best treatment or way to prevent the onset of obesity".

14 March 2008108 UK academic professors (including scientists, lawyers, philosophers and theologians) have written to the Times newspaper calling for the Prime minister Gordon Brown to allow Members of Parliament (MPs) a free vote in the House of Commons on the Human Fertilisation and Embryology Bill. Proposed amendments to this legislation will be voted on, and the writers have said that ‘conscience voting’ (ie. not dictated by the political party, but left to the individual consciences of the MPs) should be maintained for bioethical issues such as this, despite the fact that they themselves did not share a common position on the proposals.Presently, MPs have been given permission to abstain from voting, but not to vote according to their own preferences; MPs have also been calling for a free vote (see BBC news).

Earlier the same week, forty cross-party MPs wrote to the Telegraph newspaper to express dismay at the decision of the Human Fertilisation and Embryology Authority to grant licences to conduct research with hybrids before the debate on the Human Fertilisation and Embryology Bill (see previous news).

13 March 2008Ageing has become a subject of considerable interest in many developed countries with an ageing population, both in terms of health and social care policy development, and scientific research. The underlying genetic mechanisms and biological pathways involved in the ageing process have been an area of biomedical research for some years; for useful review see Martin GM, Bergman A, Barzilai N. PLoS Genet. 2007 Jul;3(7):e125 and published and a Nature supplement on ageing published last year. Ultimately, the aim of research into ageing is to develop interventions and strategies that might boost normal life span.

 

A new publication has reported rare genetic mutations that appear to be associated with a longer life span; research based around a group of nearly 400 Ashkenazi Jews between the ages of 95 and 108 has led to the identification of two mutations that affect how cells respond to a particular growth factor, termed insulin-like growth factor 1, or IGF1 [Suh Y et al. Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3438-42]; see also press reports from 4th March in the Guardian and the Medical News Today.

 

IGF1 is crucial for normal growth in children, and it influences tissue generation in adults.It is already known that defects in the activity of this hormone can almost double the normal lifespan in yeasts, mice, nematodes and flies. Until now, however, it has not been possible to identify a similar link in humans because of the lack of suitable control groups. To overcome this, the researchers investigated both the centenarians and their children (aged 49-88 years) alongside a control group provided by Ashkenazi Jews of similar ages without a family history of unusual longevity.  

 

The study shows that the female (but not male) offspring of the centenarians have higher concentrations of IGF1 in their bloodstream than do controls, leading the authors to suggest that there is a defect in this pathway. Indeed, genetic analysis of the receptor through which IGF-I mediates its effects identified two mutations that were more common in long-lived families than in controls and that reduce the sensitivity of cells to IGF1. However, the reason for the increased in IGF1 in females but not males remains unclear.

 

Although more common in long-lived families, these mutations are still rare, leaving open the question of what other factors may be involved. No doubt ageing, in common with complex diseases, involves multiple different genetic and environmental factors (for example, see previous news). Further studies comparing the genetic make-up of long-lived individuals and families with normal age-span may reveal new insights into the process.

11 March 2008The PHG Foundation and the Royal College of Pathologists recently co-hosted a two-day meeting of leading experts to discuss the evaluation of laboratory diagnostic tests and complex biomarkers. Although such tests are used routinely to diagnose patients and to predict the risk that someone who is currently well will develop a disease in the future, there are no formal guidelines in place to ensure that individual tests are safe and useful for the patient or their physician. 

 

Launching the report of the meeting, PHG Foundation’s Director, Dr Ron Zimmern, said “In the UK, around 1 billion laboratory tests are performed each year. NHS laboratories have sophisticated systems to ensure the analytical accuracy of the tests, but no systems for ensuring that individual tests are clinically effective and useful. This is akin to pharmaceutical companies having tight control over the chemical purity of drugs, but there being no formal requirement for them to prove that the drugs produce any benefit for patients.” The report calls for a new body to be established to ensure the evaluation of laboratory diagnostic tests, and for the creation of a publically accessible database containing evidence of test performance, or lack of it, so that medical testing can be evidence-based. It also suggests that commissioners and health care professionals should be encouraged to use only those tests where appropriate evidence of clinical performance exists and that statutory regulators should call for a more responsive and proportionate risk assessment to ensure patient safety.

 

The report concludes that the processes recommended would not only assist health service professionals and patients, but would also provide much-needed clarity for commercial companies and academic researchers seeking to bring their innovations into NHS use.

 

The report, entitled “The Evaluation of Diagnostic Laboratory Tests and Complex Biomarkers”, is being published in tandem with a leaflet called “Making Sense of Testing” written by Sense about Science and aimed at the general public. The reports have received wide media interest, including an interview with Dr Ron Zimmern on the BBC Radio 4 Today program, articles in New Scientist, the Times, the Guardian and BBC News, and an editorial with accompanying paper in the BMJ.

 

The PHG Foundation and others will be attending a parliamentary briefing at the House of Commons in the afternoon of 11th March to discuss the report. This work will also feed into The House of Lords Science and Technology Committee inquiry into genomic medicine, for which the PHG Foundation will also be producing a formal response.

6 March 2008The European Biobanking and Biomolecular Resources Research Infrastructure was officially launched at a meeting held at the Wellcome Trust Sanger Center in Cambridge from 10-12 February 2008. This ‘European Biobank’ is intended to form a central computerised system linking the records of biological samples held in different research centres and biobanks across Europe; it has been established with 5 million Euros in funding from the EU [Stafford N. BMJ 2008 Mar 1;336(7642):467].

Its aim is to facilitate pan-European research into “the association between disease subtypes and small, but systematic, variations in genotype, phenotype, and lifestyle”, which requires the study of suitably documented epidemiological, clinical and biological information and material from large numbers of individuals. It is anticipated that researchers from both public and private centres will use the resource, which seeks to have an infrastructure and legal system in place by 2010. Partners include biobanks from Finland, Denmark, Sweden, Germany, Austria, Hungary, Estonia and the UK, including the UK Biobank, the UK DNA Banking Network and Generation Scotland, as well as European groups such as the European prospective study of nutrition and cancer (EPIC) and the European Research Council.

The venture is distinct from the EuroBioBank, an operating network of European biobanks from France, Italy, Spain, Germany, Hungary, Slovenia and Malta, which provides human DNA, cell and tissue samples for research into rare diseases. EuroBioBank is coordinated by Eurordis (European Organisation for Rare Diseases) and receives some EC funding, although individual biobanks within the network are financed by their own national or charitable bodies.

5 March 2008The ever increasing tide of genetic tests aimed directly at consumers is causing increasing concern amongst scientific and medical experts, who believe that the clinical validity and clinical utility of many of the tests have not been properly evaluated.

 

This increase is at least partly due to the publication of more and more genome-wide association studies, which are steadily uncovering genetic markers for numerous complex diseases [Baker, M. (2008) Nature 451: 516-518]. At least 27 web-based companies now offer genetic tests directly to consumers, offering around 1,400 different tests [Schmidt, C. (2008) Nature Biotechnology 26: 145-146] ranging from single diagnostic tests for rare, inherited monogenic disorders to multiple susceptibility tests for dozens of complex diseases. It is this last set of predictive tests from genome-wide scans that has caused both the most excitement and the most concern; some of the associations are considered by many to be statistically unsound, and the clinical validity entirely unproven. In addition, the utility of the tests, in terms of how the results can be used to improve health, has not been established and in many cases is entirely uncertain. Many people are asking what is the use of having a test to establish a relative risk of developing a disease such as Alzheimer’s, if we can neither predict whether an individual will actually develop it, nor can we prevent, delay or cure the disease? [Couzin, J. Science (2008) 319: 1022-1023] The psychological effects of ordering a whole genome scan over the internet – and subsequently receiving rather variable levels of information regarding your relative risk of developing various devastating diseases – remain unclear, but are certainly providing interesting fodder for journalists across the globe (see The Times, 1st Mar 2008).

 

Currently, there is no formal evaluation framework or coherent regulation for genetic tests that are sold directly to the consumer and do not claim to make a diagnosis. Although the analytical validity of the test must be adequate, there is no requirement for manufacturers to prove clinical validity or utility of the tests. Experts are worried that not only the public, but also many medical professionals, do not know how to interpret these predictive tests. As the dangers associated with invalid tests are being realised, efforts are ongoing around the world to change the regulatory situation. In the US, the Food and Drugs Agency (FDA) is likely to play an increasing role in genetic test oversight, though the exact details are still being worked out. “There is a major gap in the oversight of genetic tests when it comes to evaluation of clinical validity” said Dr Reed Tuckson, chair of a US Department of Health and Human Services advisory panel tasked with drafting a better model for genetic test oversight, adding “we find that unacceptable and it has to be fixed” (see Medical Devices Today, 25th Feb 2008).

 

Comment: Earlier this year, the PHG Foundation co-hosted an expert Diagnostics Summit with the Royal College of Pathologists, to address some of these issues and discuss how laboratory diagnostic tests for complex biomarkers should be evaluated. The report and key recommendations from this meeting will be published on Tuesday 11th March 2008, and will be available to download from our website.

3 March 2008The US Genetics and Public Policy Center has made a new internet resource available; the International Law Search facility allows users to search a database of laws in 16 countries related to human cloning, human genetic modification, and reproductive genetic modification. The database contains information derived from a 2004 survey of laws on prenatal genetic testing and preimplantation genetic diagnosis (PGD) by Bartha M. Knoppers and Rosario M. Isasi of the University of Montreal, Canada [Hum Reprod. 2004 19(12):2695-701], but is reportedly to be updated soon.

12 March 2008An extensive evaluation of the scientific basis for commercial genetic tests, published in the Americal Journal of Human Genetics, suggests that evidence of clinical validity is often minimal and sometimes entirely absent [Janssens ACJW et al. (2008), Am. J. Med. Genet. 82: 593-599]. This article is extremely timely, following the recent media interest in over-the-counter genetic tests sold directly to the consumer (see previous news article) and the two recent reports on diagnostic testing from the PHG Foundation and Sense about Science (see previous news article).

 

The authors looked specifically at seven companies – Genelex, Genovations, Integrative Genomics, Salugen, Sciona and Suracell – that all offer predictive genetic testing using multiple susceptibility markers, for conditions such as asthma, various cancers, psoriasis and Alzheimer’s disease Many of these tests are available directly to the consumer over the internet. They found that, of the 56 genes tested amongst the seven companies, just under half (43%) were not reviewed in meta-analysis. Furthermore, of those single nucleotide polymorphisms (SNPs) that had undergone meta-analysis, only 38% were found to have a statistically significant, albeit generally modest, association with the disease in question. These results suggest that only a third of tests have a well proven association between the SNP tested and the disease.

 

However, whilst a real association between a particular gene or SNP and a disease is necessary for a test to be clinically valid, it is by no means sufficient. The authors of this study comment that, “because the predictive value of genetic testing depends upon disease risk, genotype frequencies and odds ratios for the association… the profiles should be evaluated in the target population.” Although not addressed in this article, preliminary research at the PHG Foundation suggests that evidence of the second facet of clinical validity – assessment of the clinical performance of a test in terms of sensitivity, specificity and positive predictive value – is absent from the majority of predictive genetic tests sold directly to the consumer.

 

These results underline the importance of recent recommendations from the American Society for Human Genetics, as well as the PHG Foundation and Royal College of Pathologists amongst others, calling for transparency of evidence for diagnostic tests.

10 March 2008From theory to practice: translating research into health outcomes

Barbour V, Chinnock P, Peiperl L, Veitch E, Yamey G. PLoS Med. 2008 Jan 8;5(1):e15.

Genome studies: genetics by numbers.

Baker M. Nature. 2008 Jan 31;451(7178):516-8.

A navigator for human genome epidemiology.

Yu W, Gwinn M, Clyne M, Yesupriya A, Khoury MJ. Nat Genet. 2008 Feb;40(2):124-5.

Moving towards transparency of clinical trials

Zarin DA, Tse T. Science. 2008 Mar 7;319(5868):1340-2.

Are epigeneticists ready for big science?

Pennisi E. Science. 2008 Feb 29;319(5867):1177.

Should data from demographic surveillance systems be made more widely available to researchers?

Chandramohan D, Shibuya K, Setel P, Cairncross S, Lopez AD, Murray CJ, Zaba B, Snow RW, Binka F. PLoS Med. 2008 Feb;5(2):e57.

When authorship met authenticity

Johns A. Nature. 2008 Feb 28;451(7182):1058-9.

Collaboration, genetic associations, and lupus erythematosus.

Crow MK. N Engl J Med. 2008 Feb 28;358(9):956-61.

On the origin of deleterious mutations

Check-Hayden E. Nature. 2008 Feb 21;451(7181):876.

Regulators weigh risks of consumer genetic tests
Schmidt C.Nat Biotechnol.  Feb;26(2):145-6.Nat Biotechnol. 2008 Feb;26(2):145-6

A spot of genetic instability in autism

Eichler EE, Zimmerman AW. N Engl J Med. 2008 Feb 14;358(7):737-9.

What will whole genome searches for susceptibility genes for common complex disease offer to clinical practice?

Lango H, Weedon MN. J Intern Med. 2008 Jan;263(1):16-27.

Structural genomic variation and personalised medicine

Lee C, Morton CC. N Engl J Med. 2008 Feb 14;358(7):740-1.

What can the genome tell us about LDL cholesterol?

Krauss RM. Lancet. 2008 Feb 9;371(9611):450-2.

Genetics benefits at risk

Editorial. Nature. 2008 Feb 14;451(7180):745-6.

In search of common ground

Blow N. Nature. 2008 Feb 14;451(7180):855-8.

Genetic testing and tumor surveillance for children with cancer predisposition syndromes
Rao A, Rothman J, Nichols KE. Curr Opin Pediatr.  2008 Feb;20(1):1-7.

Complexities of prostate-cancer risk.

Gelmann EP. N Engl J Med. 2008 Feb 28;358(9):961-3.

Genetics of common disease: a primary care priority aligned with a teachable moment?

Feero WG. Genet Med. 2008 Feb;10(2):81-2.

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