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22 January 2007European Union (EU) Ministers from the 27 Member States have informally agreed unanimously to explore a plan that would enable the exchange of personal data, such as motor vehicle registration, DNA and fingerprint data, across national borders (see press release). The aim is to “create a modern police information network for more effective crime control throughout Europe,” according to German interior minister Wolfgang Schäuble. Ministers are now planning to propose transposing the existing Treaty of Prüm into EU legislation. This Treaty, agreed between six Member States in 2005, created a network of national databases to facilitate the exchange of personal data.
Specifically, the Treaty sets up a system for requesting and receiving information, allowing countries to grant automated access to specific national databases. Vehicle registration data is directly accessible. DNA and fingerprint files are handled differently. Representatives from one country can query another country’s DNA database and receive a ‘hit’ or ‘no hit’ response in return. If there is a ‘hit’ then additional information can then be requested. The Treaty states that “Reference data must not contain any data from which the data subject can be directly identified.” In addition, “a reasonable standard of data protection” is required on the part of the receiver of the data. Currently, Germany and Austria have each checked their databases against the other to trace ‘untraceables’ and have had successful results. According to Minister Schäuble, the success of the efforts of Germany and Austria shows that “…the idea behind the Prüm Treaty to create a network of existing national databases is a simple, yet very effective means to fight cross-border crime and international terrorism” (see press release).
While the UK has agreed with other Member States to explore turning the Treaty into EU legislation, representatives, together with those from Ireland, Poland and the Czech Republic, have stated that, “ they needed more time to examine the financial and judicial implications… ” Deliberations will no doubt be slow as there are many issues to take into account. The text of the existing Treaty is expected to form the basis of draft legislation, but revisions in that text are expected.
22 January 2007The US House of Representatives has introduced legislation aimed at protecting individuals against potential genetic discrimination in the areas of employment and the provision of health insurance. The Genetic Information Nondiscrimination Act of 2007 (H.R. 493) was introduced in the House earlier this month. The text of the draft bill notes that Federal law addressing genetic discrimination is incomplete and that State laws vary widely, creating inconsistencies. This ‘patchwork’ of legislation is confusing to the medical community as well as to the public. Federal legislation is therefore needed to create a uniform national and basic standard to protect the public from discrimination and allay their fears regarding this issue. With protections in place, it is hoped that people will be more likely to take advantage of genetic therapies, such as genetic testing.
This is certainly not the first time such legislation has been introduced in either the House or the Senate. Senate-led attempts in 2003 and 2005 were passed unanimously within the Senate (see news story), only for the legislation to ‘die’ in committee in the House of Representatives. Senator Barak Obama’s 2006 draft bill on personalised medicine also addressed genetic discrimination issues, but never progressed beyond the Senate committee review stage (see news story). This 2007 draft bill may have a better chance with the new Democratic majority in Congress, provided agreements on the text can be reached. In addition, President Bush has spoken out in favour of legislation. Recently at a visit to the National Institutes of Heath he told reporters, “If a person is willing to share his or her genetic information, it is important that that information not be exploited in improper ways, and Congress can pass good legislation to prevent that from happening” (see news article). With support from all sides, this draft bill has a better chance than previous bills of successfully making it through the US law-making process.
11 January 2007The Human Fertilisation and Embryology Authority (HFEA) has decided that applications to create hybrid human-animal embryos (see previous news story) as part of stem cell research “would potentially fall with the remit of the HFEA to regulate and licence” and would not be prohibited by current legislation (see press release). However, because the issues associated with hybrid and chimera research differ from those relating to other forms of human embryo research, the HFEA intends to hold a formal consultation on the topic before the applications may be passed to the licensing committee for consideration.
Chief Executive Angela McNab said that the HFEA had decided “that there needs to be a full and proper public debate and consultation as to whether, in principle, licences for these sorts of research could be granted…From the evidence considered so far this issue is far from black and white. There is not clear agreement within the scientific community about the need for and benefits of this science”. She added that it would be wrong to make a judgement on such complex and controversial matters without first considering the evidence.
Hybrid embryo research formed part of the wider public consultation performed by the Department of Health as part of the updates to the Human Fertilisation and Embryology (HFE) Act 1990 (see previous news story), but the HFEA feels that a new consultation relating specifically to such work is required. The consultation should be completed by autumn 2007. Scientists behind the applications for licenses to create hybrid human-animal embryos have expressed approval for the opportunity to promote “the merit of this research which we feel will provide valuable new research tools for developing new therapies for devastating neurological disorders" (see BBC news report).
11 January 2007The US Agency for Healthcare Research and Quality (AHRA) has released a report on the utility of testing for cytochrome P450 (CYP450) polymorphisms in adults prior to the use of selective serotonin reuptake inhibitor (SSRI) anti-depressants. Common variants in the P450 enzymes that metabolise SSRIs can affect the rate of drug metabolism, and hence the therapeutic dose; individuals who metabolise SSRIs more rapidly than normal would require higher doses for a therapeutic effect, whilst those who metabolise them very slowly would be at risk of side-effects from standard doses. The first commercial microarray-based pharmacogenetic test, Roche’s AmpliChip CYP450 test, which detects polymorphisms in the CYP2C19 and CYP2D6 genes for the purpose of determining the probable metabolic status of patients was licensed by the US FDA in 2005 (see previous news story).
After considering 1,200 scientific abstracts and reviewing a total of 37 articles, the authors conclude that there were tests with “high sensitivity and specificity for detecting only a few of the more common known polymorphisms of 2D6, 2C19, 2C8, 2C9, and 1A1”. There was found to be a general paucity of good-quality data on utility of testing for CYP450 genotypes and mixed evidence for an association between different genotypes and the metabolism or efficacy of SSRIs in the treatment of depression. In particular, there were said to be no data regarding whether testing polymorphism testing led to improved outcomes; was useful for medical, personal or public health decision making; influenced management decisions by patients or healthcare providers; or was associated with direct or indirect harms for patients.
The report was funded by the National Office of Public Health Genomics (NOPHG), and is part of their Evaluation of Genomic Applications in Practice and Prevention (EGAPP) pilot project, which aims to evaluate gene-based tests and other genomic applications that are in transition from research to clinical and public health practice. The EGAPP working group will produce recommendations later this year on the use of CYP450 polymorphisms tests for the treatment of depression based on the new report, plus additional issues such as accessibility and affordability.
NOPHG Director Dr Muin Khoury commented: "This report emphasizes that well-designed observational studies and clinical trials are needed to clearly establish the clinical validity and utility of the many emerging genomic tests for treatment and prevention of common diseases of public health significance…Early availability of the evidence base is key to the effective use of genomics for the benefit of population health" (see press release).
5 January 2007Controversy over proposals to create hybrid human-animal embryos as part of stem-cell research (see previous news story) continues as the Human Fertilisation and Embryology Authority (HFEA) considers whether it has the authority to assess the two applications made for licences to produce such hybrid embryos, and whether the proposed research is even legal. As part of the recent White Paper reviewing the Human Fertilisation and Embryology Act (see previous news story), the government has proposed that the creation of human-animal hybrids or chimeras should be outlawed, partly in response to public opinion weighted against the process. Scientists behind the licence applications to the HFEA, who hope to circumvent the acute shortage of human oocytes for the creation of embryonic stem cells by using animal oocytes fused with human genetic material, have accused the Authority of “bowing to government pressure” should it fail to consider the applications, and are presenting the proposed work as an essential step forward in the development of stem-cell based therapies for serious diseases such as Parkinson’s and Motor Neurone disease.
An HFEA spokesman said that: "We need to decide whether the law prohibits this research, whether it falls under our remit at all, and then we can look at whether we have a fundamental view on this type of research” (see BBC news report). The HFEA is due to make a policy decision on the licensing of human-animal embryo research on 10th January, and issue a statement the following day.
5 January 2007The American College of Obstetricians and Gynecologists (ACOG) has issued new recommendations calling for all pregnant women in the US to be offered screening for Down syndrome, irrespective of their age. Previously, only women over the age of 35 have been routinely offered invasive, diagnostic testing for the chromosomal abnormality, but the new guidance says that non-invasive screening before the twentieth week of pregnancy should be offered to all women, along with genetic counselling and the option of amniocentesis or chorionic villus sampling to permit diagnostic testing for those in whom screening indicates an increased risk of Down’s. The ACOG says that it “recognizes that a woman's decision to have an amniocentesis or CVS is based on many factors, such as a family or personal history of birth defects, the risk that the fetus will have a chromosome abnormality or an inherited condition, and the risk of pregnancy loss from an invasive procedure” (see press release).The guidance document outlines the available forms of screening (such as maternal serum screening and ultrasound nuchal translucency testing) and the factors that determine which are appropriate, suggesting alternative screening strategies.
In the UK, antenatal screening for Down Syndrome is already available for all women. The National Screening Committee (NSC) target for the Down's Syndrome Screening Programme is to provide the combined test (nuchal translucency measurement by ultrasound plus serum tests) for women requesting first trimester screening, and the integrated test (which combines the results of full first and second trimester screens) for all others by April 2007.
19 January 2007The prevalence of some monogenic (Mendelian) diseases such as cystic fibrosis varies between populations, due to different frequencies of the mutant alleles within each population. Similarly, many complex diseases (with multiple genetic and environmental factors affecting disease susceptibility) also show varying prevalence between populations. For example, individuals from South Asian populations living in the UK have a greater than average prevalence of coronary heart disease, whilst those of Afro-Caribbean origin have a relatively high prevalence of hypertension. Similarly, Mexican Americans and American Indians have generally higher rates of type II diabetes than Americans of predominantly European origin. These differences are presumed to arise from differing allele frequencies for multiple polymorphisms that affect key genes involved in disease resistance and susceptibility.
A new study published in Nature Genetics uses microarray technology to analyse the expression of more than 4000 genes in white blood cells from Asian and Caucasian populations [Spielman RS et al. (2007) Nat Genet. Jan 7; Epub ahead of print]. The distinct characteristics of specialised cell types arise from the pattern of gene expression for that cell type – which genes are expressed, and at what level. More than 1000 of the genes analysed were found to show differential expression levels between the population groups. The researchers found that much of these differences were the result of sequence variation in the form of single nucleotide polymorphisms (SNPs) – but in the non-coding regulatory regions adjacent to the genes, rather than the coding regions of the genes themselves. They conclude that allele frequency differences at regulatory polymorphisms account for some of the observed differences between populations in the prevalence of complex diseases by causing variation in gene expression.
Comment: This work adds a new element to the undoubtedly complex genetic variation that affects the susceptibility of different population groups to various disease states, although firm conclusions cannot really be drawn from a study that looked at gene expression in only one cell type, from a limited number of different samples (142). The true in vivo situation with respect to gene expression could also differ from that in a laboratory maintained cell line.18 January 2007Hereditary haemochromatosis is a condition in which the iron levels in the blood are too high, associated with heritable mutations in the HFE gene which are common in Caucasian populations. Although the complications that can result from iron overload are severe (such as cirrhosis and cancer of the liver), and there is a simple and effective intervention to prevent such end-stage disease (regular blood-letting), the utility of population screening for the condition is questionable, because the disease shows very low penetrance. Although most individuals with clinical iron-overload are homozygous for HFE mutations (the most common variants being C282Y and H63D), a substantial proportion of homozygotes remain asymptomatic.
For any proposed genetic screening programme the potential benefit, in terms of disease prevention, must be weighed against the potential negative effects on those found to carry relevant mutations, in terms of psychological wellbeing. However, a study reported in a recent edition of Genetics in Medicine did not look at patients found to have mutations or clinical signs associated with risk of hereditary haemochromatosis, but rather those found to have ’indeterminate’ results – HFE genotypes and/or iron levels in the blood with uncertain associations with disease risk [Anderson RT et al. (2006) Genet Med. 8(11):681-7].
The researchers compared levels of psychological well-being and health anxieties among over 1000 such patients with that of healthy controls, having no HFE mutations or elevated iron levels. They found that confusion existed among participants about what their reported test results actually meant, particularly among those who received indeterminate results (19.5% compared with 5.4% of controls). More of this group believed that they had haemochromatosis mutations and/or clinical disease, and such beliefs were associated with poorer outcomes in terms of health and mental well-being. The authors conclude that “when screening results are vague or indeterminate regarding risk of disease, people may conclude that they have an abnormality that threatens their health and, as a result, feel less well and worry more”.
Comment: The authors of this paper also note that conventionally, trivial or indeterminate risk results are not reported to screening participants, precisely in order to prevent the sort of psychological harms outlined above. Some would argue that this approach is inappropriate as it entails undermining patient autonomy and withholding information that may, in the future, be useful to assess disease risk. However, in this particular instance - given that only a small proportion of those found to be homozygous for the HFE mutations associated with haemochromatosis are likely to be at genuine risk of clinical disease - these results would seem to strengthen the argument that population screening should not be introduced.
11 January 2007Stem cells are believed to hold great therapeutic promise for a wide range of serious diseases and types of injury, and are the subject of considerable research. However, perhaps the most contentious and problematic issue in the field of stem cell medicine is the source of stem cells and stem cell lines for research (and potentially also therapeutic) purposes. Embryonic stem (ES) cells are pluripotent – capable of developing into any type of adult cell – and ES cell lines are thus considered to be the most useful source of stem cells, but their derivation is complex, especially given the scarcity of human ova to create the embryos, and the subject of intense ethical debate. Multipotent adult stem cells are an alternative source of stem cells, but show limited capacity for cellular differentiation. A new paper published in Nature Biotechnology reports the derivation of both rodent and human multipotent stem cells (capable of differentiating into multiple different specialized cell types) from amniotic fluid [De Coppi P et al. (2007) Nat Biotechnol. 25(1):100-6].
The authors used stem cells selected from discarded amniotic fluid (obtained from a total of nineteen pregnant women for the purposes of prenatal genetic diagnosis) to establish stable cell lines, which they have termed amniotic fluid stem (AFS) cell lines. The AFS cell lines were found to be capable of extensive self-renewal and, under appropriate conditions, of differentiation to form multiple cell types from each of the different embryonic germ cell lineages. For example, neuronal, osteogenic, myogenic and hepatic cell lineages were established, which give rise to specialised nerve, bone, muscle and liver cell types. The cell lines were concluded to comprise “broad-spectrum multipotent (that is, pluripotent) stem cells”.
The researchers note that consistent presence of a Y chromosome in lines derived from amniocentesis donors carrying a male child implies that the AFS cells are fetal in origin, and based on cell surface marker profiles suggest that they are a new type of stem cells, which represent an intermediate stage between ES cells and adult stem cells.
Comment: AFS cells could represent a novel and highly useful source of human stem cells. They are more readily (and less controversially) obtainable than ES cells, apparently easily grown and capable of a much higher degree of differentiation than adult stem cells. If the findings of these authors prove to be consistent in further independent studies, then further investigation of the properties and applications of AFS cells will be certain. A commentary accompanying the research paper also notes that they may also have relatively low immunogenicity – since this is generally repressed during gestation to avoid immune rejection of the fetus by the mother – and if so could be especially useful for transplantation into allogenic (non-related) recipients [Trounson A (2007) Nat Biotechnol. 25(1):62-3].
5 January 2007Three new papers published in the January edition of Nature Genetics combine to produce a key map of common genetic variation in the genome of Plasmodium falciparum, the parasite that causes the most severe form of human malaria. Research groups at the US National Institutes of Health, the US Broad Institute in Harvard and the UK Wellcome Trust Sanger Institute have used complementary approaches to look at genetic diversity in Plasmodium.
Two of the groups used whole-genome shotgun sequencing: the Harvard-led team looked at more than 80 different P. falciparum isolates including the reference strains Dd2 and HB3 [Volkman SK et al (2007) Nat Genet. 39(1):113-9], whilst the Sanger researchers sequenced just two P. falciparum isolates, but alsoproduced a partial genome sequence for the related species P. reichenowi, which infects great apes but not humans, and does not produce severe pathology [Jeffares DC et al (2007) Nat Genet. 39(1):120-5].The NIH team resequenced around 3,500 genes from four P. falciparum clones - including Dd2 and HB3 - and analysed data on 183 SNPs from 99 parasite isolates [Mu J et al. (2007) Nat Genet. 39(1):126-30]. Each group has aligned their own sequence data to the reference P. falciparum genome sequence (published in 2002) to produce maps of sequence variation between different isolates of the same species of parasite.
The papers all consider the potential applications of the current haplotype map, and of future refined versions of the map, to inform understanding of the parasite’s biology (lifecycle, population genetics, pathogenicity), as well as to identify key factors involved in virulence and drug resistance that may allow the development of novel vaccines and drugs.
Comment: Together, these three papers make a substantial impact in adding to current knowledge of Plasmodium genetics, and set the scene for the creation of a more comprehensive (and hence useful) version of the genome-wide haplotype map. In addition to scope for technical improvements in genomic sequence quality, the commentary accompanying the papers notes the absence of data for P. falciparum isolates from the Indian subcontinent [Carlton JM (2007) Nat Genet. 39(1):5-6] as well as the outstanding need for robust phenotypic assays to allow genotype-phenotype links to be identified by association studies. Given the massive global impact of malaria on population health, it will be worth pursuing these goals.
17 January 2007In search of a familial cancer risk assessment tool. Kelly K and Sweet K (2007) Clin Genet 71(1):76-83. Review of web-based familial cancer risk assessment tools, and recommendations for the development of future tools (PubMed).
Sudden cardiac death in the young: a clinical genetic approach. Ingles J and Semsarian C (2007) Intern Med J 37(1):32-7. Review on the genetics of sudden cardiac death and the necessity for multidisciplinary clinical management of affected families (PubMed).
Polycomb silencing mechanisms and the management of genomic programmes. Schwartz YB and Pirrotta V (2007) Nature Genetics 8(1): 9-22. Review on the function of polycomb group complexes in epigenetic regulation (PubMed).
An evolutionary view of human recombination. Coop G and Przeworski M (2007) Nature Genetics 8(1): 23-34. Review looking at determinants of genetic recombination rates an d the implications for human genetics (PubMed).
Heterochromatin revisited. Grewal SI and Jia S (2007) Nature Genetics 8(1): 35-46. Review on the role of heterochromatin in different chromosomal processes (PubMed).
Dosage compensation: the beginning and end of generalization. Straub T and Becker PB (2007) Nature Genetics 8(1): 47-57. Review of sex chromosome dosage compensation mechanisms and implications for gene expression (PubMed).
The mouse as a model for human biology: a resource guide for complex trait analysis. Peters LL, Robledo RF, Bult CJ, Churchill GA, Paigen BJ and Svenson KL(2007) Nature Genetics 8(1): 9-22. Review on the availability and use of mouse genetics resources for complex genetic traits analysis (PubMed).
Innovations: Prenatal diagnosis: progress through plasma nucleic acids. DennisLo YM and Chiu RWK (2007) Nature Genetics 8(1): 71-76. Perspectives piece on the emergence of and prospects for using extracellular fetal nucleic acids for prenatal diagnosis (PubMed).
Genetic influences on preterm birth. Defranco E, Teramo K, Muglia L (2007) Semin Reprod Med 25(1):40-51. Review of the genetic contributions to the multifactorial condition of premature birth (PubMed).
Pharmacogenetics of cytochromes P450 in tropical medicine. Ribeiro V and Cavaco I (2006) Curr Drug Targets 7(12):1709-19. Review of the pharmacogenetics of P450 enzymes among ethnic groups in tropical regions (PubMed).
HMDB: the Human Metabolome Database. Wishart DS et al. (2007) Nucleic Acids Res 35:D521-6. Report on the database of human metabolic information, a resource for academic and clinical scientists, geneticists and nutritionists (PubMed).
5 January 2007Overview of the pharmacoeconomics of pharmacogenetics. Dervieux T, Bala MV (2006) Pharmacogenomics 7(8):1175-1184. Review of pharmacoeconomics looking at how genetic markers of drug efficacy and toxicity may be used cost-effectively for improved patient care, with examples (PubMed).
Pharmacogenetics of irinotecan: clinical perspectives on the utility of genotyping. Innocenti F, Ratain MJ (2006) Pharmacogenomics 7(8):1211-1221. Perspective article on UGT1A1 genotyping prior to the use of irinotecan to prevent toxicity (PubMed).
Pharmacogenomics of asthma. Pahl A, Benediktus E, Chialda L (2006) Curr Pharm Des12(25):3195-206. Review looking at polymorphisms that influence the asthma therapy, and the potential benefits of genomic expression studies using microarray technology (PubMed).
Genetic testing without consent: the implications of the new Human Tissue Act 2004. Lucassen A and Kaye J (2006) J Med Ethics 32(12):690-2. Commentary expressing concern about the HTA’s provision for DNA analysis without consent when an individual has yet to make a decision, and calling for new guidelines for this situation (PubMed).
Exploring the uses of RNAi - gene knockdown and the Nobel Prize. Bernards R (2006) N Engl J Med 355(23):2391-3. Perspective article on RNA interference and its applications in ‘knockdown’ of gene expression (PubMed).
Unraveling the Genetics of Human Obesity. Mutch DM and Clement K (2006)PLoS Genet 2(12):e188. Review on the insights into the physiology of obesity provided by rare genetic disorders, and on emerging understanding of key genetic and environmental interactions involved in different forms of obesity (PubMed).
The genetics of fibromyalgia syndrome. Buskila D, Sarzi-Puttini P, Ablin JN (2007) Pharmacogenomics 8(1):67-74. Review of the role of genetic polymorphisms in predisposition to FMS and the scope for future genetic studies (PubMed).
Vascular endothelial growth factor pharmacogenetics: a new perspective for anti-angiogenic therapy. Pasqualetti G, Danesi R, Del Tacca M, Bocci G (2007) Pharmacogenomics 8(1):49-66. Review of clinical genetic studies of antigentic determinants, proposing that pharmacogenetic profiling of patients prior to the use of anti-angiogenic drugs could be beneficial (PubMed).
From molecular diagnostics to personalized testing. Finan JE, Zhao RY (2007) Pharmacogenomics 8(1):85-99. Review of the future of molecular-based testing and prospects for a transition towards personalised medicine (PubMed).
Predicting risk of breast cancer recurrence using gene-expression profiling. Ignatiadis M, Desmedt C (2007) Pharmacogenomics 28(1):101-11. Special report on molecular profiling of breast tumors using microarray technology, and the potential to integrate information about prognostic genetic signatures, pharmacogenetics and clinical parameters to create a decision-making algorithm for management (PubMed).
Unraveling the genetics of atherosclerosis: implications for diagnosis and treatment. Seo DM, Goldschmidt-Clermont PJ (2007) Expert Rev Mol Diagn. 7(1):45-51. Review of different approaches for studying the genetics of atherosclerosis and the implications clinical practice (PubMed).