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According to the news reports, the advantage of this methodology is that it can be used to screen a far wider range of genetic conditions as well as multiple genetic traits, and produces results in a shorter time period (BBC news). The technique involves the analysis of single nucleotide polymorphisms (SNPs) in DNA from parents and embryos to produce a ‘karyomap’ showing which parts of the embryo’s chromosomes have been inherited from which parent. In other words, it allows the origin of specific chromosomal segments to be identified and consequently also allows tracing of chromosomal segments that might be associated with a particular disease or phenotype. Thus far, the methodology used in producing karyomaps sounds remarkably similar to pre-implantation genetic haplotyping (PGH), which is used to identify haplotypes associated with familial disease regions (see previous news). However, a karyomap reportedly allows the identification of multiple genetic variations and aneuploidies, in addition to single gene defects.
Despite wide media coverage, the scientific basis or clinical utility of this technique is currently unclear. The divergence from (and purported superiority over) PGH remains uncertain, as there have been no scientific publications describing the details of the new methodology, and no clear explanation of how exactly multiple genetic traits are identified.
The Bridge Centre is currently undertaking clinical trials prior to applying for a licence from the HFEA for the use of the technique, and the possibility of being able to test rapidly for a wide range of different mutations associated with genetic forms of disease is exciting. However, proposals that it may be used as a “MoT” for embryos or for the production of “designer babies” are distinctly premature. Although this technique may be able to identify some genetic variants associated with physical traits or susceptibility to common diseases, the effect or risk of these individual variants on multi-factorial developmental or pathological processes could be very small, and potentially entirely non-pathogenic variants (such as copy number changes) could be found. It would not be feasible to select embryos on this basis, nor would the HFEA be likely to grant a licence for screening without a proven medical benefit.
In addition, IVF is a specialised procedure typically only undertaken where normal fertility is impaired, and may be coupled with PGD to prevent the conception of embryos with inherited forms of serious genetic diseases, the genetic basis of which is generally already known. Moreover, the process entails small but significant risks to the health of the mother and often fails to result in an established pregnancy. Together with the expense of the test (£1500), these factors mean that it is unlikely to become a routine procedure for couples who do not require IVF, but possibly as a potential additional technique to help select the most viable embryos for implantation where a couple is already undergoing IVF. However, a thorough evaluation of the clinical validity and utility of the test will be required before it can be offered even for this purpose.
24 October 2008The UK Human Fertilisation and Embryology Bill had its long awaited report and third reading in the House of Commons on 22 October 2008 (see BBC news). Although MPs from all parties were given a free vote on the amendments, there was general frustration at the lack of time devoted to the Bill (less than four hours) and the way in which amendments had been timetabled, which effectively prevented substantive debate on clauses relating to abortion, or the need for a father.
Although a number of amendments went to a vote, there were comfortable Government majorities rejecting all amendments seeking to limit the scope of the Bill. There were particularly heated exchanges regarding the repeal of the Human Reproductive Cloning Act 2001 which established the ban in the UK on human reproductive cloning. Dawn Primarolo explained that although the Bill continued to provide ‘a clear prohibition on human reproductive cloning and the genetic modification of gametes or embryos that are to be used for treatment purposes’, an exception might be made in the future for the processing of embryos and eggs to avoid the risk of serious mitochondrial diseases (a wide range of rare diseases including certain types of dementia, stroke and brain atrophy).
Before such regulations are enacted, a further wide ranging consultation will take place, not least because the use of these technologies raise issues about the status of a woman who donates only mitochondria. The Bill now provides that in certain cases, the requirement for donor consent can be waived where embryos are to be used for research, so to provide that existing holdings of tissue taken for research can continue to be used for that purpose. This is particularly relevant where disability or disease is likely to result in mental incapacity or where it affects children who are never able to consent for themselves.
These final amendments to the Bill now need to be ratified by the House of Lords before the Bill can gain Royal Assent. No date has yet been set for its return to the House of Lords.
23 October 2008The US National Heart, Lung and Blood Institute has announced $25 million funding for a six-year program to fund collaborative genomics studies between different centres, focusing primarily on the genetic causes of congenital heart disease.
The NHLBI Pediatric Cardiac Genomics Consortium is to be a collaborative venture with the Institute of Circulatory and Respiratory Health (ICRH) of the Canadian Institutes of Health Research, and is calling for applications from potential researchers to to conduct research that can lead “to a comprehensive understanding of congenital heart disease” (see GenomeWeb news article). The purpose of this consortium, which will form part of a larger programme of translational research in pediatric cardiovascular disease, is to perform clinical and translational research on the genetic causes of congenital heart disease, and on genetic contributions to outcome in individuals with congenital heart disease.
It is intended that this collaborative approach will make it feasible to recruit sufficient patients for large-scale studies; although collectively cardiac defects are the most common type of birth defect, each individual form of congenital heart disease tends to be very rare. Applicants to form one of up to six research centres will have to propose investigation of the genetics and genomics of one or more human cardiac malformations; they may focus on different aspects as set out in the announcement:
Of note, the PHG Foundation’s cardiac genetics project is reviewing current NHS provision for patients with inherited forms of cardiac disease in the UK, and working with stakeholders to develop recommendations for improving cardiac genetics care.
Many of the issues associated with personalised health care (see previous news) have already been raised in relation to personalised genomics (see previous news). This includes questions about informed consent and data confidentiality, the usefulness of such information to the individual, how it will affect lifestyle choices, regulation of direct-to-consumer tests, and the impact of such information on insurance policies and the NHS as people seek follow-up support. Although the NHS already utilises some forms of the technologies that the project is focusing on, their application as tools for ‘personalised’ healthcare is at present primarily offered by commercial companies.
The recent plethora of genome-wide association studies revealing genetic risk variants with very low penetrance has raised particular questions regarding the interpretation, validity and utility of tests that purport to predict genetic susceptibility to future disease, which are becoming increasingly availability through private providers. Although these tests, in conjunction with other biomarkers, may ultimately be useful for stratifying the population for the purpose of offering more targeting screening programmes (see previous news), their usefulness at an individual level is still in doubt, particularly in cases where there is no recommended intervention or treatment. Some of these difficulties are discussed in a recent publication [Janssens ACJW & van Duijn CM (2008) Hum Mol Genet 17(2):R166-173], which emphasises that, unlike rare single gene disorders, the complete causal pathway of common multifactorial diseases is likely to differ between individuals, and this inherent complexity means that accurate prediction of risk at an individual level may never be possible.
20 October 2008The Centre for Arab Genomic Studies (CAGS) has warned that a growing prevalence of genetic disorders in the Arab world will place greater financial strain on health systems and public health infrastructure (see UAE National news article).
CAGS, which collects data from the United Arab Emirates (UAE), Bahrain and Oman, reports that single-gene disorders such as sickle cell disease and thalassaemia, as well as some rarer genetic diseases, are much more common in the region than elsewhere. This increased birth prevalence is attributed to a combination of factors, including a high frequency of consanguinity (marriages between cousins and other relatives), which can increase the number of carriers of mutations associated with autosomal recessive forms of genetic disease. Another problem is a lack of public awareness about such conditions, their diagnosis, identification and prevention.
Assistant director of CAGS Dr Ghazi Tadmouri reportedly spoke in favour of wider awareness of such diseases, and of improved public health and genetics services (from pre-conceptual carrier screening programmes to prenatal and preimplantation diagnosis) commenting: “Now it is becoming mandatory to do basic screening for thalassaemia and other diseases before marriage…Of course no one would oblige partners to not marry if they were both carriers of a disease”. Earlier diagnosis was also noted to be essential to reducing mortality rates associated with genetic diseases.
Chromosomal abnormality Down Syndrome (trisomy 21) is also more common in some Arab populations, with 21.4 babies per 100,000 affected in the UAE; this is much higher than in countries such as the UK, and around double the average global rate. It has been suggested that this may be related to a “social trend to have more children until menopause” (see Hindu News article), since the risk of Down Syndrome increases significantly with maternal age.
The CAGS Catalogue of Transmission Genetics in Arabs (see previous news) is planning to widen contributions to include collection of data from Qatar, Kuwait, Saudi Arabia, Egypt and Iraq.
Comment: Several commercial companies offer personal genome scans; however, their utility is often brought into question by regulators and it is uncertain if genetic susceptibility information can have a positive impact on lifestyle choices. This project may help us reach an understanding as to the extent that genetic information gained from such scans can influence our behaviour and health choices. Such studies can also be valuable in assessing the effectiveness of these tests for use in clinical practice and some studies to address this issue have already been initiated (see previous news).
The US Food and Drug Administration (FDA) has recently licensed for marketing, a new therapy for use in the routine prophylaxis of Hereditary Angioedema attacks (see press release). Hereditary Angioedema (HAE) is a rare genetic disorder, which results in deficiencies in a plasma protein known as C-1-inhibitor. This protein is involved in regulating clotting and inflammatory responses, consequently, deficiencies can lead to excessive tissue swelling. HAE is an autosomally inherited disorder that affects approximately 1 in 50, 000 people, although in some cases it can occur spontaneously as a result of mutations in the C-1-inhibitor gene.
A HAE attack occurs spontaneously and can be caused by stress, surgery or infection and results in rapid swelling of the hands, feet, limbs, face, intestinal tract or airway which is potentially fatal. Current treatment regimes in the US and UK for HAE attacks involve the use of steroid drugs in order to control the swelling. However, these can have adverse effects is some cases, such as liver toxicity and carcinogenicity. This new drug - Cinryze™ is a C1-esterase inhibitor product derived from human plasma. It has been approved on the basis that in clinical trials it was effective in preventing or decreasing the frequency of attack in most HAE patients and had side effects that were considered mild or moderate.
A potentially more widely useful therapeutic for selected genetic diseases is currently in development; US-based PTC Therapeutics’ PTC124 is a candidate drug in phase 2a clinical trials (seeking to demonstrate proof of clinical benefit in patients). PTC124 suppresses the effect of a particular type of mutation, nonsense mutations, which normally cause premature termination of proteins. By allowing the cellular transcription process to continue past the nonsense mutation, PTC124 has been shown to allow the production of functional CTFR protein in cystic fibrosis patients with nonsense mutations in the CTFR gene, and of functional dystrophin protein in Duchenne Muscular Dystrophy (DMD) patients with nonsense mutations in the dystrophin gene. If the drug is proven to confer clinical benefits in such patients, it could potentially be appropriate for the treatment of around 15% of all patients with genetic diseases, as this type of mutation is quite a common one.
13 October 2008According to Cancer Research UK, one in nine women in the UK will develop breast cancer at some point in their life. Some major genes involved in rare inherited (familial) forms of breast cancer are well known, and a genetic test for these BRCA1/2 mutations is already available from Myriad Genetics (see previous news), they only account for a tiny proportion of breast cancer cases. ‘Normal’ or ‘sporadic’ breast cancer is believed to arise from a combination of many different interacting environmental and genetic factors, and some relatively common genetic factors have been identified as being linked to a slightly increased lifetime risk of developing breast cancer.
The Icelandic company deCODE has now launched a new genetic test to screen for risk of the most common forms of breast cancer (see deCODE news). The deCODE BreastCancer™ test is based on seven common single nucleotide polymorphisms (SNPs), which are each associated with a small relative risk. The results from all seven SNPs are combined to estimate a woman’s risk of breast cancer relative to the population. The company claim that the test can identify those women whose relative is 1.66 or higher, representing approximately 5% of the total female population. They suggest that such women are at sufficiently high absolute risk to meet the American Cancer Society’s recommendation for regular breast screening by MRI.
Comment: The test has drawn heavy criticism from a number of commentators, who assert that the test clinically useless and could lead to women be either unduly alarmed or falsely reassured, although there is currently little or no evidence for either of these outcomes. There is a valid concern that, in the absence of professional medical advice and proper counselling, members of the public may misinterpret the test, which is currently available both direct-to-consumer as part of a larger genome-wide scan for risk of numerous diseases, and through physician referral specifically for breast cancer risk . But what are the other potential problems?
There are a number of points to consider when assessing a test of this sort. Firstly, the legitimacy of the test – does it measure what it claims to measure, and is there strong scientific evidence linking the genetic variant to the disease? In this case, the former question is addressed by the fact that the assay is carried out in a CLIA-waived laboratory, and is therefore likely to be accurate, and the latter by a number of large studies indicating a real association between each of the seven SNPs and breast cancer. The relative risk estimate generated by the test are valid and so the test itself is scientifically legitimate. However, the exact nature of the claims and the usefulness of the test may not be.
The second question is therefore one of interpretation – what do the results of the test actually mean for an individual patient? The test places an individual within a sub-population with a average specific risk, but cannot locate the exact whereabouts of that individual within the distribution of risks of the whole group. The key issue in interpretation is the conversion of relative to absolute risk. However, this task is not simple, as it is age dependent and also depends on whether competing mortality is taken into account (which many published absolute risks do not). For example, the average absolute risk that a woman who has not had breast cancer will develop the disease before the age of 85 ranges from around 8% (1 in 12.5) at ages 20 or 30, through 6.5% (1 in 15) at age 50 to 3% (1 in 33) at age 70.
Finally, there is a question of utility – do the benefits of the test outweigh the potential harms, and can the test usefully provide guidance for action? These questions are not simple to answer, and will depend enormously upon the context in which the test is used, and ultimately upon the purpose of testing. If the purpose, as is suggested by some commentators, is to accurately inform a patient whether they will, or will not, develop breast cancer, then it is unlikely to be clinically useful. However, if the purpose is to identify women at a higher than average risk in order to target them for screening, as suggested in a recent paper in the New England Journal of Medicine (see previous news), then it could potentially be very useful.
However, even this final point is fraught with difficulties, as the guidance on when to offer screening (or indeed any form of intervention) is highly controversial and varies between countries. Although the American Cancer Society recommends annual mammography from age 40, the UK NHS Breast Screening Programme is only offered to women aged 50-70, who are at a substantially higher risk of developing breast cancer within the following 10 years. Determining whether this type of test will ultimately yield tangible benefits through a reduction in the breast cancer morbidity and mortality will take much more research, a long time and a lot of data.
Therefore, although it is certainly too early to offer such a test to women routinely, and proper provision for professional medical support should always be available, our suggestion is that providing the test in the marketplace is not in itself illegitimate. How the test is to be used, how it is to be interpreted and what interventions are offered to a woman with higher risk, however, are questions that deserve much greater scrutiny.
The report Health is Global: a UK Government strategy notes that health is a ‘global public good’ benefiting societies around the world, and that “Public health interventions, such as a cure for a disease, communicable disease control or the dissemination of research, are also global public goods”. Addressing issues that relate to monitoring and control of infectious diseases that could threaten public health in the UK and those that primarily affect the developing world are one of the main concerns of the report, but several other areas are also explored.
One point of note is the potential for improved information sharing and access to innovation and health-related knowledge via the internet and wireless communications. Possible benefits cited are the capacity to create global health and public health initiatives, or to keep doctors in developing countries up to date with medical developments. A key disadvantage is proposed to be the exposure to unregulated forms of health information and products (drugs and diagnostics), which poses a risk to patient safety. The Foundation is involved in international efforts to devise an appropriate system for the evaluation and regulation of genetic tests and biomarkers, to address this problem in one specific arena; the report itself recognizes that “providing technical assistance or influencing policy is a real way to make an impact on global health”.
Another major focus of the report is on health research, suggesting that the UK has much to offer in terms of health research with potential global benefits, citing the example of UK involvement in international frameworks for health research such as the Council of Europe’s Additional Protocol to the Convention on Human Rights and Biomedicine and UNESCO’s Universal Declaration on Bioethics and Human Rights.
Ways in which the UK should maximize biomedical research and development efforts and resources to benefit global health highlighted include:
A recent study published in the journal European Urology suggests that a prostate cancer gene test may prove helpful in identifying patients in need of a repeat biopsy (see press release). Previous studies have shown that PCA3 messenger ribonucleic acid (mRNA) is over expressed in prostate cancer tissue and an assay for this gene could be an accurate means of predicting the results of a repeat biopsy. A study by Haese et al. has replicated these findings in a larger prospective study of 463 European men who had previously had negative biopsy results [Haese et al. (2008) Eur. Urol. 54(5):1081-1088]. The authors compared the levels of PCA3 mRNA in urine to repeat biopsy results, and showed that PCA3 levels were higher in men who had a positive biopsy results and were diagnosed with prostate cancer. Furthermore, their research also indicated a relationship between the PCA3 score and the significance of the cancer, suggesting it could be used as a means of identifying those patients who may need active surveillance. However, this finding needs to be evaluated further.
Comment: This new study demonstrates the clinical utility of using the PCA3 gene test and its superiority over a PSA assay in identifying those in need of a repeat biopsy. However, the relationship between PCA3 and prostate cancer is not absolutely clear, consequently for the present it will have to be used in conjunction with existing tests such as the PSA assay in order to reliably identify those at risk.
14 October 2008Schizophrenia is a group of psychiatric conditions manifesting as hallucinations, paranoid delusions, and/or disorders of thought. A genetic basis for schizophrenia has long been suspected with twin studies suggesting a heritability of over 80%, and several candidate genes have subsequently emerged [Ross CA et al. (2006) Neuron. 52(1):139-53]. Current knowledge suggests that each risk allele identified confers a small increase in risk of schizophrenia, with the constellation of alleles producing an individual’s overall genetic risk of developing this complex disorder; environmental influences are also presumed to contribute.
Writing in Nature Genetics, O’Donovan et al. have identified twelve more genetic polymorphisms that may be associated with schizophrenia [O'Donovan MC et al. (2008) Nat Genet. 40, 1053 - 1055].