In response to the "call for evidence" issued by the House of Lords Sub-Committee IIA, we wish to provide evidence concerning the on-going ADLIB (Acute coronary event DNA LIBrary) Project.

  An earlier draft of this document was submitted to our principal sponsor the British Heart Foundation (BHF), to help them to compile their own submission to you [see p 27], regarding a much wider range of genetic databases. Consequently, there will be overlap in the information provided. Nevertheless the ADLIB Project represents a unique initiative, being a high profile, publicly sponsored, national DNA/genetic resource. Consequently, we wish to make this submission on an "individual basis."

1.1  What current projects involve collecting genetic information on people in the United Kingdom?

  The ADLIB (Acute coronary event DNA LIBrary) Project represents an on-going programme of research that seeks to identify genetic determinants of premature coronary artery disease. ABLIB now has a number of key parts that have evolved together to provide a large, national resource of DNA and data. These include:

A.  The BHF funded, collaborative regional YORKSHIRE and MIDLANDS Family Heart Studies that are now merging and extending to become THE BHF FAMILY HEART STUDY (start date December 2000). The primary object of this work is to create a genome-wide map in each of two siblings affected by coronary disease up to the age of 65 years. Using linkage analysis, we are seeking to identify chromosomal locations containing genes that influence the occurrence of disease. 2,500 paired DNA samples are being collected and analysed.

B.  The BHF and NHS R&D funded GRACE 1 & 2 STUDIES form part of the ADLIB Project and are closely related, and may soon merge with the BHF Family Heart Study. The GRACE studies are designed to evaluate "candidate genes" that have been implicated in the aetiology of coronary artery disease. The approach is based on a collection of DNA from individuals with coronary disease up to the age of 65 years combined with DNA from two unaffected siblings (2000 families).

C.  Strategic funding just awarded by the Medical Research Council will permit augmentation of THE ADLIB PROJECT (start date December 2000). Specifically this will pay for some additional nursing, clerical and technical support to obtain an extra blood sample from affected siblings in families already studied (800) and also those still being sought (1,200). This funding will permit storage of white blood cells that could be immortalised in the future to permit additional DNA to be obtained. The DNA and associated epidemiological data represent a national resource, available to researchers throughout the UK.

1.2  What other projects are about to start?

  The ADLIB Project was initiated in 1997 and is now extending to recruit families on a national basis (start December 2000).

1.3  Are there collections of material (eg tissue samples) that could be used to generate databases of DNA profiles?

  So far DNA has been extracted and stored in all cases. From December 2000 an additional sample of white blood cells will be stored to permit later extraction of additional DNA.

2.  WHY ARE THESE DATABASES BEING ASSEMBLED?

  It is commonly known that heart attacks are a major cause of death and disability both in the United Kingdom and also worldwide. Over 25,000 individuals younger than 65 years die from heart artery disease in England and Wales every year. Many of these events cannot be adequately explained by recognised risk factors such as smoking, poor diet and high blood pressure. Furthermore, this type of disease occurs repeatedly within families. Both the disease and its attendant psychological and social effects represent a very great impediment to health. Numerous possible genes that may cause or predispose to early heart disease have been put forward. However, the scientific methods that have been used to study groups of unrelated individuals leave considerable room for uncertainty. We wish to assess the presence of currently unrecognised molecular mechanisms of disease causation/modification by searching for novel genetic variants. We are employing established and evolving methodologies to identify and study over 2,000 families with brothers and/or sisters who have had heart disease before the age of 65 years. Donation of a simple blood sample is allowing us to form a large, anonymised gene library (The ADLIB Project) as a focus for public education, counselling and targeted scientific research.

2.1  How are these activities funded?

  ADLIB is funded primarily by the BHF (2,500K; 80 per cent) and secondarily by the Medical Research Council (800K; 18 per cent) and the National Health Service R&D programme (100K; two per cent). Subsidiary funding of three BHF Clinical Research Fellows supports a number of research projects utilising DNA and data from the resource. Importantly, these complementary funding streams all involve monies given by the General Public either charitably (80 per cent) or as part of taxes (20 per cent). Consequently, our view is that ownership of the intellectual property emerging from the research also rightly belongs to the General Public. DNA and data are held in trust, remaining the property of the individuals (patients and their relatives) who have volunteered to help the research.

2.2  What practical considerations will constrain developments?

  Prior to the 1998 Data Protection Act we were able to identify patients who had had coronary artery disease at a young age, using NHS records. Subsequently this has been viewed by some NHS Trusts as contrary to the Act. Specifically we have been prevented from making contact with patients unless they have previously consented to our utilising knowledge of their personal details YET we cannot obtain such consent for patients who have previously been through some aspect of clinical care without contacting them! This represents a "catch 22" situation. Our current solution to this dilemma has been to make indirect contact though the media, inviting response via FREEPHONE or FREEPOST. This has worked very well. In the event that there are any difficulties with this approach on a national level we intend also to make initial contact via General Practitioners in an opportunistic way.

  Until very recently, the main practical constraint facing the ADLIB Project was the lack of adequate funding. However, after the successful completion of an initial "feasibility" phase, appropriate funding and methodologies are now in place. Having obtained Multicentre Research Ethics Committee (MREC) approval for this work, we have also had confirmation of approval from 159 Local Ethical Committees and await the response of an additional 50. This process should be completed over the next couple of months, and so will be in place for the official national launch of the project at the end of this year. Similarly, the work is being registered with NHS Trusts (management R&D departments and Data Protection Officers) throughout the country. Furthermore, two independent bodies have been identified to provide counsel to patients invited to take part in the work (Genetic Interest Group—GIG and Consumers for Ethics in Research—CERES). Consultant Cardiologists throughout the country have been informed (via the British Cardiac Society) of the work, with plans to similarly involve General Practitioners and also Nursing and other health professionals caring for Cardiac Patients. We will continue to liaise directly with local and national patient support groups and also the general public through the news (TV, radio, newspaper) and other media. These necessary procedures represent "practical constraints" against which we are making excellent progress. Our success derives from the great willingness of those with heart disease and their relatives to help with genetic studies.

2.3  Are there alternative ways of fulfilling the objectives?

  The ADLIB Project addresses a large gap in scientific understanding as to the exact mechanisms causing/modulating the occurrence of premature familial coronary artery disease. It is well recognised that first degree relatives of patients having an acute myocardial infarction prior to the age of 55 years have a risk that is two to seven times the risk of their peers. Furthermore, twin studies indicate an 8-fold increase in death from AMI if a first twin dies of AMI before the age of 55 years. Clearly a family history of AMI carries with it information that is both helpful in identifying groups at increased risk, though more particularly helps to identify individuals predisposed to premature disease. A recent paper published in the medical journal Circulation highlights six cardinal risk factors that are independently and quantifiably predictive of coronary risk in both men and women. These are: age, blood pressure, LDL cholesterol, HDL cholesterol, diabetes mellitus and smoking. The residual risk, attributable to age but assuming no other risk factors to be present, indicates the presence of currently unexplained influences that may collectively be as great as the risk that is attributable to smoking. It is also well recognised that genetic factors underlie the occurrence, and modulate the consequences of, blood pressure, cholesterol and diabetes. Furthermore, it has been suggested that adverse consequences of smoking can be genetically modulated. Based on these observations it is clear that knowledge of "conventional" risk factors alone, while helpful in evaluating groups of individuals, cannot accurately predict the risk of any single individual. For example, one of 25 38-year-old male smokers, having no other risk factors, will have a major coronary event before the age of 50 years. Consequently, although all have a theoretical 4 per cent risk, the subsequent reality will be that one individual will experience an event (100 per cent risk) while the remaining 24 will not (0 per cent). Since the individual DNA of man is readily amenable for study, it would be illogical to use biochemical surrogates.

3.  WHAT IS THE GENETIC INFORMATION THAT IS BEING COLLECTED?

  Epidemiological Database: We are currently collecting DNA from families in which at least two siblings (AA; Affected Affected) have each had one or more of the following, up to and including the age of 65 years—acute myocardial infarction (AMI); coronary artery bypass graft (CABG) surgery; percutaneous transarterial coronary angioplasty (PTCA) or angina based on appropriate history with evidence of positive exercise or electrocardiogram or angiogram showing significant coronary atheroma. We opted for use of these criteria based on our observations of affected family units where for example a sibling has already died of coronary disease and a second has survived an AMI. Not surprisingly additional siblings often have attended for revascularisation procedure. We consider such siblings to be entirely representative of those families in need of help and hence also those that we are keen to include. By selectively studying families in which at least two siblings have been affected prematurely by coronary artery disease, we anticipate that the genetic factors present will be more potent than might be expected if families with only a single affected individual were studied. Furthermore, the precision of the selected phenotype is enhanced by the requirement for each family to have at least two validated affected siblings. In all cases we independently validate the occurrence of an AMI, PTCA, CABG, positive exercise test or angiogram demonstrating significant coronary artery disease.

  Genetic Database: An appropriately powered genome-wide search for loci linked to coronary artery disease (The BHF Family Heart Study) is currently underway. The genotype of individuals at each of 400 microsatellite marker locations is being determined and stored digitally. Fine mapping, using more closely spaced multiallele markers, will allow enhanced localisation of areas of interest, though still cannot discriminate between possible contributions made by many hundreds of genes at that site. Previous investigations have had to resort to direct sequencing to discover, firstly what genes exist at a given locus, and secondly to elucidate what defects may exist within those genes. We expect to be able to take advantage of solid-state single nucleotide polymorphism (SNP) "chips" that are currently being developed, as well as the ever enlarging human genome data-base. Derived genetic information will be stored digitally. The DNA resource is also being used to evaluate candidate genes identified both by us and by others. Recent descriptions of the discordant-alleles and discordant-sibling disequilibrium tests (SDT) indicate that both pairs (AU; Affected Unaffected) and preferably trios of siblings (AAU or AUU) can be informative both separately and in combination with other data that may be available from surviving parents and additional siblings. All genotypes are being stored digitally for subsequent analysis.

3.1  How is it being stored and protected?

  Epidemiological Database: In addition to family pedigree and the details of prior AMI, PTCA, CABG, angina, we make a detailed note of the past medical history (including diabetes, hypertension, hypercholesterolaemia) and concomitant illness with current medical therapy. Original Case Record Forms are being stored at the two Project Offices (Leeds and Leicester) in locked filing cabinets within a secure room. Data are then entered onto a computer database that is stored on a primary server located within a secure machine room on NHS premises. The project is registered in accordance with the Data Protection Act (1998). The data-sets that will later be made available for wider use will be anonymised, although the project offices will continue to keep a record of the names, addresses and telephone numbers of patients contributing to the collection. This is recorded at the time of initial contact and is used for subsequent communications with the patient and their GP (ie data and DNA collection).

  Genetic Database: All DNA and white blood cell samples are anonymised from the point of receipt in the ADLIB Project laboratories, being identifiable only by a unique Case Number. All genetic information subsequently obtained is linked to the Case Number on a computer database that is entirely separate (different server and site location) from the primary Epidemiological Database. Consequently, genetic information on the database can only be linked with personal identifiers by merging the separate Epidemiological and Genetic data-sets.

  Merged National Database: Upon completion of the various phases of genotyping, and following removal of all Personal Identifiers, the two data-sets will be combined and made widely available to collaborating researchers throughout the UK. Importantly, the value of the ADLIB collection will be enhanced over time by the longitudinal survival data that is being collected via the Office of National Statistics (ONS).

   DNA and Lymphocytes: Funding currently provided permits us to provide sufficient DNA, directly from blood, for the immediate demands made on the ADLIB resource. By cryopreserving lymphocytes it will be possible to provide additional quantities of DNA limited only by costs should the demand prove to be as great as expected.

4.1  How do the organisations involved see their responsibilities regarding privacy?

  We have obtained Multiple Centre Ethics Committee (MREC) approval for national extension of the ADLIB project. When patients sign a consent form it states, "Your genes (DNA) will be used only to determine the genes underlying heart disease and will not be sold to other people. They will act as a resource to establish the genetic basis of heart disease. They will be provided free of charge to other scientists with the aim of advancing our knowledge of this condition so we can improve available treatments...you may withdraw your donated sample at any time". Based on this understanding we currently consider ourselves to be acting on behalf of the British Heart Foundation and now Medical Research Council as guardians of the collection. Future arrangements for custodianship of the extended ADLIB collection will involve agreement between representatives of the BHF and MRC together with the ADLIB Investigators.

  As guardians of the ADLIB DNA Collection and associated Epidemiological and Genetic databases, we have undertaken to safeguard a wide range of patient interests including protecting their privacy. Under no circumstances will identifiable genetic or other personal information be released to a third party without very specific individual consent. For example we have been asked by news reporters whether we are able to put them into contact with individuals who have been affected by coronary artery disease at a young age. Under such circumstances we have re-contacted individuals with whom we have recently been dealing, and asked if they would be willing to speak to a media representative. Patients have always been very willing to help in profiling the research by recounting their individual story. Any request for information coming from an insurance company is considered highly improbable and would be refused. Acknowledgement of holding the DNA of any individual would similarly not be given. A request for information coming from the police would similarly be refused unless mandated by law.

4.2  How do the organisations involved see their responsibilities regarding consent?

  The project is being performed in accordance with the principles stated in the Declaration of Helsinki. The final project protocol, including the final version of the Patient Information and Consent Form to be used, was approved by both Multicentre (MREC) and Local (LREC) Research Ethics Committees before collection of any personal data or blood samples. Each Research Assistant ensures that the patients are given full and adequate verbal and written information about the nature, purpose, possible harm and also the benefits of the project. Patients are also notified that they are free to remove their personal data/DNA from the archive at any time. Patients have the opportunity to ask questions and have time for consideration. They are provided with the contact details of two independent bodies (Genetic Interest Group—GIG and Consumers for Ethics in Research—CERES), whom they can readily approach for additional advice and information. Our Research Assistants are responsible for obtaining signed, informed consent from all patients prior to their attendance (local hospital/GP) for venepuncture. A copy of the information sheet is retained by each patient. Patients are informed in writing that data and DNA samples will be stored, maintaining confidentiality in accordance with national legislation. All computer-processed data is handled in accordance with national data protection guidelines, thereby safeguarding anonymity.

4.3  How do the organisations involved see their responsibilities regarding public accountability?

  The British Heart Foundation is directly accountable to the General Public through the laws governing charitable research organisations. Furthermore, as its funds result from bequests and other charitable giving, the BHF necessarily has a very close relationship with the General Public. The Medical Research Council is funded by the General Public through taxes, and hence is accountable directly to the government. Furthermore, through extensive consultative procedures and published Guidelines, the Medical Research Council undertakes to be fully accountable to the public. The National Health Service Research and Development programme is directly accountable to the Department of Health. The BHF and also both the MRC and NHS R&D have been extremely keen to publicise this work to demonstrate their involvement in research that is of potential value and relevance to so many.

  The ADLIB Project as a whole, and the BHF Family Heart and GRACE studies in particular, are being conducted by practising physicians who have daily contact with the General Public through their clinical duties. Furthermore, the methods used to identify and recruit families (television, radio, newspapers, newsletters, oral presentations, poster displays, and as part of delivering usual medical care) involves a continual dialogue with the public. Provision of a FREEPHONE telephone number and FREEPOST address also permits an individualised dialogue to take place. As a follow-on to the counselling provided at the time of initial contact, we have undertaken to keep patients informed with regard to the general progress of the ADLIB Project. So far this has taken the form of news updates broadcast by BBC regional television and radio as well as publication of updates by the local press. In the future we would like to circulate a biannual newsletter to supporting health care professionals, study subjects and also to the media. This is to ensure on-going public education and support for the project.

4.4  How do the organisations involved see their responsibilities regarding intellectual property rights?

  In line with current BHF and MRC recommendations (Interim Operational and Ethical Guidelines November 1999) anonymised research data will be placed on a National Database. The custodians of the ADLIB Collection (BHF/MRC/applicants) "will make it a condition of access to the samples that copies of all data generated by other users are provided to the custodian after a suitable period of exclusive access, designed to allow sufficient time to publish or gain a competitive advantage". The requirements of confidentiality and data protection will be fully met. In accordance with the British Heart Foundation Conditions of Award (Ref SCA/11/99) we draw a distinction between the samples that will be collected and stored as a result of any MRC funding and the data being collected as part of The British Heart Foundation Family Heart Study. This includes epidemiological information and also data from the genome-wide mapping currently in progress. These conditions state, "Useful results of research that it funds (whether in whole or in part) are applied for the public good. BHF therefore requires all grant holders to play an active role in ensuring the protection and exploitation of intellectual property arising out of any BHF funded activity". In line with both sets of guidelines, the Guardians of the collection will ensure that written agreements are drawn up so that source data is made generally available after primary publication of research findings. It is further suggested that the intellectual property rights for research findings derived from DNA within the collection will be allocated in a manner proportional to the level and source of grant income funding the research.

5.  HOW WILL ACTIVITIES IN THE AREA OF GENETIC DATABASES DEVELOP IN THE FUTURE?

  Identification of the genomic location of currently unrecognised abnormalities that underlie premature familial coronary artery disease should permit subsequent gene identification with enhanced understanding of disease mechanisms, disease prevention, risk evaluation, diagnosis and treatment. The study of inherited high cholesterol, and the development of effective cholesterol lowering drugs (statins) with the subsequently widespread use of a strategy and treatment able to prevent acute coronary events in susceptible individuals, illustrate the potential for a genetic approach.

5.1  What advances in sequencing, screening and database technology are anticipated?

  Comprehensive sequencing of the DNA that makes up the human chromosomes (the human genome) is near to completion, with two independent drafts already published. Molecular biological techniques and also bioinformatic programmes and systems continue to develop at a rapid rate. Using capillary-based gel systems and also robotic platforms, sequencing and also genotyping of micro-satellite markers has greatly increased in speed. This will facilitate attempts to describe biological and pathological variation within the genome. In particular the description of single nucleotide polymorphisms should open up novel scientific approaches to detection of genes that either cause or modulate the occurrence of disease states. Parallel progression of statistical approaches to data analysis ensures that there are also likely to be many new software packages to aid research. Specifically, the availability of the entire human genome sequence on compact disc (CD) is but one example of the many useful database tools that are likely to emerge.

6.  WHAT LESSONS SHOULD BE LEARNT FROM GENETIC DATABASE INITIATIVES IN OTHER COUNTRIES?

  Historically, there has been a tendency for the UK to be competent in the field of scientific innovation, yet weak at developing and applying those findings. In contrast the United States is much more enterprising, largely as a result of the vast amounts of venture capital that the American economic system makes available to innovators. It is extremely likely that the ADLIB Project will indirectly give rise to patentable or otherwise commercially exploitable results. Identification of areas of the human genome linked to premature coronary artery disease (focus of The BHF Family Heart Study) is already the subject of great commercial interest within the pharmaceutical industry who are funding two similar investigations (Glaxo Wellcome & Astra Zeneca). Subsequent linkage and also association studies are expected to advance understanding of the pathological basis of acute coronary events and hence also its diagnosis and treatment. As outlined by us in a recent review (Hall AS & Durham NP. Genes and the heart: Quest for new therapeutic strategies. Molecular Medicine Today 1995; 5: 195-197) a very large amount of money is being invested by pharmaceutical and biotechnical companies to commercially exploit this field. As a counter-balance, the charitable and public funding of the ADLIB Project has helped to secure media coverage and also enthusiastic patient support; furthermore, scientific openness and co-operation are also practised and ensured.

Professor Alistair S Hall
Professor Nilesh J Samani
Professor of Clinical Cardiology
Professor of Cardiology
Integrated Molecular Cardiology Group
British Heart Foundation Heart Research Centre
Leeds General Infirmary
Dr Anthony J Balmforth
Professor Stephen G Ball
BHF Senior Lecturer
Professor of Cardiology

4 October 2000