I have pleasure in enclosing the response from the British Heart Foundation which incorporates views and information supplied by:

Professor Stephen Ball and Professor Alistair Hall (Leeds).
Professor Morris Brown (Cambridge).
Professor Anna Dominiczak (Glasgow).
Professor Steve Humphries (UCL, London); and
Professor Nilesh Samani (Leicester).

  I anticipate that you will already have been made aware of a useful package entitled Demystifying genomics produced by the MRC, BBSRC, NERC, EPSRC and DTI.

Professor Sir Charles George BSc MD FRCP
Medical Director

28 September 2000

1.  What current projects involve collecting genetic information on people in the UK? What other projects are about to start? Are there collections of material (eg tissue samples) that could be used to generate databases of DNA profiles?

  My colleagues and I are aware of the following projects:

  ADLIB (Acute Coronary Event DNA Library) which has a number of key parts that have evolved together to provide a large national resource of DNA and data. They include the British Heart Foundation Family Heart Study, the object of which is to create a genome-wide map in each of two siblings affected by coronary heart disease up to the age of 65 years. By using linkage analysis, Professors Ball and Hall (and others) are seeking to identify chromosomal locations that contain genes that influence the occurrence of the disease. Two thousand five hundred paired DNA samples are being collected and analysed. Related to this study are GRACE Studies One and Two designed to evaluate candidate genes that have been implicated in the aetiology of coronary artery disease. More recently, strategic funding has been awarded by the Medical Research Council, which will permit augmentation of the project. To date, DNA has been extracted and stored in all cases and from December 2000, an additional sample of white blood cells will be stored to permit later extraction of additional DNA.

  Other studies involving BHF Professors include: genetics of pre-eclampsia collaborative study (GOPEG) and the United Kingdom Collaborative Study to identify the major genes responsible for human hypertension (BRIGHT study)—funded by the MRC. In addition, the British Repository of DNA in Stroke (BRAINS) collaboration is being considered for funding by the MRC and the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) has been funded by Pfizer. The WOSCOPS study involves 4,500 middle-aged men of whom 550 have had cardiovascular events during follow up and each of them has been matched with two people who did not have an event. Genetic analysis is focusing on these 1,750 individuals. Finally, I am aware of three other studies, but do not have much detail of them. They are the NPHS II involving 3,000 healthy men, based at the Wolfson Institute, St Bartholomew's and the Royal London Schools of Medicine and Dentistry, the Whitehall Study involving 10,000 healthy civil servants (UCL) and a fetal growth study of 1,500 babies and their parents (UCL).

2.  Why are these genetic databases being assembled?

  The academic community is assembling the databases in order to understand the causation of common diseases. Previous decades of research in, for instance, diabetes, asthma and hypertension have often found it difficult to distinguish those abnormalities which might cause the disease from those which are a consequence. With rare exceptions, any difference in DNA sequence that can be firmly associated with a disease will provide a priori evidence that the protein encoded by the DNA plays a role in the disease. So far, the main result from genetic research in the common diseases has been the realisation that the causes are much more complex than previously realised. This means that the number of disease subjects whose DNA needs to be sampled is very high—thousands rather than hundreds. The effort needed to assemble such DNA collections is considerable, usually requiring collaboration amongst several institutions and this effort becomes in turn hard to justify unless the "phenotypic" information collected about each subject is detailed. Some of the studies mentioned under question 1 will allow any major genetic effects on morbidity/mortality in particular conditions to be identified or whether any beneficial (or adverse) effects of drug therapy occur mainly in subjects with particular genetic profiles. Altogether, the data could have a significant impact on the way we classify, prevent and manage common disorders with treatment packages being tailored for individual patients. The commercial use of databases is clearly concerned with finding new targets for drug development.

How are these activities funded?

  ADLIB is funded primarily by the BHF and secondarily by the Medical Research Council and the National Health Service R&D Programme. The BRIGHT study is funded by the MRC and Wellcome Trust. The WOSCOPS Study was initially funded by Bristol Myers Squibb but DNA analysis for a selection of polymorphisms is being funded by the BHF. The pharmaceutical industry is funding a large DNA bank within the ASCOT Study and we are aware also of industry funding to the PROCARDIS Study.

What practical considerations will constrain developments?

  To date these have been mainly financial. However, increasingly the data protection laws are making it difficult to identify people who might be invited to participate in the studies listed under section 1. Furthermore, it is difficult to obtain permission to study multiple genes on data sets (particularly those which are already banked). The new DNA technology will allow whole-genome analysis rather than an investigation of a single gene polymorphism. Future research would be facilitated by obtaining agreement to do the former at the time of initial application to ethics committees.

Are there alternative ways of fulfilling the objectives?

  There is debate about the relative merits of linkage versus association approaches to try and identify genetic factors, but in either case genetic information is essential to fulfil the objectives set out in section 2a.

3.  What is the genetic information that is being collected?

  The genetic information that is being collected is primarily DNA which is isolated from blood samples. It is stored in freezers in locked rooms in university departments. In addition, information is collected on the phenotypic details of patients ie diagnosis, age, gender etc. Data are usually anonymised in a way that will permit the relationship with other family members to be stored.

How is it being stored and protected?

  Most genetic databases are computerised. The individuals are identified by some type of numeric code, the DNA samples are similarly coded, genotypic information is then entered for each subject, as any project is completed. In this way analysis is completely anonymous and usually done for groups of people who share a common genotype rather than individuals.

4.  How do the organisations involved see their responsibilities regarding privacy; consent; future use; public accountability; and intellectual property rights?

  The aim of the British Heart Foundation is to play a leading role in the fight against heart disease so that it is no longer a major cause of disability and premature death by funding medical research into the causes, prevention, diagnosis and treatment of heart disease.

  Research funding takes the form of either project or programme grants, requests are submitted to the Research Funds Department of the Medical Division and appropriate referees selected. The latter are asked to comment on the originality, scientific reliability, feasibility and relevance of these research proposals. In addition they are received by committee members.

  Where the work involves human subjects/patients, the protocol must also have been reviewed and approved by an appropriate ethics committee(s). Funding is conditional on the latter. In addition, patients can only be recruited into a study if they have given their informed consent. Consent forms are carefully scrutinised by ethics committees.

  Public accountability takes various forms. The researchers are accountable not only to their employing institutions (which increasingly are undertaking some form of policing of standards) but also to the patients they are recruiting. Sponsors such as the British Heart Foundation issue notes of guidance to researchers and further protection of the public interest comes from periodic reports to the Executive Committee and Council (both of which contain lay members). Finally, both the Foundation and its Medical Division produce annual reports which are in the public domain.

  Intellectual property rights remain a major cause of tension. In principle benefits are shared between the investigators, their employing institutions and the sponsors of research. In recent months BHF has been in dialogue with several other members of the Association of Medical Research Charities and is hoping to achieve a consensus on the division of income deriving from intellectual property.

5.  How do they see their activities in the area of genetic databases developing in the future? What advances in sequencing, screening and database technology are they anticipating?

  It is anticipated that micro array or other technology will permit recognition and comparison of up to 500,000 single nucleotide polymorphisms. Their use will be as markers to the existence of the functional variants that are responsible for the inherited components in disease susceptibility. Molecular biological techniques and bioinformatics programmes will continue to develop at a rapid rate. Already capillary-based gel systems and robotic platforms have greatly increased the speed at which sequencing and genotyping can be achieved. Parallel progression of statistical approaches to data analysis will be needed, and many new software packages developed. It is likely that the entire human genome sequence will be available on compact discs.

6.  What lessons should be learnt from genetic database initiatives in other countries?

  The most controversial international development in this area has been the Icelandic Healthcare Database (deCODE) programme. Arguments for and against this research have been rehearsed in the pages of the New England Journal of Medicine 2000. 342: 1827-1833. To date there have been no major research discoveries in complex oligogenic disorders using this database and another in Estonia. By contrast, smaller hypothesis-led well-funded consortia in the United States have made major progress in cardiovascular genetics (as well as some other complex common disorders). Traditionally, the UK has been a leader in the field of scientific innovation, but weak at developing and applying those findings. By contrast the USA is more enterprising and vast amounts of venture capital are available within the economic system, which are made available to innovators.