Letter from the British Heart Foundation
I have pleasure in enclosing the response from
the British Heart Foundation which incorporates views and information
Professor Stephen Ball and Professor Alistair
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
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
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 highthousands
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
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