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Cardiovascular genetics
Report of a workshop organised by the Public Health Genetics Unit on 10 May 2001
1. Introduction
Recent advances in genetics have had a profound effect on our understanding of the role of
genetic factors in susceptibility to disease. A greater appreciation of the complexities of
genetic variation, of genetic heterogeneity, of penetrance, and of the importance of geneenvironment interactions, have all been influential in helping to delineate the role of genetic
testing in clinical practice. In considering how genetics can contribute to health care, it is
important to distinguish between rare disorders caused by highly penetrant mutations in
single genes, and susceptibility to common diseases resulting from interactions between
weakly penetrant common gene variants and environmental and lifestyle factors.
It is in the field of cancer that the integration of genetics into mainstream services is most
advanced: the NHS has accepted the need for specialist expertise in cancer genetics and is
grappling with issues such as referral criteria, care pathways and the optimum configuration
of services. By contrast, developments in the field of cardiovascular genetics have not yet
impinged to the same extent on clinical practice.
The time is ripe to initiate a critical assessment of the place of genetics in the prevention and
management of cardiovascular disease, and the implications for NHS organisation and
services. With this aim in mind, a one-day workshop was organised, bringing together key
individuals in the fields of cardiovascular medicine, genetics, primary care, public health,
health service management and health policy. There were three main objectives for the day:
1. To identify aspects of cardiovascular genetics that might be ready for service intervention
2. To establish priorities for future work
3. To identify issues that NHS policy makers will need to take into account in preparing
implementation plans for cardiovascular genetic services.
2. Single-gene cardiovascular disorders
At present, the contributory genetic factors are best understood for a number of relatively rare
cardiovascular diseases caused by highly penetrant mutations in single genes. These fall into
three main classes: dyslipidaemias, cardiomyopathies and cardiac arrhythmias.
Familial hypercholesterolaemia
The most common inherited dyslipidaemia is familial hypercholesterolaemia (FH), an
autosomal dominant disorder usually caused by mutations in the gene encoding the low
density lipoprotein (LDL) receptor, though 2-4% of cases can be attributed to a mutation in
the apoB-100 gene. As explained by Andrew Neil, the disease is characterised by high blood
cholesterol levels at an early age and an elevated risk of myocardial infarction such that by
the age of 55 years 50% of men will have developed cardiovascular disease. While women
have a similar degree of cholesterol elevation, they are protected from the development of
atherosclerosis till after the menopause and may remain free of cardiovascular disease until
their sixth decade. The age of onset of disease is more similar within than between families,
suggesting an important effect of other modifying genes and of environmental factors such as
diet. Treatment with HMG CoA reductase inhibitors (statins) is an effective form of therapy
in heterozygotes, causing regression of atherosclerosis and reducing mortality. Homozygotes
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for LDL receptor mutations are severely affected and may die in their second decade of life
without aggressive treatment such as lipid apheresis.
The frequency of heterozygotes in the population has been calculated to be about 1 in 500, so
that in the UK there are an estimated 110,000 carriers. Of these only a few thousand appear
to have been identified to date, and of those who are diagnosed, most are not identified until
middle age when disease will already be fairly advanced. It has therefore been suggested that
an active programme of population screening and/or case-finding within families is
warranted. A pilot study in the UK and a large ongoing study in The Netherlands have shown
the effectiveness of such an approach. However, there are still some issues that need to be
addressed before implementation of such a strategy, including the best method of diagnosis
and the role of DNA testing.
The internationally recognised diagnostic criteria for FH combine plasma lipid levels, clinical
features and family history, but since there is overlap between the cholesterol levels seen in
non-FH subjects in the general population and in those with clinically (or genetically) defined
FH, the identification of FH patients by this means is not unequivocal. Thus the use of DNAbased mutation testing should be an aid to FH diagnosis. Helen Middleton-Price reported
that, based on experience from her DNA diagnostic laboratory in London, currently a
mutation can be detected in only 30-50% of individuals who fulfil the diagnostic criteria. Of
the remainder, a small percentage may have LDL receptor mutations that are not detectable
for technical reasons and some may have a mutation in another as yet unidentified single
gene causing FH, but it is likely that in many the hypercholesterolaemia may not be due to a
mutation in any one gene (that is, the patient does not have classical FH). To date over 700
different LDL receptor mutations have been reported world wide with at least 50 found in the
UK, and none being found in more than 2-3% of patients except in certain geographically
defined areas. Both mutation-positive and mutation-negative patients benefit from statin
treatment, with drug dosage being increased to obtain target lipid lowering levels.
The Health Technology Assessment programme has published a report on the cost
effectiveness (cost per life year gained as a result of statin treatment) of various screening
strategies for FH. Dalya Marks explained that each strategy was analysed for both a "clinical
only" and a "clinical plus DNA" diagnostic method, over a range of age bands, and separately
in males and females. The conclusions from the study were that universal or opportunistic
screening of adults aged 16-55 would not be cost effective, but that both cascade screening
within affected families, using either clinical or genotypic diagnosis, and screening of all 16
year olds using clinical criteria, would be cost-effective, as would cascade screening in the
families of patients with early myocardial infarction.
An important factor when contemplating the introduction of any type of screening
programme is its psychological impact, and some consider that this is particularly important
in relation to genetic screening. Vicky Senior presented preliminary "vignette" evidence that
people may be more likely to be negative and fatalistic if they are given a genetic diagnosis
of disease than if the diagnosis is clinical. A randomised trial of the psychosocial impact of
genetic versus non-genetic diagnosis of FH is underway to examine this possibility. More
research is needed on how to present genetic risk information in such a way as to minimise
alarm while motivating risk-reducing behaviour.
Cardiomyopathies
The inherited cardiomyopathies, discussed by Bill McKenna, are all autosomal dominant
heart muscle disorders that confer an increased risk of sudden death. The most prevalent,
hypertrophic cardiomyopathy (HCM), is estimated to affect about 120,000 people in the UK,
most of whom are undiagnosed. Reliable prevalence figures for familial dilated
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cardiomyopathy and right ventricular cardiomyopathy are lacking, but each is thought to
affect 5-50% as many people as HCM.
Risk factors for HCM include a family history of sudden premature death, abnormal blood
pressure on exercise, unexplained syncope, left ventricular hypertrophy and heart rhythm
defects. Individuals with at least three of these factors have a risk of sudden death of
approximately 6% per year. Effective treatments are available for the high-risk cohort but
clinical judgements have to be made on a case by case basis for those at medium risk. To
date, a variety of mutations in eight functionally related genes have been found in HCM, all
in genes coding for structural components of cardiac muscle. In some cases, knowledge of
the specific DNA mutation in a family can be important to identify family members who are
at high risk, as clinical symptoms may be mild and variable until the sudden occurrence of a
heart attack. This is particularly true of disease caused by mutations in the troponin T gene,
which confer a high risk of sudden death during adolescence. DNA diagnosis may also be
useful for myosin binding protein C-associated disease, which has a much later onset but
once expressed is also associated with very high risk. In contrast, for disease caused by
mutations in the beta-myosin heavy chain gene, clinical features provide all the information
that is needed for management, and there is little added value in DNA testing.
Cardiac arrhythmias
Heart rhythm defects are very common, with about 4-6% of people showing atrial fibrillation
by the age of 65. However, in rare cases (prevalence approximately 1/5,000 to 1/10,000),
arrhythmias arise early in life and are associated with mutations in single genes encoding
membrane ion channels. The best characterised of the inherited arrhythmias is the long QT
syndrome. In this condition, arrhythmias are often coincident with exercise or excitement and
confer a high risk of sudden death during childhood or adolescence. Currently, causative
mutations have been identified in five different loci; many of these mutations appear to be
unique to individual families. Importantly, those who carry a mutation may be at risk of
sudden death even if they do not show the long QT phenotype. Andrew Grace stressed the
importance of identifying family members who are at risk, so that they can be given
information on how to reduce their risk, for example by avoiding triggers such as strenuous
exercise and certain classes of drugs. In order to achieve this, he suggested, more research is
needed to clarify the range of mutations in the UK and the risks associated with them, with
the aim eventually of establishing a national mutation-detection service. Affected families
also need a defined management programme that involves both cardiac specialists and
geneticists. Molecular-genetic information gleaned from studying the inherited arrhythmias
may also help to shed light on the disease process in the more common multifactorial disease.
Multifactorial cardiovascular disease
In most people, susceptibility to cardiovascular disease is associated with common, weakly
penetrant genetic variants interacting with environmental factors. What role does genetic
assessment have to play here? Steve Humphries pointed out that individual variants that
increase or decrease risk by, say, 50%, are unlikely to be clinically relevant, but if subgroups
of people can be identified in which the risk is more than doubled by a particular variant, then
genotype information may be clinically useful.
Specific environmental or lifestyle factors may interact with genetic factors in such a way as
to have a significant effect on risk. As an example, Steve Humphries presented evidence from
a prospective study of over 3,000 healthy men in the UK, where the effect on risk associated
with apoE genotype had been examined. In non-smokers, there was no association between
apoE genotype and risk of coronary heart disease. Smoking conferred a relative risk of about
1.7 in people with the common E3 allele, but in carriers of the E4 allele the relative risk
associated with smoking was more than 3. In the future, a quantitative understanding of
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interactions between specific genetic variants and environmental factors may be useful in
drawing up individual risk profiles, perhaps in the context of a "risk clinic" (see below), so
that individually tailored advice can be given on risk reduction. In order for such a service to
be beneficial, we need to know more about the best way of presenting risk information, and
its psychological impact on those receiving it.
Epidemiological data on the contributions of phenotypic and genotypic risk factors, and the
interactions between them, are essential for reliable risk assessment. As Melissa Austin
showed, studies on familial forms of dyslipidaemia can contribute useful information to the
analysis by demonstrating increased risk of death from cardiovascular disease among
relatives in such families. A genetic epidemiological study on 85 kindreds affected by two
different forms of familial hypertriglyceridaemia was carried out to estimate the additive
contribution of shared genetic factors and shared non-genetic (environmental) factors to the
blood lipid "triad" of indicators: LDL particle size, triglyceride levels, and plasma HDL
cholesterol levels. The results suggested that both genetic and environmental factors make a
substantial contribution to the observed variance in these characteristics. Moreover, the well
known correlations within the lipid triad (for example, high risk individuals tend to have
small LDL particles, elevated triglyceride and low plasma HDL cholesterol) are probably
attributable to the effects of common underlying gene(s). Similarly, environmental factors
affect all three blood lipid characteristics in a coordinated way.
Like high blood cholesterol, hypertension has long been recognised as a risk factor for
cardiovascular disease, and family studies suggest an important contributory role for genetic
factors in determining blood pressure. As Anna Dominiczak explained, many candidate
genes have been suggested to play a role, including genes for components of the reninangiotensin system and genes encoding various membrane proteins. Whole genome scans
have identified some chromosomal segments that may harbour genes associated with blood
pressure or hypertension, while comparative mapping studies in animal models are helping to
delineate genomic regions that should be investigated in more detail. Unfortunately, none of
the associations identified so far have proved robust enough to be clinically useful, but the
hope is that eventually there will be a place for genetic profiling in the clinical management
of hypertension. The benefits would be several: development of new treatments based on a
better understanding of the molecular pathology of the condition, early identification of those
at risk, with the possibility of preventive treatment, and the development of more effective
drug therapies targeted at those with specific genotypes. It is already known, for example,
that the TT genotype for the G protein beta3-subunit predicts a better response to treatment
with a thiazide diuretic, an example of how pharmacogenetics may be useful in the future.
Patrick Vallance described a service that may be a paradigm for the cardiovascular disease
risk assessment clinic of the future. Based on observational data from the Framingham Heart
Study, computer software has been developed that uses factors such as an individual's weight,
blood lipids, blood sugar, blood pressure and smoking status to calculate his or her 10-year
risk of heart attack or stroke, compared to the age- and sex-matched population average.
Importantly, the programme can also be used to highlight the patient's modifiable risk, so that
they can see the effect of interventions such as lowering their blood cholesterol or stopping
smoking, and can participate in decisions about management of their disease. So far, no
genotypic information is used in the clinic because its predictive value is not clear, but a
future service could be envisaged in which genotypic, phenotypic and lifestyle information
all contribute to the risk assessment.
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3. Workshops
Three groups discussed different aspects of the development and implementation of
cardiovascular genetics in the health service.
Group 1
 Which aspects of cardiovascular genetics are ready, or could soon be ready, for
implementation as a service intervention?
The group thought that the most immediate priority was to establish effective diagnosis
and management programmes for individuals affected by single-gene forms of
cardiovascular disease. It was essential that clinicians in all relevant specialties should be
alert to the possibility of Mendelian disease in patients with characteristic clinical
features, to ensure prompt diagnosis (which could include DNA testing) and appropriate
care. The establishment of such a service would involve developing an effective
relationship between GPs, cardiac specialists and geneticists. Initial recognition could be
by either the GP or the cardiac specialist, both of whom would need guidelines to help
them identify at-risk individuals. Cardiac specialists would manage patient care, and
would refer to genetic specialists (laboratory and clinical) for genetic testing and
counselling of family members.
 What should the priorities be for further work in developing service interventions?
Further work is needed across a wide range of areas, for example:
- Health-economic analysis of service models, such as those proposed for the singlegene cardiovascular disorders, will be needed in setting service priorities
- Consideration of the role of DNA testing: for each disease, does testing affect
diagnosis and/or treatment, and does it make a difference to the patient? The group
thought that DNA tests for cardiovascular diseases that are proposed as candidates for
service introduction should be assessed by the same criteria as tests for other diseases.
Tests should only be carried out by accredited molecular-genetic laboratories and
should be subject to proper quality assurance.
- Research on other single-gene disorders with cardiac or hypertension involvement,
including Marfan syndrome, primary pulmonary hypertension, adult polycystic kidney
disease, and other familial hyperlipidaemias.
- Research on risk assessment and communication including psychosocial aspects
- Research involving the setting up and evaluation of pilot programmes
 What are the criteria for implementing genetic testing in the context of multifactorial
disease?
In the group's opinion, there are currently no individual gene variants implicated in
susceptibility to cardiovascular disease or hypertension that are sufficiently robust to be
useful in a clinical context. If/when useful genetic variants are identified, they should not
be considered separately from other risk factors but as part of an overall risk assessment
strategy.
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Group 2
Assuming familial hypercholesterolaemia is one of the priorities for developing genetic
services:
 Have we got all the data we need, and if not, what is missing?
The group considered that adequate data are available for disease incidence and
prevalence in populations of European origin, performance of clinical and DNA-based
tests, optimal care pathways, and costs associated with testing, screening and treatment.
However, in order to prepare a business case for a service that would satisfy criteria of
access and equity, we need to know more about the incidence, prevalence and mutation
spectrum in different ethnic groups. An estimate of the population attributable risk is also
needed.
 What issues would policy makers have to take into account in preparing implementation
plans?
Should a decision be made to implement the recommendations of the HTA report
(screening of all 16-year-olds and patients with early myocardial infarction by blood
cholesterol measurement, and cascade screening within affected families), the group
identified the following policy and service issues:
- What importance should be placed on mutation testing in affected families, and at what
age should it be offered? DNA testing in the proband does not affect clinical
management, but if a mutation is found then it can be used to clarify risk status in other
family members, some of whom may have borderline cholesterol. If they have not
inherited the mutation they may be spared unnecessary intervention. The group
endorsed the view that treatment decisions should be based on overall risk, not simply
on cholesterol measurements.
- Guidelines (and perhaps also decision support tools) should be developed to enable
GPs to perform a gatekeeping function for referral to a lipid clinic. The group
suggested a service model in which referral would be on the basis of family history,
patient care would be managed by the lipid clinic, and genetic testing, family tracing
and counselling would managed from the genetics centres. Implementation of such a
model would require development and maintenance of information systems and family
registers, with consequent funding implications.
- The designation and funding of DNA testing centres would need to be considered. The
group suggested designation of 2-3 centres nationally, in order to provide back up of
service and to facilitate exchange of samples for quality control (these considerations
apply equally to testing for other single-gene heart diseases such as HCM and the long
QT syndrome).
- Research into genotype-phenotype relationships is needed: R&D policy makers should
consider whether to back this.
- The group suggested that experience with FH could serve as a useful paradigm for
service development for other single-gene, adult-onset, treatable diseases.
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Group 3
If sudden death syndromes, hypertrophic cardiomyopathies and cardiac arrhythmias were
amongst the priorities for developing services:
 Have we got all the information we need, and if not, what is missing?
The group agreed that there were substantial knowledge gaps concerning the inherited
cardiac arrhythmias. Although knowledge about effective management of patients is
adequate, more information is needed on which genes and mutations are associated with
the long QT syndrome in the UK. There should be a national long QT syndrome register
recording details of mutations and phenotypes; such a register is also important for longterm follow-up of patients and at-risk family members. Economic modelling is needed to
assess the likely effectiveness of a cascade screening programme in affected families.
Knowledge about HCM is more complete but we do not have enough information about
the size of the problem in the UK (that is, the true number of cases); modelling studies are
also needed to determine what could be achieved through various types of intervention.
 What issues would policy makers have to take into account in preparing implementation
plans?
The group felt that integrated NHS services should be developed for both the
cardiomyopathies and the cardiac arrhythmias. In order to achieve this:
- More communication and joint work is needed between cardiologists and geneticists.
Cardiologists need to learn how to communicate with families about genetic risk and
how to implement extended family screening, which at present is very ad hoc.
- Guidelines should be developed to aid the assessment of cardiac risk in affected
individuals and family members. Draft guidelines already exist for HCM but they need
further development and wider implementation. No guidelines are currently available
for long QT syndrome.
- Laboratory services for DNA testing need development as the group felt that current
capacity for testing for these disorders was inadequate and not well organised.
Decisions need to be made on which DNA tests should be offered and by how many
labs.
- Practical proposals for service models are needed. Professionals from a wide range of
disciplines - cardiologists, paediatric cardiologists, clinical and laboratory geneticists
and public health specialists - should be involved in preparing the business case.
4. The way forward
Three main recommendations emerged from the workshop:
1. The introduction of coordinated services for the diagnosis and clinical management of
some single-gene forms of cardiovascular disease should be given priority consideration.
Genetic screening programmes for such diseases (whether in the general population or in
asymptomatic relatives of affected individuals) raise additional and complex issues, which
must be addressed before service implementation. We will need sound epidemiological
information, as well as analysis of the economic implications of different service models,
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the cost:benefit ratio, the optimal service configuration, psychosocial issues surrounding
testing, and the implications for manpower and training.
2. Genetic knowledge in the field of multifactorial cardiovascular disease is not sufficiently
well-defined for application in clinical services in the short term. However, it is essential
to plan for the future, when genetic factors are likely to be integrated into individuallytailored risk assessment and decisions about the most effective treatment. The
implications of genetics for cardiovascular services should always be considered as policy
develops in future years.
3. This workshop should be followed up by a meeting of cardiac specialists, genetic
specialists and GPs to consider the practical options for taking its recommendations
forward.
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