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What molecular
genetics has to offer those suffering from alcoholism
Alcohol abuse and dependence
is a neglected cause of morbidity and mortality. For example
in the United Kingdom some twenty eight per cent of adult
males and eleven percent of adult females drink more than
the recommended safe limits. In addition some 5-10 percent
of males and 3-5 percent of females are estimated to become
alcohol dependent during their lifetime. Furthermore alcohol
is thought to contribute to approximately 50,000 deaths per
year, for example through driving while intoxicated. These
rates are reflected throughout most of Europe where there
has been an increase in the medical and surgical complications
associated with alcohol.
Understanding the social,
genetic and developmental factors that contribute to alcohol
dependence will permit a better comprehension of the reasons
why some individuals within society are unable to control
their drinking. Such information will permit the development
of effective management and prevention policies.
The impact of finding genes
implicated in alcohol dependence can be used as an example
of how molecular genetic research will shape future health
policies for common and complex disorders.
Plutarch commented that 'drunks
beget drunkards' and this long held view that alcoholism runs
in families has been confirmed by family studies. While this
is a necessary prerequisite for a genetic disorder this does
not prove a genetic aetiology. Further evidence has been obtained
from twin and adoption studies. Identical twins have 100%
of their genes in common with their co-twins whereas non-identical
twins share on average 50%.
If alcohol dependence is genetic,
it would be expected that if one twin were affected then there
would be a greater number of co-twins affected in identical
pairs compared with non-identical pairs. Most twin studies
have demonstrated an increase in these concordance rates in
identical twins thus supporting a genetic contribution to
alcohol dependence. Furthermore, adoption studies have demonstrated
that adopted away sons with biological parents who are alcohol
dependent have an increased risk of developing this disorder.
In one such study the risk was increased fourfold, roughly
equal to that of being raised by the alcoholic parent. In
addition excessive drinking in the environment into which
these individuals were adopted did not increase the risk of
alcohol dependence.
The recent advances in molecular genetics have increased our
knowledge of the hereditary material, DNA, to such a level
that it is now possible to look for the genes that provide
this genetic contribution to alcoholism. Throughout the world
the concerted effort by scientists affiliated to the Human
Genome Project is rapidly determining the sequence of the
23 volumes of hereditary information, the chromosomes, that
comprise the human genome. Subsequently the 'typographical'
errors that constitute genetic variation and mutation will
be identified and as a consequence the multiple small genetic
contributions to common and complex diseases elucidated. These
findings will have a profound impact on our lives and particularly
those of subsequent generations that further propagate our
genes.
Perhaps one of the clearest
demonstrations that a single gene can profoundly affect drinking
behaviour is afforded by the protection conferred by a genetic
difference in one of the genes that metabolises alcohol in
the liver. Following absorption, alcohol is metabolised to
acetaldehyde by a group of enzymes called the alcohol dehydrogenases
(ADH). The toxic product, acetaldehyde is then metabolised
by aldehyde dehydrogenase 2 (ALDH2). Should the activity of
ALDH2 be inhibited, this metabolite accumulates and the individual
experiences flushing, palpitations and nausea following ingestion
of a small quantity of alcohol. This mechanism can be exploited
clinically and disulfiram (antabuse) acts pharmacologically
by blocking this enzyme (ALDH2). However some 40% of Orientals
carry an inactive variant of the enzyme which causes these
aversive symptoms following the ingestion of alcohol. As a
result carrying the gene for this inactive enzyme strongly
protects the individual against alcohol dependence.
When the DNA for these two
forms of enzyme were compared they differed by a single base
(the smallest building block of DNA). Thus this single genetic
difference greatly reduces the risk that an individual will
develop alcoholism and alcohol related conditions including
cirrhosis. This particular genetic variant is extremely rare
in western Europeans demonstrating that distinct genetic mechanisms
may be important in different populations.
There are many clinical implications
of finding genes that predispose to alcohol dependence and
other such complex behaviours. Firstly understanding the genetic
factors that contribute to alcohol dependence will enable
a better understanding of the other important developmental
and environmental factors that contribute to this condition.
Thus in the future it is mandatory that researchers from many
diverse disciplines collaborate to explore the 'hyphen' in
the nature-nurture interaction.
Secondly, it will permit a
better understanding of the biological mechanisms involved
in the development of the disorder. For example molecular
genetic studies have suggested that the dopamine receptor
2 (DRD2) gene is important in alcohol dependence. Dopamine,
one of the brain chemical messengers, is thought to participate
in an important reward mechanism. Most of the drugs abused
by man, including alcohol and nicotine, have been demonstrated
to activate this system. It is envisaged that these drugs
usurp this mechanism producing an immediate and intense reward
that is not coupled to the usual environmental stimuli.
Differences, caused by genetic
variation, may result in an under functioning of this reward
system which could thereby predispose such an individual to
drugs that increase activity. This hotly debated finding suggests
a dependence mechanism that may be common to all drugs of
abuse and possibly other behaviours such as gambling. As genes
implicated in the aetiology of alcohol dependence are identified,
the diverse mechanisms that increase vulnerability to this
disorder will be elucidated and understood.
Thirdly, understanding the
biological mechanisms implicated in alcohol dependence would
enable the development of better informed, targeted treatment
strategies and policies. Following the reports that reduced
dopamine activity may predispose towards alcohol dependence
it has been suggested that increasing this function may improve
outcome in the treatment of alcohol dependence. That this
may be the case has been reported following a trial of bromocriptine,
a drug that increases dopamine function, in alcoholics. Furthermore
the benefit attributed to bromocriptine was only demonstrated
in those with the predisposing DRD2 genetic variant. Thus
novel treatments can be developed which may be applicable
to subgroups of patients identified by a genetic test.
Finally, identifying the genes
that contribute to complex and common diseases will permit
the development of genetic tests that could be used to identify
individuals prior to the onset of symptoms. In complex conditions
such tests would merely alter an individual's predicted risk.
Using results from several tests, combined with environmental
and developmental factors, an individual's predicted risk
of developing alcohol dependence could be dramatically raised
or lowered.
Previous experience has been
gained in risk alteration in Huntington's disease, a genetic
disorder caused by a mutation in a single gene. In this disease
before the actual gene mutation was identified, risks were
increased or reduced on the basis of genetic testing. Prolonged
counselling was essential if the individual was to understand
the nature and significance of their alteration in risk and
on occasions this was dramatically misinterpreted. Clearly
such risk refinement in common diseases will require expert
and comprehensive genetic counselling with important resource
implications.
Using such a test it would
also be possible to screen populations, to identify individuals
at increased risk, who could be targeted for early intervention
and prevention. While this could reduce morbidity and mortality,
such information would also be of interest to those in personnel
departments and insurance companies. In the future it may
be necessary to provide a genetic curriculum vitae, in the
form of a blood sample, prior to obtaining life assurance,
a mortgage, job or promotion. When considering these ethical
issues it is important to remember the important lessons of
the past. For example genetic conditions, including specifically
severe alcoholism, were included in a compulsory sterilisation
law introduced in Germany in 1933 and similar laws were introduced
in many other countries during this period of applied eugenics.
Furthermore, it is pertinent for each individual to consider
that we are all carrying on average two pieces of deadly DNA,
which are not expressed because they are balanced by another
copy.
In summary, the interaction
of genes environment and development predispose certain individuals
to alcohol dependence. Finding the genetic contributions will
profoundly alter the way we understand this condition and
will permit the introduction of improved management policies.
New treatments will be developed and targeted to subgroups
identified by genetic tests. In addition, it will be possible
to provide genetic tests that alter an individual's predicted
risk which could be used for counselling, screening and prevention
programmes. Particular benefits in the future will therefore
result from the collaboration between researchers from many
diverse disciplines seeking to explore the spectrum of factors
in the nature-nurture continuum. In looking forward to this
exciting future the important moral and ethical lessons of
the past should be heeded and the implications considered
and widely debated.
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