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This section, which will be updated regularly will
report on current research in the area of adult onset
genetic diseases. New information comes out almost daily
but we will focus on those issues that are likely to
be of more immediate importance.
One other function of this section is the introduction
of new terminology necessary to understand and evaluate
the new technology. So let us begin by providing definitions
for two new, but very important terms.
A polymorphism is a relatively common (generally more
than 1% of the population) variation in the sequence
of DNA. There are millions of polymorphisms in the human
genome. The vast majority of these sequence variations
are of no clinical significance but there are probably
thousands that do effect gene functions. The most common
current use of polymorphic variations is in the area
of forensics and paternity testing.
The most ubiquitous type of polymorphism is a single
nucleotide polymorphism (SNP, pronounced ‘snip’.)
These are changes in a single base pair of DNA and are
the type of variant most likely to be of medical importance.
Perhaps the best known example of a SNP in medicine
is Factor V Leiden, a single base pair change that results
in increased risk for thrombosis and is present in 7%
of the US population. Since the SNP is heritable, once
the SNP has been identified in a patient, there may
also be value in screening at risk family members.
Just to add a little confusion to the terminology,
it is now common that any SNP which results in a clinical
effect to be called a mutation. By strict definition
a mutation is a rare event, but information is coming
out faster than new words, so a bad SNP is called a
mutant.
In the current literature:
| 1. |
March 10, 2005 -- Two papers recently
appeared in the journal Science which found a polymorphism
linked to Age-related Macular Degeneration.
Complement
Factor H Variant Increases the Risk of Age-Related
Macular Degeneration
Haines, J. L.; Hauser, M. A.; Schmidt, S.;
Scott, W. K.; Olson, L. M.; Gallins, P.; Spencer,
K. L.; Kwan, S. Y.; Noureddine, M.; Gilbert, J.
R.; Schnetz-Boutaud, N.; Agarwal, A.; Postel,
E. A.; Pericak-Vance, M. A.
Complement
Factor H Polymorphism in Age-Related Macular Degeneration
Klein, R. J.; Zeiss, C.; Chew, E. Y.; Tsai, J.-Y.;
Sackler, R. S.; Haynes, C.; Henning, A. K.; SanGiovanni,
J. P.; Mane, S. M.; Mayne, S. T.; Bracken, M.
B.; Ferris, F. L.; Ott, J.; Barnstable, C.; Hoh,
J.
Age-related Macular Degeneration (ARMD) is a
common adult onset disorder. These two reports
identified a polymorphism on a gene on chromosome
1 which may account for 50% of the risk for the
disease and 43% of all cases. A change of tyrosine
to histidine at amino acid 402 in the gene CFH
is the cause of the problem. That region of the
gene is known to bind heparin and C-reactive protein.
What it all means:
This result not only identifies a major risk
group but confirms earlier evidence of the role
of this gene in macular degeneration. Since there
are no preventive therapies available at this
time, screening is of no value. However, the result
provides a major target for therapeutic intervention.
Once we understand what changes in the function
of the CFH gene is caused by this variant, drug
and other therapies to prevent the disorder will
be investigated.
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| 2. |
A report in Neuron, Jan. 6, 2005
Loss-of-Function
Mutation in Tryptophan Hydroxylase-2 Identified
in Unipolar Major Depression
Xiaodong Zhang, Raul R. Gainetdinov
, Jean-Martin Beaulieu , Tatyana D. Sotnikova ,Lauranell
H. Burch, Redford B. Williams, David A. Schwartz,
K. Ranga R. Krishnan, and Marc G. Caron
This report identifies a SNP in
a gene coding for tryptophan hydroxylase-2, an enzyme
of neuronal serotonin synthesis, which appears more
frequently in persons with unipolar depression than
controls. About 10% of patients had the mutation,
while only about 1.4% of the control population
had the SNP. The authors conclude that this loss
of function mutation may be a major risk factor
in unipolar depression.
What
it all means:
This work is an example of the step
wise process that is required to bring new genetic
information into clinical practice. What is now
required are additional studies to determine if
population screening of people would result in a
decrease in incidence by pre-event intervention.
Likewise it will be important to determine if patients
with this particular polymorphism respond to drug
or other treatment options differently from patients
without the SNP.
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| 3. |
An article and commentary of the role of Homocysteine
and Stroke appeared in the January 15, 2005 edition
of the Lancet.
Homocysteine
and Stroke: Evidence on a Causal Link From Mendelian
Randomisation
Juan P Casas MD, Leonelo E Bautista
DrPH, Liam Smeeth MRCGP, Pankaj Sharma PhD, and
Aroon D Hingorani FRCP)
This is a composite analysis of
111 studies on the possible relationship of increased
homocysteine (an amino acid in the blood) levels
and increased risk of stroke. The results are that
“The observed increase in risk of stroke among
individuals homozygous for the MTHFR T allele is
close to that predicted from the differences in
homocysteine concentration conferred by this variant.
This concordance is consistent with a causal relation
between homocysteine concentration and stroke.”
What it all means:
As indicated, the authors evaluated
a common recessive SNP in the gene MTHFR. This gene
is known to be involved in folate and homocysteine
metabolism. The SNP in this case results in lower
efficiency of the enzyme and has been linked to
increased risk of cardiovascular disease and birth
defects. The frequency of affected persons in the
population varies by ethnicity. In Caucasians it
is about 13%. Linking the MTHFR variant to diseases
related to homocysteine levels has been difficult
because homocyteine level is dependent not only
on genetics but also nutrition.
This study focused on the genetics because unlike
nutrition is does not vary by food intake. While
the results demonstrate an increased risk for stroke
in persons with the MTHFR variant, what to do with
this information is not yet clear. For example,
there is no evidence that identifying all persons
with the MTHFR variant and recommending dietary
changes or supplementation (e.g. increases in folic
acid and vitamins B6 and B12) would result in a
cost effective reduction in stroke in the population.
However, people are increasingly being tested at
younger ages for MTHFR polymorphisms because of
pregnancy related problems and when identified,
such individuals could be counseled about their
increased risks related to other diseases and recommend
dietary habits to ameliorate the risk. |
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