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 John
H. Newman, MD
Elsa S. Hanigan Professor of Pulmonary Medicine
Vanderbilt University School of Medicine
Nashville, Tennessee
Support: VA TVHS GRECC, NHLBI PPG 072058
Research into the genetic basis of pulmonary arterial
hypertension is going forward with increasing intensity. It appears
that
mutations in bone morphogenetic protein receptor type II
(BMPR2) and activin receptor-like kinase-1 (ALK1) genes will
be the most common genetic risk factors for the development
of pulmonary arterial hypertension. However, there are more
than 10 other genes encoding transforming growth factor-beta
receptors, and a systematic search needs to undertaken to
determine if mutations in these other receptors are associated
with pulmonary arterial hypertension. It is possible that other
major genes causing pulmonary arterial hypertension exist, but
the evidence to date in familial disease is that BMPR2 causes
at least 75% of cases, and ALK1 somewhere fewer than 5% of
cases.
It is unclear whether any other specific genetic predisposition
is necessary for the development of pulmonary arterial
hypertension. Because pulmonary arterial hypertension can
occur in response to multiple stimuli, such as appetite suppressants
or liver disease, there may be many kinds of genetic
predisposition, depending on the stimulus. In each form of pulmonary
arterial hypertension associated with another disorder
or risk factor, the percentage of patients who develop pulmonary
arterial hypertension is quite small, less than 1% to
10%, so that other susceptibilities almost certainly play a role
in the development of disease.
 Primary
pulmonary hypertension can be induced in susceptible individuals
by a number of conditions or stimuli, shown in circumference
around the cartoon of the lungs. These conditions elicit a response
which is modulated by genetic susceptibility, in the form of functional
polymorphisms of an unknown number of genes. Listed are some
genes with functional polymorphisms known to influence vascular
function, including NOS (nitric oxide synthases), SERT (serotonin
transporter), VIP (vasoactive intestinal peptide), AII (angiotensin
II),
CPS (carbomyl phosphate synthetase), E-receptors (endothelin).
The
state of knowledge with regard to modifying genes is in its infancy.
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One of the mysteries of familial pulmonary arterial hypertension
has recently been solved by Cogan et al.1 We have
known for the past 4 years that most family mutations are in the
area of chromosome 2 where BMPR2 resides, but have been
unable to find mutations in the approximately 50% of families.
By studying messenger RNA in lymphocytes from patients with
familial pulmonary arterial hypertension, mutations in the noncoding
intronic regions that lead to errors in splicing and duplication
of messenger RNA, and ultimately to altered protein synthesis,
have been discovered. This finding has led to the identification
of additional mutations in familial pulmonary arterial
hypertension and clears up much of the mystery but also seriously
complicates the process of genetic testing.
Another major uncertainty that has not been settled is
how many patients with apparently idiopathic pulmonary arterial
hypertension have BMPR2 mutations, and whether these mutations
are inherited or are spontaneous and new. The implications
are large. The presence of a BMPR2 or ALK1 mutation
changes the disease from sporadic to heritable and increases
the risk of other family members having the mutation and
developing disease. A large-scale study is needed to better
define and quantitate the prevalence of BMPR2 mutations in
the population of patients with apparently idiopathic pulmonary
arterial hypertension. Work by several groups is probing the
extent of BMPR2 mutations in a variety of pulmonary and cardiovascular
diseases. BMPR2 mutations have now been identified
in association with congenital heart anomalies, underscoring
the developmental importance of the gene. See Dr. Morse’s
article in this issue for more details.
Beyond looking for major genes of lesser and lesser frequency
in pulmonary arterial hypertension, the thrust over the
next several years will be to identify genes that modify expression
of disease and outcome. These genes include those known
to encode products important in pulmonary arterial hypertension,
such as serotonin receptors and the serotonin transporter,
endothelin receptors, prostacyclin, inflammatory mediators,
potassium channels, immune genes, and others to be identified.
Additional genes that determine cardiac function and
response to stress need evaluation, and genes involved in vasoconstriction
and vasodilation need elucidation. This kind of
genetic work will enhance our understanding of the different
ways patients respond to vascular changes of pulmonary arterial
hypertension and to treatment. Ultimately, this should allow
for more targeted therapies. Coupling genomic studies with proteomics
will allow more rapid advancement in the field.
Genetic testing will become a more important part of pulmonary
arterial hypertension evaluation when the technology of
scanning the very large BMPR2 gene is improved. Currently,
only half of presumptive BMPR2 mutations can be identified by
standard exonic analysis, because a large minority of cases
have intronic mutations that are revealed as abnormalities only
in receptor protein product. Newer RNA-based techniques are
improving this yield so that we can now probably identify 75%
of inherited cases. Still, this leaves an unsettling percentage of
inherited risk that cannot currently be identified, a problem of
sensitivity of the test. Over the next several years, genetic testing
will likely have a sensitivity closer to 90% for determining
BMPR2 mutations in familial pulmonary arterial hypertension.
Genetic counseling remains absolutely essential to help
sporadic and familial patients understand the limitations and
implications of testing. This is a complex problem because of
the low penetrance of disease in patients with known mutations,
and because of the lack of sensitivity of testing in
patients without an already known family mutation. We have
found that most persons who have expressed extreme interest
in testing have not taken advantage of it now that it is available,
a finding similar to that of many other serious inherited diseases.
Nonetheless, genetic testing should be made available
when possible after counseling with an expert and after a period
of reflection and consideration by the applicant. All persons need counseling; only some will choose testing.
As to the future, there should be a sense of optimism.
The real payoff from all this work will be when sufficient understanding
of the aberrant actions of the mutated BMPR2 points
to either preventive treatments or specific therapies to reverse
pulmonary arterial hypertension and restore health. Ongoing
work by many talented investigators almost assures this ultimate
outcome.
Reference
1.Cogan JD, Vnencak-Jones CL, Pratap
S, et al. Gross BMPR2 gene
rearrangements constitute a new cause for primary pulmonary hypertension.
Genet Med. 2005. In press.
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