|
 Karen
A. Fagan, MD
Associate Professor of Medicine
Pulmonary Hypertension Center
University of Colorado Health Sciences Center
Denver, Colorado
The recent Venice Classification of pulmonary hypertension1 includes diseases that are definitely or possibly genetic and
associated with the development of pulmonary hypertension.
These include “other” or “miscellaneous” diseases,
including
Gaucher disease, hemoglobinopathies, myeloproliferative
disorders, thyroid disorders, sarcoidosis, Langerhans
cell histiocytosis (histiocytosis X), and lymphangioleiomyomatosis.
Other genetic diseases associated with the development
of pulmonary arterial hypertension include hereditary
hemorrhagic telangiectasia and are addressed in another
article in this issue. There are also the potential genetic
contributions to our interactions with the environment such
as high altitude and chronic hypoxemic lung diseases such
as COPD and alveolar hypoventilation that may also predispose
certain individuals to the development of pulmonary
hypertension in these settings. The purpose of this review is
to consider some of the potential genetic contributions that
may underlay the development of pulmonary hypertension in
association with other disorders. While some of these diseases
can be defined by a single gene mutation, more frequently,
associations between certain genes and susceptibility
to pulmonary hypertension have been reported.
Hemoglobinopathies
The spectrum of known hemoglobinopathies associated with
pulmonary hypertension is wide and may suggest a role of
chronic hemolysis and/or splenectomy in the pathogenesis
of pulmonary arterial hypertension. Indeed, many patients
with inherited hemoglobin or red cell disorders are surgically
or functionally asplenic, which may be a risk factor for the
development of pulmonary arterial hypertension.2 Thalassemia
The thalassemias are a group of inherited disorders in hemoglobin
characterized by hemolysis of varying severity. Alphathal
is due to deletion of one of the alpha alleles of hemoglobin
resulting in decreased alpha-chain synthesis. Alphathal
is most common in persons from Asia and in the most
severe form (missing all but one allele) the disease is called
hemoglobin H (the hemoglobin formed when excess beta
chains form tetramers). Beta-thalassemias are caused by
point mutations and most frequently affect persons of
Mediterranean descent. The genetic defect results in
decreased transcription of the gene or premature chain termination.
The net result is a decrease in beta-chain hemoglobin
and increase in other hemoglobin forms including A
and F. Additionally, the excess beta-chains precipitate in the
red cell membrane leading to intramedullary and intravascular
hemolysis.
Beta-thal is the most severe form of thalassemia but with
a variable clinical course likely representing the severity of
the underlying gene defect. Cardiomyopathy from iron overload
as a result of repeated transfusions is the most common
cardiopulmonary complication seen in patients with betathal.
However, isolated pulmonary hypertension, not due to
left ventricular dysfunction, is increasingly recognized in
patients with beta-thal. While the numbers of patients who
develop pulmonary hypertension is not clear, incidences
ranging from 10% to 66% have been reported.3,4 Factors
associated with the development of pulmonary arterial
hypertension in these patients include a history of splenectomy,
thrombocytosis, severity of anemia, elevated nucleated
red blood cells, hepatic cirrhosis, and iron overload.
Some investigators have also reported an association with
pulmonary thromboembolism.5-9 How these patients with thalassemia and pulmonary
hypertension should be managed is not clear, as there have
been no clinical trials performed in this patient population.
General care includes maintaining near normal hematocrits,
antiplatelet therapy (ie, aspirin), and consideration of anticoagulation.
Sickle cell anemia
Sickle cell anemia is the most common inherited hemoglobinopathy
worldwide, affecting millions of individuals primarily
of African descent. In the United States, the incidence
is estimated at 1 in 400 to 600 African Americans.
The molecular abnormality, a single amino acid substitution
in the hemoglobin gene that is inherited in an autosomal
recessive manner, results in the clinical syndrome of sickle
crisis with microvascular occlusion and marked episodic
intravascular hemolysis.
 Figure. Kaplan-Meier
survival of patients
with sickle cell anemia with and without
pulmonary hypertension. The upper line is
the survival estimate for sickle cell anemia
patients without pulmonary hypertension,
that is, with normal MPAP. The lower line is
the survival estimate for sickle cell anemia
patients with pulmonary hypertension, that
is, with MPAP more than 25 mm Hg. The
x-axis measures months of follow-up after
cardiac catheterization. From: Castro O,
Hoque M, Brown BD. Pulmonary hypertension
in sickle cell disease: cardiac catheterization
results and survival. Blood. 2003;101:
1257-1261. Copyright American Society of
Hematology, used with permission.
|
There is considerable variation in the clinical course
between affected individuals. Chronic complications include
avascular necrosis of long bones, iron overload states,
thrombosis, chronic infections, cardiomyopathy, hepatic cirrhosis,
and pulmonary hypertension.
Factors associated with the development
of pulmonary hypertension in
patients with sickle cell anemia include
older age, hypertension, ongoing
intravascular hemolysis, and lower fetal
hemoglobin concentrations.10,11 The
incidence of pulmonary hypertension is
estimated between 20% and 40% of
patients with sickle cell anemia and is
associated with a higher likelihood of
death (50% at 2 years, Figure).10-12 There is considerable
debate as to whether pulmonary hypertension in sickle
cell anemia is a primary pulmonary
vascular process or a secondary process
related to a number of complications of
sickle cell anemia, including direct
endothelial injury due to sickle cells,
recurrent acute chest syndrome, chronic
pulmonary infections, high-output states
due to anemia thrombosis and, more
recently described, decreased nitric
oxide bioavailability due to scavenging
by hemoglobin and superoxide.13 Therefore,
whether the development of pulmonary
hypertension is a surrogate marker
for advanced heart and lung disease
resulting from the sequelae of sickle cell anemia or whether
pulmonary hypertension per se is a risk factor for increased
mortality is uncertain. It is evident that at least a significant
percentage of patients included in studies of sickle cell anemia-
associated pulmonary hypertension have evidence of
elevated postcapillary pressure indicating that the pulmonary
hypertension in these patients is a secondary, reactive
process. Half of the patients with pulmonary hypertension in
one study demonstrated an elevated pulmonary wedge pressure
(PWP) as high as 28 mm Hg, whereas none of 14 patients
without pulmonary hypertension had a PWP of >15.12 Pathologically, lung vessels demonstrate medial and intimal
hypertrophy/hyperplasia, fibroelastic degradation of
small arteries, arterioles, and venules, and thrombosis with
recanalization. One autopsy study of 20 patients with sickle
cell anemia reported that 60% of patients had evidence of
plexiform lesions, a change characteristic of advanced pulmonary
arterial hypertension, in lung sections.14 While the
pathogenesis of sickle cell anemia-associated pulmonary
hypertension remains uncertain, and is likely multifactorial
in most patients, greater numbers of patients and more
detailed investigation are needed to accurately determine
the role of pulmonary vascular disease in sickle cell anemia.
Treatment of patients with sickle cell anemia-associated
pulmonary hypertension is also not clear. Supportive treatment
is currently the mainstay of therapy for patients with
sickle cell anemia, which includes folate supplementation,
hydration, oxygen, transfusions, and measures aimed at
increasing fetal hemoglobin levels (such as hydroxyurea).
One report suggested that enhancing nitric oxide production
with arginine supplementation may be helpful.15 Other red cell defects
Pulmonary arterial hypertension has also
been associated with other, more rare
defects in red cells. A common factor in
these diseases is hemolytic anemia, as it
is in the thalassemias and sickle cell
anemia, and frequency of splenectomy,
either surgical or due to splenic infarcts.
Hereditary spherocytosis is due to an
autosomal dominant defect in the red
cell membrane protein spectrin that
leads to a change in cell configuration
from a bi-concave disc to a rounded
phenotype. This in turn leads to poor distensability
of the red cell and hemolysis
primarily within the spleen. The disease
presents with variable severity and has
been associated with pulmonary arterial
hypertension in a few individuals in
whom other causes of pulmonary arterial
hypertension have been excluded.16 Paroxysmal nocturnal hemoglobinuria
is an acquired stem cell disorder.
There is a genetic mutation leading to
the inability of a group of cell surface
proteins, complement-regulating surface
proteins, to bind to cell membranes. The
corresponding gene PIGA (phosphatidylinositol
glycan class A) is on the X chromosome, and several
mutations, from deletions to point mutations, have been
reported. These changes increase the susceptibility of red
cells to intravascular lysis by complement components. The
disorder is manifest by episodic episodes of hemolysis, usually
occurring at night, and can lead to severe anemia or
pancytopenia. The syndrome is also associated with thrombosis,
especially of the mesenteric and hepatic veins. The
development of pulmonary arterial hypertension has been
reported in association with paroxysmal nocturnal hemoglobinuria. 17 Chronic Hypoxia
Hypoxia-induced pulmonary hypertension occurs in a wide
variety of pulmonary diseases ranging from airways diseases,
parenchymal lung diseases, high altitude exposure, and ventilatory
control problems. While some of these diseases may
have clearly defined genetic links (ie, alpha-1-antitrypsin
caused emphysema), others may involve genes important in
modifying the host response to chronic hypoxia (angiotensin
converting enzyme and endothelial nitric oxide synthase
gene polymorphisms, long-term population residence at high
altitude, etc).
High-altitude exposure
Hints that moving to higher altitude may cause pulmonary
hypertension come from both animal and population studies.
In both situations, differences in genetic backgrounds
and in physiologic adaptation to hypoxia are discernable. In
the early 20th century, two Colorado veterinarians, George
Glover and Isaac Newsom, reported the development of “brisket
disease” in cattle grazing on high Colorado
plateaus. Brisket disease is edema of the dependent brisket
and is associated with severe pulmonary hypertension and
enlargement of the right ventricle. They noted that this disease
was more common in cattle brought to the region for
grazing than in the offspring of disease-free animals residing
at high altitude.18 In studies completed 50 years later using
breeding of susceptible and resistant cattle, a genetic predisposition
to the development of brisket disease was identified.
19-21 What this gene or genes are remains unknown.
The physiologic mechanism for this susceptibility to high
altitude-induced pulmonary hypertension is, in part, related
to an exaggerated acute hypoxic pulmonary pressor
response. Interestingly, other mammals with a history of
high altitude cultivation, including the llama and yak, which
are resistant to the development of high altitude-induced
pulmonary hypertension, have markedly blunted acute
hypoxic pulmonary pressor responses.22,23 Increasingly, humans are extending their range
of altitudes to include higher elevations for long-term residence.
The development of pulmonary hypertension related to
hypoxia varies considerably among distinct human populations
living at high altitudes and may be related in part to
the number of generations of high altitude living. Residents
of Tibet, with the longest history of high altitude living, have
a blunted hypoxic pulmonary pressor response compared to
Andean Indians, who, in turn, have a blunted response compared
to relative high altitude newcomers in the Rocky
Mountains. Other physiologic differences more pronounced
in Tibetans include blunted hypoxic ventilatory responses,
higher lung diffusing capacities, higher hemoglobin concentrations,
and slightly larger lungs, all suggesting long-term
genetic adaptation to the environment. However, the nature
of these genetic adaptations is largely unknown. Several
hypotheses such as alterations in oxygen-sensing molecules,
ion channel expression, redox states, and degree of muscularization
of pulmonary vessels have been proposed.22,23 While the above discussion pertains to chronic exposure
of populations at high-altitude, the acute adaptation to high
altitude may also have a genetic component. Acute maladaptation
to high altitude includes a spectrum of disease
ranging from the relatively mild acute mountain sickness to
more severe and life-threatening high altitude pulmonary
edema (HAPE) and high altitude cerebral edema (HACE).
Several gene polymorphisms have been purported to be
associated with the development of HAPE, including polymorphisms
in the rennin-angiotensin system, endothelial
nitric oxide synthase, and the major histocompatibility complex.
Polymorphisms in the angiotensin converting enzyme
have been associated with the development of chronic
hypoxic pulmonary hypertension with the I/I genotype overrepresented24,25 while other studies have failed to find a role
of these polymorphisms in HAPE.26,27 Polymorphisms in
endothelial nitric oxide synthase and major histocompatibility
complexes HLA-DR6 and -DQ4 are overrepresented in
persons who develop HAPE.28,29 Interestingly, the HLA-DR6
polymorphisms are also associated with hypoxic pulmonary
hypertension.29 While these associations are interesting,
unfortunately they only begin to hint at the possible mechanisms
for genetic susceptibility to hypoxia-induced pulmonary
vascular disease.
How chronic exposure to higher altitude should be taken
in the context of a diagnosis of pulmonary hypertension
must be determined on a case-by-case basis. Many pulmonary
hypertension specialists recommend that patients
living at higher altitudes consider relocating to remove this
as a confounding factor.
Hypoxia due to lung disease
Chronic hypoxia is a consequence of many different lung
diseases and is thought to underlie the development of pulmonary
hypertension in some of these patients. However,
not all patients with hypoxemic lung disease develop pulmonary
hypertension. Pulmonary hypertension in association
with diseases such as chronic obstructive pulmonary disease
(COPD) is therefore likely associated with other modifying
conditions, which might be genetic in nature. The development
of pulmonary hypertension in association with COPD
can be clinically variable and carries a poor prognosis.
Several genetic modifiers have been proposed to contribute
to the development of pulmonary hypertension in some
patients with COPD.
Involvement of the serotonin transporter has been implicated
in the development of pulmonary hypertension in
patients with COPD (see article by Eddahibi and Adnot in
this issue).30 The BB genotype of a polymorphism in intron
2 of the endothelial nitric oxide synthase gene has also been
associated with more severe pulmonary hypertension in COPD
patients compared to the AA or AB genotypes.31
Polymorphisms in the angiotensin converting enzyme
gene have also been implicated in some studies of COPD-associated
pulmonary hypertension. However, as opposed to
chronic hypoxia-induced pulmonary hypertension, where the
II genotype is overrepresented, the DD genotype appears to
correlate with more severe COPD-associated pulmonary
hypertension.32 Patients with the DD genotype demonstrated
more exercise impairment and higher pulmonary arterial
pressures and were less likely to improve with treatment with
angiotensin converting enzyme inhibitors or with oxygen.33-36 While these observations may suggest potential mechanisms
for the apparent variable course of patients with similar
impairment of lung function, to date clinical treatment
decisions based on these genotypes are not available. At present,
for COPD-associated pulmonary hypertension, cessation of
smoking, treatment of airway obstruction, and supplemental
oxygen remain the mainstays of therapy for all patients.
Hypoxia due to disorders of ventilation
Impaired ventilatory control can lead to alveolar hypoxemia
and pulmonary hypertension. The most common situation in
which this occurs is in nocturnal hypoventilation associated
with sleep apnea. However, hypoventilation syndromes can
also occur during waking hours and may be associated with
pulmonary hypertension.
Sleep apnea is common and is frequently found in families.
While this may be associated with the presence of obesity,
which also occurs more frequently in families, there
may be a genetic predisposition to sleep apnea. Recently,
a
Advances in Pulmonary Hypertension 27
whole genome scan identified a susceptibility
loci in a region
on chromosome 8q that was associated with increased
apnea-hypopnea indexes in an African American
family
cohort.37 Others have also identified polymorphisms
in the
haptoglobin gene and found that patients with
the 2-2 genotype
had a 2.3-fold risk of cardiovascular complications
of
sleep apnea compared to patients with the 2-1
genotype.38 Thus, genetic modifiers may play a role not
only in the development
of sleep apnea, but also in the complications
of
sleep apnea. To date, potential associations
with, or modifiers
of, the development of pulmonary hypertension
in association
with sleep apnea have not been identified.
Congenital central hypoventilation syndrome,
also known
as Ondine’s curse, is associated with mutations in
the PHOX2B gene family. Mutations in this gene lead
to
impaired noradrenergic neuronal development.39 This
results in significant central hypoventilation
as well as other
abnormalities of autonomic nervous innervation,
in particular,
Hirschsprung disease of the intestine. The syndrome
is
frequently associated with significant cor pulmonale
likely
due to severe alveolar hypoxemia.
Metabolic Diseases
The presence of pulmonary arterial hypertension
in association
with rare genetic metabolic diseases suggests
the possibility
that the mechanisms for the development of
pulmonary arterial
hypertension may include other previously
unknown metabolic
pathways or alternative effects of known genetic
mutations.
Gaucher disease
Gaucher disease is a lysosomal storage disease
due to inherited
deficiency of glucocerbrosidase enzyme activity
leading
to accumulation of lipid-laden cells (Gaucher
cells) in multiple
organs including the central nervous system,
spleen,
liver, lymph, and lung. It is an autosomal
recessive disease
with variable clinical expression thought
in part to be due to
genetic heterogeneity of the mutations with
the L444P
mutation most commonly associated with pulmonary
complications40 and non-N370S mutations associated with
the
development of pulmonary arterial hypertension.41
Pulmonary arterial hypertension in Gaucher
disease may be
related to direct pulmonary vascular involvement
with
Gaucher cells42 as well as chronic hepatic
dysfunction and
portal hypertension. Splenectomy is also
associated with
pulmonary arterial hypertension in these
patients.41,43
Interestingly, the presence of the ACE I
allele is associated
with pulmonary arterial hypertension in
these patients as
well.41 Enzyme replacement therapy has been
reported to
decrease rates of disease and has been associated
with
regression of pulmonary arterial hypertension.41
Other Metabolic Diseases
Type Ia glycogen storage disease has been
reported in association
with pulmonary arterial hypertension.44 It is an autosomal
recessive disorder leading to deficiency
of the glucose-6-phosphatase enzyme. It
is associated with dyslipidemias
and hepatic steatosis, hepatic adenomas,
and
increased rates of vascular thrombosis.
While the occurrence
of pulmonary arterial hypertension in
these patients is rare,
it may be related to the presence of hepatic
dysfunction,
portosystemic shunts, and in a recent
report, markedly
increased levels of plasma serotonin.44 Unfortunately, in the
patients with type-1a glycogen storage
disease and pulmonary
arterial hypertension, rapid progression
of right heart
with failure and death has been observed.
Serotonin may also play a role in the
report of pulmonary
arterial hypertension in a patient with
familial platelet storage
pool disease. This disease is an autosomal
dominant,
rare disease characterized by normal platelet
counts but
impaired platelet aggregation and decreased
numbers of dense
granules. This leads to decreased platelet,
but
increased plasma, serotonin levels among
other defects. In
a single patient with pulmonary arterial
hypertension and
familial platelet storage pool disease,
treatments with a
serotonin receptor antagonist, ketanserin,
improved his pulmonary
vascular resistance.45 Summary
The genetic contributions that may hint
at the pathogenesis
of pulmonary hypertension are expanding
at a rapid pace.
While in some instances, such as familial
pulmonary arterial
hypertension or in HHT-related pulmonary
arterial hypertension,
a specific gene has been identified,
we are also
beginning to recognize the important
contributions that
other modifier genes may have in susceptible
individuals (ie,
angiotensin converting enzyme, endothelial
nitric oxide synthase,
etc). We are also beginning to expand
our hypotheses
regarding the pathogenesis of pulmonary
hypertension by
considering the metabolic and physiologic
derangements
that characterize other genetic disorders
that are associated
with its development (ie, hemoglobin
disorders, metabolic
disease). Pharmacogenomic studies, wherein
a patient is
characterized both clinically and genetically
in order to identify
the treatment most likely to be of benefit
to that particular
individual, are increasingly being conducted.
Unfortunately, we are still a long way
from this type of directed
therapy; however, each new genetic and
clinical association
brings us closer to this goal. References
1. Simonneau G, Galie N, Rubin LJ,
Langleben D, Seeger W,
Domenighetti G, Gibbs S, Lebrec D, Speich R, Beghetti M, Rich S,
Fishman A. Clinical classification of pulmonary hypertension. J Am Coll
Cardiol. 2004;43:5S-12S.
2. Hoeper MM, Niedermeyer J, Hoffmeyer F, Flemming P, Fabel
H.
Pulmonary hypertension after splenectomy? Ann Intern Med.
1999;130:506-509.
3. Derchi G, Fonti A, Forni GL, Galliera EO, Cappellini MD, Turati
F,
Policlinico OM. Pulmonary hypertension in patients with thalassemia
major. Am Heart J. 1999;38:384.
4.Du ZD, Roguin N, Milgram E, Saab K, Koren A. Pulmonary hypertension
in patients with thalassemia major. Am Heart J.
1997;134:532-537.
5. Aessopos A, Farmakis D, Karagiorga M, Voskaridou E, Loutradi
A,
Hatziliami A, Joussef J, Rombos J, Loukopoulos D. Cardiac involvement
in thalassemia intermedia: a multicenter study. Blood.
2001;97:3411-3416.
6. Atichartakarn V, Likittanasombat K, Chuncharunee S, Chanda
namattha P, Worapongpaiboon S, Angchaisuksiri P, Aryurachai K.
Pulmonary arterial hypertension in previously splenectomized patients
with beta-thalassemic disorders. Int J Hematol. 2003;78:139-145.
7. Hahalis G, Manolis AS, Apostolopoulos D, Alexopoulos D,
Vagenakis
AG, Zoumbos NC. Right ventricular cardiomyopathy in beta-thalassaemia
major. Eur Heart J. 2002;23:147-156.
8.Taher A, Abou-Mourad Y, Abchee A, Zalouaa P, Shamseddine
A.
Pulmonary thromboembolism in beta-thalassemia intermedia: are we
aware of this complication? Hemoglobin. 2002;26:107-112.
9. Wu KH, Chang JS, Su BH, Peng CT. Tricuspid regurgitation
in
patients with beta-thalassemia major. Ann Hematol. 2004;83:779-783.
10. Ataga KI, Sood N, De Gent G, Kelly E, Henderson AG, Jones
S,
Strayhorn D, Lail A, Lieff S, Orringer EP. Pulmonary hypertension in
sickle cell disease. Am J Med. 2004;117:665-669.
11. Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF,
Minter
K, Brown B, Coles WA, Nichols JS, Ernst I, Hunter LA, Blackwelder
WC, Schechter AN, Rodgers GP, Castro O, Ognibene FP. Pulmonary
hypertension as a risk factor for death in patients with sickle cell disease.
N Engl J Med. 2004;350:886-895.
12. Castro O, Hoque M, Brown BD. Pulmonary hypertension
in sickle
cell disease: cardiac catheterization results and survival. Blood.
2003;101:1257-1261.
13. Aslan M, Freeman BA. Oxidant-mediated impairment of nitric
oxide signaling in sickle cell disease—mechanisms and consequences.
Cell Mol Biol (Noisy-le-grand). 2004;50: 95-105.
14. Haque AK, Gokhale S, Rampy BA, Adegboyega P, Duarte A,
Saldana MJ. Pulmonary hypertension in sickle cell hemoglobinopathy:
a clinicopathologic study of 20 cases. Hum Pathol. 2002;33:1037-1043.
15. Morris CR, Morris SM, Jr., Hagar W, Van Warmerdam J, Claster
S,
Kepka-Lenhart D, Machado L, Kuypers FA, Vichinsky EP. Arginine therapy:
a new treatment for pulmonary hypertension in sickle cell disease?
Am J Respir Crit Care Med. 2003;168:63-69.
16. Hayag-Barin JE, Smith RE, Tucker FC Jr. Hereditary spherocytosis,
thrombocytosis, and chronic pulmonary emboli: a case report and
review of the literature. Am J Hematol. 1998;57:82-84.
17. Heller PG, Grinberg AR, Lencioni M, Molina MM, Roncoroni
AJ.
Pulmonary hypertension in paroxysmal nocturnal hemoglobinuria.
Chest. 1992;102:642-643.
18. Glover GH, Newsome IE. Brisket disease (dropsy of high altitudes).
Colorado Agriculture Experimental Station Bulletin No. 204, 1915.
19. Weir EK, Tucker A, Reeves JT, Will DH, Grover RF. The genetic
factor
influencing pulmonary hypertension in cattle at high altitude.
Cardiovasc Res. 1974;8:745-749.
20. Will DH, Hicks JL, Card CS, Alexander AF. Inherited susceptibility
of cattle to high-altitude pulmonary hypertension. J Appl Physiol.
1975;38:491-494.
21. Will DH, Hicks JL, Card CS, Reeves JT, Alexander AF. Correlation
of acute with chronic hypoxic pulmonary hypertension in cattle. J Appl
Physiol 1975;38:495-498.
22. Fagan KA, Weil JV. Potential genetic contributions to control
of the
pulmonary circulation and ventilation at high altitude. High Alt Med
Biol. 2001;2:165-171.
23. Ward MP, Milledge JS, West JB. High Altitude Medicine and
Physiology. London: Arnold; 2000.
24. Aldashev AA, Sarybaev AS, Sydykov AS, Kalmyrzaev BB, Kim
EV,
Mamanova LB, Maripov R, Kojonazarov BK, Mirrakhimov MM, Wilkins
MR, Morrell NW. Characterization of high-altitude pulmonary hypertension
in the Kyrgyz: association with angiotensin-converting enzyme
genotype. Am J Respir Crit Care Med. 2002;166:1396-1402.
25. Morrell NW, Sarybaev AS, Alikhan A, Mirrakhimov MM, Aldashev
AA. ACE genotype and risk of high altitude pulmonary hypertension in
Kyrghyz highlanders. Lancet. 1999;353:814.
26. Dehnert C, Weymann J, Montgomery HE, Woods D, Maggiorini
M,
Scherrer U, Gibbs JS, Bartsch P. No association between high-altitude
tolerance and the ACE I/D gene polymorphism. Med Sci Sports Exerc.
2002;34:1928-1933.
27. Hotta J, Hanaoka M, Droma Y, Katsuyama Y, Ota M, Kobayashi
T.
Polymorphisms of renin-angiotensin system genes with high-altitude
pulmonary edema in Japanese subjects. Chest. 2004;126:825-830.
28. Droma Y, Hanaoka M, Ota M, Katsuyama Y, Koizumi T, Fujimoto
K,
Kobayashi T, Kubo K. Positive association of the endothelial nitric
oxide synthase gene polymorphisms with high-altitude pulmonary
edema. Circulation. 2002;106:826-830.
29. Hanaoka M, Kubo K, Yamazaki Y, Miyahara T, Matsuzawa Y,
Kobayashi T, Sekiguchi M, Ota M, Watanabe H. Association of highaltitude
pulmonary edema with the major histocompatibility complex.
Circulation. 1998;97:1124-1128.
30. Eddahibi S, Chaouat A, Morrell N, Fadel E, Fuhrman C, Bugnet
AS,
Dartevelle P, Housset B, Hamon M, Weitzenblum E, Adnot S.
Polymorphism of the serotonin transporter gene and pulmonary hypertension
in chronic obstructive pulmonary disease. Circulation.
2003;108:1839-1844.
31. Yildiz P, Oflaz H, Cine N, Erginel-Unaltuna N, Erzengin
F, Yilmaz
V. Gene polymorphisms of endothelial nitric oxide synthase enzyme
associated with pulmonary hypertension in patients with COPD. Respir
Med. 2003;97:1282-1288.
32. van Suylen RJ, Wouters EF, Pennings HJ, Cheriex EC, van
Pol PE,
Ambergen AW, Vermelis AM, Daemen MJ. The DD genotype of the
angiotensin converting enzyme gene is negatively associated with right
ventricular hypertrophy in male patients with chronic obstructive pulmonary
disease. Am J Respir Crit Care Med. 1999;159:1791-1795.
33. Kanazawa H, Hirata K, Yoshikawa J. Effects of captopril
administration
on pulmonary haemodynamics and tissue oxygenation during
exercise in ACE gene subtypes in patients with COPD: a preliminary
study. Thorax. 2003;58:629-631.
34. Kanazawa H, Hirata K, Yoshikawa J. Influence of oxygen administration
on pulmonary haemodynamics and tissue oxygenation during
exercise in COPD patients with different ACE genotypes. Clin Physiol
Funct Imaging. 2003;23:332-336.
35. Kanazawa H, Okamoto T, Hirata K, Yoshikawa J. Deletion polymorphisms
in the angiotensin converting enzyme gene are associated with
pulmonary hypertension evoked by exercise challenge in patients with
chronic obstructive pulmonary disease. Am J Respir Crit Care Med.
2000;162:1235-1238.
36. Kanazawa H, Otsuka T, Hirata K, Yoshikawa J. Association
between
the angiotensin-converting enzyme gene polymorphisms and tissue
oxygenation during exercise in patients with COPD. Chest.
2002;121:697-701.
37. Palmer LJ, Buxbaum SG, Larkin EK, Patel SR, Elston RC, Tishler
PV, Redline S. Whole genome scan for obstructive sleep apnea and
obesity in African-American families. Am J Respir Crit Care Med.
2004;169:1314-1321.
38. Lavie L, Lotan R, Hochberg I, Herer P, Lavie P, Levy AP.
Haptoglobin polymorphism is a risk factor for cardiovascular disease in
patients with obstructive sleep apnea syndrome. Sleep. 2003;26:592-595.
39. Amiel J, Laudier B, Attie-Bitach T, Trang H, de Pontual
L, Gener
B, Trochet D, Etchevers H, Ray P, Simonneau M, Vekemans M,
Munnich A, Gaultier C, Lyonnet S. Polyalanine expansion and
frameshift mutations of the paired-like homeobox gene PHOX2B in
congenital central hypoventilation syndrome. Nat Genet.
2003;33:459-461.
40. Santamaria F, Parenti G, Guidi G, Filocamo M, Strisciuglio
P, Grillo
G, Farina V, Sarnelli P, Rizzolo MG, Rotondo A, Andria G. Pulmonary
manifestations of Gaucher disease: an increased risk for L444P
homozygotes? Am J Respir Crit Care Med. 1998;57:985-989
41. Mistry PK, Sirrs S, Chan A, Pritzker MR, Duffy TP, Grace
ME,
Meeker DP, Goldman ME. Pulmonary hypertension in type 1 Gaucher’s
disease: genetic and epigenetic determinants of phenotype and
response to therapy. Mol Genet Metab. 2002;77:91-98.
42. Ross DJ, Spira S, Buchbinder NA. Gaucher cells in pulmonary-capillary
blood in association with pulmonary hypertension. N Engl J Med.
1997;336:379-381.
43. Elstein D, Klutstein MW, Lahad A, Abrahamov A, Hadas-Halpern
I,
Zimran A. Echocardiographic assessment of pulmonary hypertension in
Gaucher’s disease. Lancet. 1998;351:544-1546.
44 Humbert M, Labrune P, Sitbon O, Le Gall C, Callebert J, Herve
P,
Samuel D, Machado R, Trembath R, Drouet L, Launay JM, Simonneau
G. Pulmonary arterial hypertension and type-I glycogen-storage disease:
the serotonin hypothesis. Eur Respir J. 2002;20:59-65.
45. Herve P, Drouet L, Dosquet C, Launay JM, Rain B, Simonneau
G,
Caen J, Duroux P. Primary pulmonary hypertension in a patient with a
familial platelet storage pool disease: role of serotonin. Am J Med.
1990;89:117-120.
|
