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Blood, Vol. 92 No. 9 (November 1), 1998:
pp. 3455-3459
Apolipoprotein E  4 Allele as a Genetic Risk Factor for Left
Ventricular Failure in Homozygous  -Thalassemia
By
Effrosini Economou-Petersen,
Athanassios Aessopos,
Athina Kladi,
Panagiota Flevari,
Fotis Karabatsos,
Christina Fragodimitri,
Peter Nicolaidis,
Helen Vrettou,
Dimitris Vassilopoulos,
Markissia Karagiorga-Lagana,
Dimitrios Th. Kremastinos, and
Michael B. Petersen
From the Hellenic Red Cross Hospital, Athens; the Eginition
University Hospital, Athens; the Laiko University Hospital, Athens; the
Onassis Cardiac Surgery Center, Piraeus; the "Aghia Sophia"
Children's Hospital, Athens; the Mitera Maternity Hospital, Athens;
and the Institute of Child Health, Athens, Greece.
 |
ABSTRACT |
In homozygous  -thalassemia, the organ damage is mainly attributed
to excessive iron deposition through the formation of oxygen free
radicals. Despite appropriate transfusion and chelation therapy and low
ferritin levels, patients still develop organ failure, heart failure
being the main cause of death. This study was designed to determine
whether the decreased antioxidant activity of the apolipoprotein E
(APOE)  4 allele could represent a genetic risk factor for the
development of left ventricular failure (LVF) in -thalassemia
homozygotes. A total of 251 Greek -thalassemia homozygotes were
studied. Patients were divided in three groups: group A (n = 151)
with no cardiac impairment, group C (n = 47) with LVF, and 53 patients with LV dilatation and normal LV systolic function constituted
the group B. DNA was obtained from all patients, and the polymerase
chain reaction was used to analyze the polymorphism at the APOE locus.
The APOE allele frequencies were compared with those of a Greek control
sample of 216 healthy blood donors. Patients with no cardiac impairment
had an APOE 4 allele frequency (7.9%) not different from population
controls (6.5%, P > .05), while patients with LVF had a
significantly higher frequency of APOE 4 (12.8%) than the controls
(P < .05, odds ratio = 2.11, 95% confidence interval 1.03 to 4.32). The APOE 4 allele may represent an important genetic risk
factor for the development of organ damage in homozygous
-thalassemia.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
THE HEMOGLOBINOPATHIES are the most
common monogenic disorders in the world population, and they were the
first diseases to be analyzed by recombinant DNA
technology.1-3 More is known about their molecular
pathology than any other genetic disease, and it has been possible to
trace almost all of the diverse pathophysiologic features back to
primary molecular defects in single genes.4 In monogenic
disorders, most of the phenotypic variability is expected to be due to
allelic heterogeneity, although siblings with the same
genotype can show big phenotypic differences. The molecular basis of
such difference in clinical expression is not yet fully understood.
Homozygous -thalassemia is characterized by severe hemolytic anemia
associated with chronic tissue damage, disease- or treatment-related organ failure and premature death.
Heart failure remains the main cause of death and is traditionally
attributed to iron overload because of regular transfusions, increased
iron intestinal absorption, and ineffective erythropoiesis during the
life span of the patients.5,6 During the last two decades,
a striking improvement in life quality and life expectancy has been
observed, mainly due to proper transfusion and effective chelation
therapy to prevent secondary hemosiderosis.7
Regular chelation therapy with deferoxamine mesylate, a naturally
occurring trihydroxamic acid produced by Streptomyces
pilosus, increases urinary and fecal iron excretion, resulting in
amelioration of cardiac dysfunction8,9 and increased
survival.7 Although many patients benefit from this
therapy, others continue to have organ dysfunction and die, sometimes
despite intensive treatment with deferoxamine.10 It can
thus be hypothesized that either the deferoxamine therapy is not
effective in those patients, or they have reduced defense mechanisms
against the iron overload. The present study was designed to test the
hypothesis whether a postulated genetically determined decreased
antioxidant (and iron binding) activity in some patients with
homozygous -thalassemia could represent an independent risk factor
for the development of heart failure.
Apolipoprotein E (apoE) is a plasma protein with known
functions in cholesterol transport and metabolism and Alzheimer's
disease.11,12 The APOE gene is located on chromosome 19, and a polymorphism exists at the APOE locus with the three most common
alleles designated  2, 3, and 4, corresponding to three
isoforms of the apoE protein.13 It was recently shown that
apoE at physiologic levels has isoform-specific effects in protecting a
rat neuronal cell line from oxidative cell death, and that these
effects correlated with apoE's antioxidant activity in in vitro assays
(ranked E2>E3>E4).14 The demonstrated metal binding
ability (including iron) of apoE was postulated to be one mechanism
accounting for its antioxidant properties.14 We
hypothesized that a decreased antioxidant activity of apoE4 in
-thalassemia homozygotes might be a genetic risk factor for the
development of left ventricular failure (LVF). We tested our hypothesis
by comparing the frequency of APOE allele 4 in -thalassemia major
patients divided into three groups according to their cardiac status
with the 4 frequency in a Greek control sample.
| |
MATERIALS AND METHODS |
Subjects.
The subjects were 251 -thalassemia major patients of Greek origin
(117 men and 134 women), followed systematically by three major
thalassemia treatment units in the Athens area belonging to the public
health system. Transfusion therapy had started in all patients before
the age of 5 years. Each patient was receiving blood transfusions every
15 to 25 days to maintain a hemoglobin level above 9 g/dL during all of
the years of follow-up. All patients were receiving chelation therapy
with subcutaneous deferoxamine. The therapy had been initiated in each
patient after the serum ferritin level had reached 2,000 ng/mL. To
evaluate the transfusion therapy and the hemosiderosis level, we
obtained the mean pretransfusion hemoglobin level and mean serum
ferritin level in each patient over the last 2 and 5 years of
follow-up, respectively. Serum ferritin was measured two times per year
in each patient by an enzyme-linked immunosorbent assay (ELISA) method
(Abbott, Chicago, IL), and values were rounded off to the
nearest 10.
Clinical and laboratory cardiac evaluation included medical history,
clinical examination, electrocardiographic (ECG), as well as
echocardiographic studies. The echocardiographic examination was
performed as follows: two-dimensional and M-mode echocardiograms were
obtained using instruments with a 3-MHZ transducer. A two-dimensional study was first performed to identify the overall cardiac anatomy and
motion. Long-axis and parasternal short-axis views at the midventricular level were used to derive the following M-mode measurements: left ventricular end-systolic and end-diastolic dimensions, left atrial and right ventricular cavity dimensions, thickness of interventricular septum and posterior left ventricular wall according to the recommendations of the American Society of
Echocardiography.15 Four- and two-chamber apical views were used to estimate ventricular systolic and diastolic volumes, which were
calculated using the discs method.16 Left ventricular
ejection fraction (LVEF) was calculated as [(end-diastolic volume
minus end-systolic volume) divided by end-diastolic volume] multiplied by 100.
The patients were divided into three groups according to the severity
of heart disease based on clinical evaluation and echocardiographic findings. Group A patients had no symptoms or signs of heart failure, and their echocardiographic study was within normal limits. Group C
patients had symptoms and signs of LVF and concomitant
echocardiographic findings. These patients exhibited dyspnea on
exertion (New York Heart Association [NYHA] functional class I-IV)
and fulfilled at least two major Framingham criteria for heart failure
diagnosis. Finally, patients in group B were asymptomatic, but
exhibited LV dilatation (LV end diastolic diameter index [LVEDDI]
higher than 30 mm/m2) without left ventricular systolic
dysfunction (LV fractional shortening [FS] higher than 28%), as
assessed echocardiographically. Patients in this group did not receive
treatment.
Another type of heart failure in -thalassemia major is associated
with right ventricular dilatation. Patients of this kind were excluded
from the study, as right ventricular failure in -thalassemia major
is due to different pathophysiologic reasons.17,18
APOE genotyping.
Genomic DNA was extracted from EDTA blood samples by a salting out
procedure.19 Genotyping of polymorphic APOE alleles was done after polymerase chain reaction amplification of genomic DNA,
digestion with Hha I restriction enzyme, and agarose gel electrophoresis as described previously.20,21 The control
sample for which data on APOE genotype were available consisted of a random sample of 216 voluntary, healthy Greek blood
donors.22 The blood donors were 146 men and 70 women, and
the mean age was 35.6 years (range, 19 to 64 years).22
Statistical analysis.
We used analysis of variance (ANOVA) for multiple groups to assess
differences regarding echocardiographic measurements between the three
patient groups and the  2 test to compare the 4 allele
frequency in the different patient groups with that of the population
controls.
| |
RESULTS |
From the 251 patients studied, 151 belonged to group A, 53 to group B,
and 47 to group C. Three cases were excluded from the study, as they
presented a clinical picture of congestive heart failure and
echocardiographic findings of profound right ventricular dilatation,
good LV function, and pulmonary hypertension at the Doppler study.
Hematologic and hemosiderosis parameters of the patients are shown in
Table 1. No statistically significant
differences were found between the hemoglobin and ferritin levels of
the patient groups.
The cardiologic characteristics of the three patient groups are
depicted in Table 2. Twenty-eight patients
of group C were in severe cardiac failure of NYHA class III-IV and 19 of class I-II. All patients in groups B and C had LV dilatation and
LVEDDI higher than 30 mm/m2. Groups A and B had good LV
function with a significant difference in fractional shortening and
ejection fraction with the group C (Table 2). All 47 patients of group
C were receiving treatment with angiotensin-converting enzyme (ACE)
inhibitors, diuretics ± digitalis. The 53 patients of group B and
the 151 patients of group A were not in cardiac failure and had
echocardiographically normal LV function.
Table 3 gives the APOE allele frequencies
in the three patient groups, as well as in controls. The APOE 3
allele had the highest frequency in all three patient groups, while the
2 allele frequency of 5.6% in patient group A and 6.4% in group C
does not show any statistical difference from the control group. The APOE 4 allele frequency in -thalassemia homozygotes without cardiac impairment (7.9%) was not different from the frequency in
population controls (6.5%, 2 = 0.58, P > .05). The 4 frequency in patients with heart failure (12.8%) was
significantly higher than in controls (2 = 4.34, P
< .05, odds ratio = 2.11, 95% confidence interval 1.03 to 4.32),
and so was the 4 frequency in group B patients (12.3%, 2 = 4.04, P < .05). Taking patient groups B
and C together, the 4 frequency of 12.5% was significantly higher
than in controls (2 = 6.45, P < .02). All -thalassemia homozygotes irrespective of cardiac diagnosis
had an 4 frequency (9.8%) not different from the population of
healthy blood donors (2 = 3.30, P > .05). Four
patients were homozygous for the 4 allele, the three belonged to
group C and one to group B.
| |
DISCUSSION |
The severity of iron toxicity in -thalassemia major seems to be
related to the magnitude of the body iron burden.23,24 The
exact mechanism of iron overload toxicity has been uncertain for many
years. Via the iron-driven Fenton and Haber-Weiss reactions, the
nontransferrin plasma iron, in its bivalent or trivalent form, has a
high toxicity through the formation of hydroxyl radicals (OH.).25 This leads to peroxidative damage of
membrane lipids and proteins. Imbalance between production of oxygen
free radicals and antioxidant defense mechanisms can result in
oxidative stress and human disease.26 In the heart, the
imbalance between free radicals and antioxidant mechanisms is
manifested as impaired function of the mitochondrial inner-membrane
respiratory chain resulting in abnormal energy metabolism expressed
clinically with fatal cardiomyopathy. Apart from iron overload, it has
been recently shown by our group that myocarditis appears to be
involved in the pathogenesis of LVF in a certain number of patients
with homozygous -thalassemia.27 As shown in animal
models, oxygen free radicals may also contribute to the pathogenesis of
infectious myocarditis.28,29
In the present study, we categorized the patients in three groups
according to the severity of heart disease. The normal cases of group A
and the severely affected cases of group C had clear clinical and
echocardiographic characteristics and were easily distinguished.
Patients of group B were characterized by LV dilatation and good LV
function. In these cases, LV and left atrial (LA) dilatation could
possibly represent the first step of LV dysfunction without overt LV
decreased contractility, or a compensatory mechanism due to anemia.
Some of these patients will eventually develop LVF.
The results of the functional polymorphism at the APOE locus in our
study suggest that the 4 allele may be a genetic risk factor for the
development of LVF (and other organ damage) in homozygous
-thalassemia. It represents the first demonstration of a genetic
factor unlinked to the globin gene cluster contributing to the
clinical manifestations of the disease. The 4 allele could represent
a predictive marker for development of LVF in patients with
-thalassemia major and LV dilatation (our patient group B),
suggesting a closer follow-up of such patients. As the APOE 4
frequency was found in only 12.8% of patients with homozygous -thalassemia and LVF, it is obvious that other genetic and
environmental factors, as for instance, the number of transfusions,
iron overload, chelation therapy, and viral myocardial inflammation,
play a role in the development of organ damage. The fact that patients
in groups B and C, as shown in Table 1, did not have either higher ferritin levels or were transfused more inadequately than those without
cardiac impairment, supports the role of APOE 4 allele as a genetic
risk factor for LVF development. Furthermore, some patients of group A
with 4 allele could still develop LVF. Additional evidence for the
relationship between the 4 allele and heart disease comes from an
analysis of patients homozygous for the 4 allele, of whom three had
LVF and one LV dilatation, but numbers in this category are small. The
increase in the 4 allele frequency among patients with cardiac
disease comes with a reduction in 3 rather than 2 allele
frequency, but the 2 allele frequency is already very low in the
Greek population,22 and other factors may influence the
level of this allele.
As the APOE 4 allele was found in patients of advanced age with no
cardiac impairment, the presence of the 4 allele does not guarantee
the development of LVF in -thalassemia. In addition, as more than
85% of patients with LVF do not carry the 4 allele, this is neither
a necessary prerequisite for the development of LVF. This is equivalent
to the association of APOE 4 with Alzheimer's disease, where the
association has been confirmed in almost 100 studies around the
world.30 A consensus statement on APOE genotyping in
Alzheimer's disease concluded that APOE genotyping can be used as an
adjunct to other diagnostic tests, but that prospective investigations
of dementia as a function of APOE genotype are needed,31
and something similar might apply to -thalassemia.
Allelic variation at the APOE locus has been studied in many
populations. Significant differences have been observed between Caucasian, Chinese, Japanese, and black races. Also among Caucasian populations there is a significant variation in the allele
frequencies.32 Average allele frequencies from Caucasians
show an 4 allele frequency of 15.0%. The very low 4 frequency in
the Greek population22 is in agreement with the gradient
found for the frequency of this allele in Europe, and is supported by a
similar low frequency (7.0%) in Greek Cypriots.33 Our
finding of an association between the APOE 4 allele and LVF in Greek
-thalassemia homozygotes now needs confirmation from other
populations using appropriate population controls.
The well-known isoform-specific influence of apoE on plasma cholesterol
level and atherosclerosis32 cannot explain the association found between APOE allele 4 and LVF in -thalassemia homozygotes, as atherosclerosis is not a general feature of the pathophysiology of
the disorder.
It is recognized now that the severity of a monogenic disorder may be
modified by a second locus, depending on the genetic background.34 Any genes involved in the pathogenic pathway
represent candidate modifier genes.35 The boundaries
between monogenic and polygenic disorders might not always be so
clear-cut as previously thought,34 as more genes and gene
interactions become known from the progress of the Human Genome
Project.
The finding of an increased frequency of APOE 4 allele in
-thalassemia homozygotes with LVF provides additional evidence to
the theory of oxygen free radicals as contributing to the organ damage,
due to the recently demonstrated antioxidant and iron binding activity
of apoE.14 This suggests that several other genetic loci
could be of potential relevance to the oxidative damage of organs in
-thalassemia. Such loci include genes modulating genesis of oxygen
free radicals (ie, cytochrome C oxidase), genes for scavenger enzymes
(superoxide dismutases, catalase), genes regulating mitochondrial DNA
replication, structural genes for membrane lipoproteins, and genes
involved in DNA repair mechanisms.36 It is noteworthy that
mutant mice lacking the Mn-superoxide dismutase enzyme suffer neonatal
lethality due to dilated cardiomyopathy.37 Other functional
polymorphisms in such genes could be examined for association with
organ failure in -thalassemia. It is also believed that genetic
susceptibility for a majority of common diseases will be associated
with relatively common alleles of one or several loci.38
| |
FOOTNOTES |
Submitted September 29, 1997;
accepted June 30, 1998.
Address reprint requests to Effrosini Economou-Petersen, MD, Hellenic
Red Cross Hospital, 4 Alkibiadou, GR-10439 Athens, Greece.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
REFERENCES |
1.
Kan YW,
Dozy AM:
Polymorphism of DNA sequence adjacent to human -globin structural gene: Relationship to sickle mutation.
Proc Natl Acad Sci USA
75:5631,
1978[Abstract/Free Full Text]
2.
Boehm CD,
Antonarakis SE,
Phillips JA,
Stetten G,
Kazazian HH Jr:
Prenatal diagnosis using DNA polymorphisms. Report on 95 pregnancies at risk for sickle-cell disease or -thalassemia.
N Engl J Med
308:1054,
1983[Abstract]
3.
Pirastu M,
Kan YW,
Cao A,
Conner BJ,
Teplitz RL,
Wallace RB:
Prenatal diagnosis of -thalassemia. Detection of a single nucleotide mutation in DNA.
N Engl J Med
309:284,
1983[Abstract]
4.
Wood WG:
The hemoglobinopathies
, in Scriver CR,
Beaudet AL,
Sly WS,
Valle D
(eds):
The Metabolic and Molecular Bases of Inherited Disease,
New York, NY, McGraw-Hill
, 1995
, p 3417
5.
Sapoznikov D,
Lewis N,
Rachmilewitz EA,
Gotsman MS,
Lewis BS:
Left ventricular filling and emptying patterns in anemia due to beta-thalassemia: A computer-assisted echocardiographic study.
Cardiology
69:276,
1982[Medline]
[Order article via Infotrieve]
6.
Lau KC,
Li AMC,
Hui PW,
Yeung CY:
Left ventricular function in -thalassemia major.
Arch Dis Child
64:1046,
1989[Abstract/Free Full Text]
7.
Olivieri NF,
Nathan DG,
MacMillan JH,
Wayne AS,
Liu PP,
McGee A,
Martin M,
Koren G,
Cohen AR:
Survival in medically treated patients with homozygous -thalassemia.
N Engl J Med
331:574,
1994[Abstract/Free Full Text]
8.
Freeman AP,
Giles RW,
Berdoukas VA,
Walsh WF,
Choy D,
Murray PC:
Early left ventricular dysfunction and chelation therapy in thalassemia major.
Ann Intern Med
99:450,
1983
9.
Wolfe L,
Olivieri N,
Sallan D,
Colan S,
Rose V,
Propper R,
Freedman MH,
Nathan DG:
Prevention of cardiac disease by subcutaneous deferoxamine in patients with thalassemia major.
N Engl J Med
312:1600,
1985[Abstract]
10.
Marcus RE,
Davies SC,
Bantock HM,
Underwood SR,
Walton S,
Huehns ER:
Desferrioxamine to improve cardiac function in iron-overloaded patients with thalassaemia major.
Lancet
1:392,
1984[Medline]
[Order article via Infotrieve]
11.
Mahley RW:
Apolipoprotein E: Cholesterol transport protein with expanding role in cell biology.
Science
240:622,
1988[Abstract/Free Full Text]
12.
Strittmatter WJ,
Saunders AM,
Schmechel D,
Pericak-Vance M,
Enghild J,
Salvesen GS,
Roses AD:
Apolipoprotein E: High-avidity binding to -amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease.
Proc Natl Acad Sci USA
90:1977,
1993[Abstract/Free Full Text]
13.
Zannis VI,
Breslow JL,
Utermann G,
Mahley RW,
Weisgraber KH,
Havel RJ,
Goldstein JL,
Brown MS,
Schonfeld G,
Hazzard WR,
Blum C:
Proposed nomenclature of apoE isoproteins, apoE genotypes, and phenotypes.
J Lipid Res
23:911,
1982[Medline]
[Order article via Infotrieve]
14.
Miyata M,
Smith JD:
Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and -amyloid peptides.
Nat Genet
14:55,
1996[Medline]
[Order article via Infotrieve]
15.
Sahn DJ,
De Maria A,
Kisslo J,
Weyman A:
The committee on M-mode standardization of the American Society of Echocardiography: Results of a survey of echocardiographic measurements.
Circulation
58:1072,
1978[Abstract/Free Full Text]
16.
Schiller NB,
Shah PM,
Crawford M,
DeMaria A,
Devereux R,
Fligenbaum H,
Gutgesell H,
Reicher N,
Sahn D,
Schnittger I,
Silverman NH,
Tajih AJ:
Recommendations for quantitation of the left ventricle by two-dimensional echocardiography: American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiography.
J Am Soc Echocardiogr
2:358,
1989[Medline]
[Order article via Infotrieve]
17.
Crisaru D,
Rachmilewitz EA,
Mosseri M,
Gotsman M,
Latair JS,
Okon E,
Goldfard A,
Hasin Y:
Cardiopulmonary assessment in -thalassemia major.
Chest
98:1138,
1990[Abstract/Free Full Text]
18.
Aessopos A,
Stamatelos G,
Skoumas V,
Vassilopoulos G,
Mantzourani M,
Loukopoulos D:
Pulmonary hypertension and right ventricle failure in patients with beta-thalassemia intermedia.
Chest
107:50,
1995[Abstract/Free Full Text]
19.
Miller SA,
Dykes DD,
Polesky HF:
A simple salting out procedure for extracting DNA from human nucleated cells.
Nucleic Acids Res
16:1215,
1988[Free Full Text]
20.
Wenham PR,
Price WH,
Blundell G:
Apolipoprotein E genotyping by one-stage PCR.
Lancet
337:1158,
1991[Medline]
[Order article via Infotrieve]
21.
Avramopoulos D,
Mikkelsen M,
Vassilopoulos D,
Grigoriadou M,
Petersen MB:
Apolipoprotein E allele distribution in parents of Down's syndrome children.
Lancet
347:862,
1996[Medline]
[Order article via Infotrieve]
22.
Sklavounou E,
Economou-Petersen E,
Karadima G,
Panas M,
Avramopoulos D,
Varsou A,
Vassilopoulos D,
Petersen MB:
Apolipoprotein E polymorphism in the Greek population.
Clin Genet
52:216,
1997[Medline]
[Order article via Infotrieve]
23.
Leon MB,
Borer JS,
Bacharach SL,
Green MV,
Benz EJ Jr,
Griffith P,
Nienhuis AW:
Detection of early cardiac dysfunction in patients with severe beta-thalassemia and chronic iron overload.
N Engl J Med
301:1143,
1979[Abstract]
24.
Brittenham GM,
Griffith PM,
Nienhuis AW,
McLaren CE,
Young NS,
Tucker EE,
Allen CJ,
Farrell DE,
Harris JW:
Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major.
N Engl J Med
331:567,
1994[Abstract/Free Full Text]
25.
Halliwell B:
The role of oxygen radicals in human disease, with particular reference to the vascular system.
Haemostasis
23:118,
1993(suppl 1)
26.
Kukreja RC,
Hess ML:
The oxygen free radical system: From equations through membrane-protein interactions to cardiovascular injury and protection.
Cardiovasc Res
26:641,
1992[Abstract/Free Full Text]
27.
Kremastinos DTh,
Tiniakos G,
Theodorakis GN,
Katritsis DG,
Toutouzas PK:
Myocarditis in -thalassemia major: A cause of heart failure.
Circulation
91:66,
1995[Abstract/Free Full Text]
28.
Hiraoka Y,
Kishimoto C,
Takada H,
Kurokawa M,
Ochiai H,
Shiraki K,
Sasayama S:
Role of oxygen derived free radicals in the pathogenesis of coxsackievirus B3 myocarditis in mice.
Cardiovasc Res
27:957,
1993[Abstract/Free Full Text]
29.
Suzuki H,
Matsumori A,
Matoba Y,
Kyu BS,
Tanaka A,
Fujita J,
Sasayama S:
Enhanced expression of superoxide dismutase messenger RNA in viral myocarditis. An SH-dependent reduction of its expression and myocardial injury.
J Clin Invest
91:2727,
1993
30.
Roses AD:
Apolipoprotein E genotyping in the differential diagnosis, not prediction, of Alzheimer's disease.
Ann Neurol
38:6,
1995[Medline]
[Order article via Infotrieve]
31.
National Institute on Aging/Alzheimer's Association Working Group:
Apolipoprotein E genotyping in Alzheimer's disease.
Lancet
347:1091,
1996[Medline]
[Order article via Infotrieve]
32.
Davignon J,
Gregg RE,
Sing CF:
Apolipoprotein E polymorphism and atherosclerosis.
Arteriosclerosis
8:1,
1988[Abstract/Free Full Text]
33.
Cariolou MA,
Kakkofitou A,
Manoli P,
Christou S,
Karagrigoriou A,
Middleton L:
Underexpression of the apolipoprotein E2 and E4 alleles in the Greek Cypriot population of Cyprus.
Genet Epidemiol
12:489,
1995[Medline]
[Order article via Infotrieve]
34.
Estivill X:
Complexity in a monogenic disease.
Nat Genet
12:348,
1996[Medline]
[Order article via Infotrieve]
35.
Houlston RS,
Tomlinson IPM:
Modifier genes in humans: Strategies for identification.
Eur J Hum Genet
6:80,
1998[Medline]
[Order article via Infotrieve]
36.
Martin GM,
Austad SN,
Johnson TE:
Genetic analysis of ageing: Role of oxidative damage and environmental stresses.
Nat Genet
13:25,
1996[Medline]
[Order article via Infotrieve]
37.
Li Y,
Huang T-T,
Carlson EJ,
Melov S,
Ursell PC,
Olson JL,
Noble LJ,
Yoshimura MP,
Berger C,
Chan PH,
Wallace DC,
Epstein CJ:
Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase.
Nat Genet
11:376,
1995[Medline]
[Order article via Infotrieve]
38.
Brown PO,
Hartwell L:
Genomics and human disease variations on variation.
Nat Genet
18:91,
1998[Medline]
[Order article via Infotrieve]
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D. Th. Kremastinos, D. P. Tsiapras, A. G. Kostopoulou, E. S. Hamodraka, A. S. Chaidaroglou, and E. D. Kapsali
NT-proBNP levels and diastolic dysfunction in {beta}-Thalassaemia major patients
Eur J Heart Fail,
May 1, 2007;
9(5):
531 - 536.
[Abstract]
[Full Text]
[PDF]
|
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|
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M. Bazrgar, M. Karimi, F. Peiravian, and M. Fathzadeh
Apolipoprotein E gene polymorphism and left ventricular function in Iranian patients with thalassemia major
Haematologica,
February 1, 2007;
92(2):
256 - 257.
[Abstract]
[Full Text]
[PDF]
|
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G Bosi, R Crepaz, M R Gamberini, M Fortini, S Scarcia, E Bonsante, W Pitscheider, and M Vaccari
Left ventricular remodelling, and systolic and diastolic function in young adults with {beta} thalassaemia major: a Doppler echocardiographic assessment and correlation with haematological data
Heart,
July 1, 2003;
89(7):
762 - 766.
[Abstract]
[Full Text]
[PDF]
|
|
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J. E. Eichner, S. T. Dunn, G. Perveen, D. M. Thompson, K. E. Stewart, and B. C. Stroehla
Apolipoprotein E Polymorphism and Cardiovascular Disease: A HuGE Review
Am. J. Epidemiol.,
March 15, 2002;
155(6):
487 - 495.
[Abstract]
[Full Text]
[PDF]
|
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L.J. Anderson, S. Holden, B. Davis, E. Prescott, C.C. Charrier, N.H. Bunce, D.N. Firmin, B. Wonke, J. Porter, J.M. Walker, et al.
Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload
Eur. Heart J.,
December 1, 2001;
22(23):
2171 - 2179.
[Abstract]
[PDF]
|
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D. T. Kremastinos, P. Flevari, M. Spyropoulou, H. Vrettou, D. Tsiapras, and C. G. Stavropoulos-Giokas
Association of Heart Failure in Homozygous {beta}-Thalassemia With the Major Histocompatibility Complex
Circulation,
November 16, 1999;
100(20):
2074 - 2078.
[Abstract]
[Full Text]
[PDF]
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Abstract
Introduction
Abstract