Download Lack of association between polymorphisms of eight candidate

Journal of the American College of Cardiology
© 1999 by the American College of Cardiology
Published by Elsevier Science Inc.
Vol. 35, No. 1, 2000
ISSN 0735-1097/00/$20.00
PII S0735-1097(99)00522-7
Lack of Association Between
Polymorphisms of Eight Candidate
Genes and Idiopathic Dilated Cardiomyopathy
The CARDIGENE Study
Laurence Tiret, PHD,* Christine Mallet, MSC,† Odette Poirier, PHD,* Viviane Nicaud, MA,*
Alain Millaire, MD, PHD,‡ Jean-Brieuc Bouhour, MD,§ Gérard Roizès, PHD,㛳 Michel Desnos, MD,¶
Richard Dorent, MD,# Ketty Schwartz, PHD,†† François Cambien, MD,* Michel Komajda, MD,** FOR
CARDIGENE GROUP
Paris, Lille, Nantes, and Montpellier, France
OBJECTIVES
THE
The study investigated the potential role of eight candidate genes in the susceptibility to
idiopathic dilated cardiomyopathy (IDC).
BACKGROUND Idiopathic dilated cardiomyopathy has a familial origin in 20% to 25% of cases, and several
genetic loci have been identified in rare monogenic forms of the disease. These findings led
to the hypothesis that genetic factors might also be involved in sporadic forms of the disease.
In complex diseases that do not exhibit a clear pattern of familial aggregation, the candidate
gene approach is a strategy widely used to identify susceptibility genes. All genes coding for
proteins involved in biochemical or physiological abnormalities of cardiac function are
potential candidates for IDC.
METHODS
We studied 433 patients with IDC and 401 gender- and age-matched controls. Polymorphisms investigated were the I/D polymorphism of the angiotensin I-converting enzyme
(ACE) gene, the T174M and M235T polymorphisms of the angiotensinogen (AGT) gene,
the A-153G and A⫹39C polymorphisms of the angiotensin-II type 1 receptor (AGTR1)
gene, the T-344C polymorphism of the aldosterone synthase (CYP11B2) gene, the G-308A
polymorphism of the tumor necrosis factor-alpha (TNF) gene, the R25P polymorphism of
the transforming growth factor beta1 (TGFB1) gene, the G⫹11/in23T polymorphism of the
endothelial nitric oxide synthase (NOS3) gene and the C-1563T polymorphism of the brain
natriuretic peptide (BNP) gene.
RESULTS
None of the polymorphisms were significantly associated with the risk or the severity of the
disease.
CONCLUSIONS We did not find evidence for an involvement of any of the 10 investigated polymorphisms in
the susceptibility to IDC. (J Am Coll Cardiol 2000;35:29 –35) © 1999 by the American
College of Cardiology
Dilated cardiomyopathy (DCM) is a myocardial disease
characterized by impaired systolic function and dilation of
the left or both ventricles (1). Despite recent advances in
medical and surgical therapies, it remains an important
cause of mortality and morbidity and is a leading indication
for heart transplantation. The etiology of DCM is idiopathic in about half the patients. Family studies using
From the *INSERM U525, Paris; †INSERM SC7, Paris; ‡CHR de Lille; §CHR
de Nantes; 㛳INSERM U249, Montpellier; ¶Hôpital Boucicaut, Paris; #Service de
Chirurgie Cardiaque and **Service de Cardiologie, Groupe Hospitalier PitiéSalpêtrière, Paris; ††INSERM U523, Paris, France. The CARDIGENE study was
supported by grants from Parke Davis France, the “Délégation à la Recherche
Clinique AP-HP” (EMUL and PHRC) and INSERM.
Manuscript received February 19, 1999; revised manuscript received July 29, 1999,
accepted October 5, 1999.
echocardiography to identify individuals with presymptomatic disease revealed that 20% to 25% of idiopathic dilated
cardiomyopathy (IDC) had a familial origin, a proportion
that had been considerably underestimated previously (2,3).
This finding raised the hypothesis that gene defects might
play an important role in the disease pathogenesis. Indeed,
several genetic loci responsible for rare autosomal dominant
or X-linked forms of DCM have been subsequently localized by linkage analysis in large pedigrees (review in [4]).
The recognition of familial DCM led to the notion that
even in sporadic cases, genetic factors might contribute to
the disease susceptibility. In complex diseases that do not
exhibit a clear pattern of familial aggregation, the candidate
gene approach, which tests the role of known genes selected
for their potential implication in the pathophysiological
30
Tiret et al.
Dilated Cardiomyopathy and Candidate Genes
Abbreviations
ACE
AGT
AGTR1
BNP
CYP11B2
DCM
IDC
NOS3
TGFB1
TNF
and Acronyms
⫽ angiotensin I-converting enzyme
⫽ angiotensinogen
⫽ angiotensin-II type 1 receptor
⫽ brain natriuretic peptide
⫽ aldosterone synthase
⫽ dilated cardiomyopathy
⫽ idiopathic dilated cardiomyopathy
⫽ endothelial nitric oxide synthase
⫽ transforming growth factor beta1
⫽ tumor necrosis factor-alpha
process, is a strategy widely used (5,6). In DCM, all genes
coding for proteins involved in biochemical or physiological
abnormalities of cardiac function are potential candidates.
The CARDIGENE study is a large case-control study
designed to identify genetic factors involved in the predisposition to IDC. This article reports the results of an
investigation of eight candidate genes: the angiotensin
I-converting enzyme (ACE), the angiotensin-II type 1
receptor (AGTR1), the angiotensinogen (AGT), the aldosterone synthase (CYP11B2), the tumor necrosis factoralpha (TNF), the transforming growth factor beta1
(TGFB1), the endothelial nitric oxide synthase (NOS3) and
the brain natriuretic peptide (BNP) genes.
METHODS
Ethics approval for the study was obtained from the relevant
committees, and each subject gave written informed consent
for the study.
Patients. Patients aged 18 to 65 years (n ⫽ 433) were
recruited between 1994 and 1996 from 10 hospitals (see list
in Appendix). The diagnosis of IDC was based on impaired
left ventricular systolic function (ejection fraction ⱕ40% on
ventriculography, radionucleotide angiography or echocardiography) and left ventricular dilation (end-diastolic volume ⬎140 ml/m2 on ventriculography or end-diastolic
diameter ⬎34 mm/m2 on echocardiography), confirmed
over a six-month period. For transplanted patients, these
criteria had to be fulfilled before heart transplantation.
Coronary angiography had to be performed in all subjects
aged ⬎35 years, and patients with ⱖ50% obstruction of one
or more coronary arteries were excluded. Patients with
myocardial infarction, sustained systemic arterial hypertension, insulin-dependent diabetes, intrinsic valvular disease,
congenital cardiopathy, documented myocarditis, specific
primary or secondary heart muscle disease were also excluded. All patients had to be born in France, and their
parents had to be born in France or neighboring countries.
The mean left ventricular ejection fraction was 23.3 ⫾
7.6% (n ⫽ 433), the mean end-diastolic volume was 194 ⫾
37 ml/m2 on ventriculography (n ⫽ 182) and the mean
end-diastolic diameter was 40.1 ⫾ 5.1 mm/m2 (n ⫽ 371) on
JACC Vol. 35, No. 1, 2000
January 2000:29–35
echocardiography. The mean duration between diagnosis
and inclusion was 7.1 ⫾ 5.3 years. Of the 433 patients, 229
(52.9%) had heart transplantation. Family history of DCM,
defined as definite or possible cardiomyopathy, or sudden
death ⱕ35 years, in first- or second-degree relatives, was
reported in 25% of patients.
Controls. Controls (n ⫽ 401) were randomly sampled
from the French population surveys carried out in Lille
(northern France), Strasbourg (eastern France) and Toulouse (southern France) within the framework of the WHO
MONICA (MONItoring in CArdiovascular diseases)
project (7). A stratification was used to match the approximate age distributions in cases and controls (age at diagnosis in cases and current age in controls). Controls with
clinical history of cardiovascular disease or insulindependent diabetes were excluded.
Genotyping. Genomic DNA was prepared from white
blood cells by phenol extraction. Polymorphisms investigated were an insertion (I)/deletion (D) polymorphism in
intron 16 of the ACE gene (8); two nucleotide substitutions
resulting in amino acid changes at codons 174 (Thr/Met)
and 235 (Met/Thr) of the AGT gene (9); two nucleotide
substitutions A-153G and A⫹39C (previously named
A⫹1166C) in the AGTR1 gene (10); a nucleotide substitution T-344C in the CYP11B2 gene (11); a nucleotide
substitution G-308A in the TNF gene (12); a nucleotide
substitution resulting in an amino acid change at codon 25
(Arg/Pro) of the TGFB1 gene (13); a G/T nucleotide
substitution in intron 23 of the NOS3 gene (14); and a
nucleotide substitution C-1563T in the BNP gene (unpublished).
Statistical analysis. Data were analyzed using the SAS
statistical software (SAS Institute, Cary, North Carolina).
Allele frequencies were estimated by gene counting. HardyWeinberg equilibrium was tested by chi-square analysis.
Genotype and allele frequencies were compared between
cases and controls by chi-square analysis. Genotypic odds
ratios (OR) for disease, assuming a dominant or a recessive
model, were computed. Association between polymorphisms and case/control status was also tested by means of
logistic regression analysis controlling for age, gender
(matching criteria) and different covariates. A p value ⬍0.05
was considered statistically significant.
RESULTS
Characteristics of cases and controls are presented in Table
1. The mean age at diagnosis was 44.6 years in male and
48.4 years in female cases. Compared to controls, cases were
shorter by approximately 1 cm (p ⬍ 0.05), had a higher
alcohol and tobacco consumption (p ⬍ 0.001) and a higher
prevalence of non–insulin-dependent diabetes mellitus (p ⬍
0.05). Transplanted patients were younger, leaner and had a
lower alcohol consumption than did nontransplanted patients, and they were characterized by a more severe left
Tiret et al.
Dilated Cardiomyopathy and Candidate Genes
JACC Vol. 35, No. 1, 2000
January 2000:29–35
31
Table 1. Characteristics of Cases and Controls
Men
Age (yr)*
Height (cm)
Weight (kg)
BMI (kg/m2)
Alcohol (g/day)
Smokers (%)
NIDDM (%)
Women
p Value
Cases
(n ⴝ 345)
Controls
(n ⴝ 329)
Cases
(n ⴝ 88)
Controls
(n ⴝ 72)
Cases vs. controls
(Both genders pooled)
44.6 (0.5)
173.1 (0.4)
76.6 (0.7)
25.5 (0.2)
78.1 (3.1)
55.1
4.4
45.2 (0.5)
174.3 (0.4)
77.6 (0.7)
25.5 (0.2)
26.7 (3.2)
27.1
1.5
48.4 (1.0)
161.7 (0.7)
60.3 (1.4)
23.1 (0.4)
9.0 (6.2)
25.0
4.6
48.9 (1.1)
162.2 (0.8)
62.8 (1.5)
23.9 (0.5)
12.2 (6.8)
19.4
2.8
0.35
0.02
0.15
0.64
⬍ 0.001
0.001
0.03
*Age at diagnosis for cases and current age for controls. Data are expressed as mean (SE) or %.
BMI ⫽ body mass index (weight/height2); NIDDM ⫽ non–insulin-dependent diabetes mellitus.
ventricular dysfunction and a lower ejection fraction (data
not shown).
There was no deviation from Hardy-Weinberg equilibrium for any of the polymorphisms considered. None of the
polymorphisms exhibited significant difference of genotype
or allele frequencies between cases and controls (Table 2).
No significant association was observed when considering
either a dominant or a recessive model for each polymorphism (Fig. 1). We further investigated whether polymorphisms were associated with the severity of disease assessed
by ejection fraction (⬍/ⱖ24%), left ventricular dilation
(end-diastolic diameter ⬍/ⱖ40 mm/m2) or heart transplan-
Table 2. Genotype and Allele Frequencies of Candidate Gene Polymorphisms in Cases and Controls
Genotypes
ACE I/D
Cases
Controls
AGT T174M
Cases
Controls
AGT M235T
Cases
Controls
AGTR1 A-153G
Cases
Controls
AGTR1 A⫹39C
Cases
Controls
CYP11B2 T-344C
Cases
Controls
TNF G-308A
Cases
Controls
TGFB1 R25P
Cases
Controls
NOS3 G⫹11/in23T
Cases
Controls
BNP C-1563T
Cases
Controls
n (%)
n (%)
n (%)
Allele
Frequency
II
94 (22.3)
71 (18.4)
TT
333 (77.8)
295 (74.1)
MM
157 (36.7)
131 (32.9)
AA
296 (69.5)
267 (67.4)
AA
223 (52.6)
209 (52.5)
TT
132 (31.0)
114 (29.0)
GG
322 (75.2)
288 (72.7)
RR
360 (85.3)
344 (86.2)
GG
186 (43.4)
177 (44.9)
CC
401 (95.3)
379 (95.7)
ID
200 (47.4)
190 (49.1)
TM
88 (20.6)
93 (23.4)
MT
200 (46.7)
195 (49.0)
AG
121 (28.4)
111 (28.0)
AC
161 (38.0)
152 (38.2)
TC
219 (51.4)
195 (49.6)
GA
100 (23.4)
95 (24.0)
RP
58 (13.7)
52 (13.0)
GT
189 (44.1)
169 (42.9)
CT
18 (4.3)
17 (4.3)
DD
128 (30.3)
126 (32.6)
MM
7 (1.6)
10 (2.5)
TT
71 (16.6)
72 (18.1)
GG
9 (2.1)
18 (4.6)
CC
40 (9.4)
37 (9.3)
CC
75 (17.6)
84 (21.4)
AA
6 (1.4)
13 (3.3)
PP
4 (1.0)
3 (0.8)
TT
54 (12.6)
48 (12.2)
TT
2 (0.5)
0 (0.0)
f (D)
0.54
0.57
f (M)
0.12
0.14
f (T)
0.40
0.43
f (G)
0.16
0.19
f (C)
0.28
0.28
f (C)
0.43
0.46
f (A)
0.13
0.15
f (P)
0.08
0.07
f (T)
0.35
0.34
f (T)
0.03
0.02
Note: No significant difference existed between cases and controls.
32
Tiret et al.
Dilated Cardiomyopathy and Candidate Genes
JACC Vol. 35, No. 1, 2000
January 2000:29–35
Figure 1. Genotypic odds ratios for DCM and 95% confidence intervals, assuming a recessive (left) or dominant (right) genetic model.
For all polymorphisms, the major allele was taken as the reference allele, except for ACE I/D where I was the reference allele. For TGFB1
R25P and BNP C-1563T, the recessive model was not considered because of the low frequency of the minor allele.
tation. No significant difference was found between subgroups of disease severity. The genotype and allele frequencies did not differ between patients with and without a
familial history of DCM. Because alcohol intake is a major
etiologic factor for DCM, we investigated whether alcohol
might modulate the effect of polymorphisms on the risk of
DCM, but we did not find any evidence for alcohol–
genotype interaction. Finally, for each polymorphism, we
performed multivariate logistic regression analysis controlling for age, gender, height, weight, diabetes, alcohol intake,
smoking status and genotype (assuming either a recessive or
a dominant model), but genotypic ORs were little modified
by adjustment and remained nonsignificant.
DISCUSSION
Selection of the candidate genes and of the polymorphisms
examined in the present study was based on pathophysiological considerations and/or results previously reported in
published data.
Genes of the renin-angiotensin-aldosterone system. The
renin-angiotensin-aldosterone system may be involved in
the susceptibility to DCM because of its action on cellular
hypertrophy, cell proliferation and cardiac remodeling. The
major biologically active product of the renin-angiotensin
system is angiotensin II, which is liberated from AGT by
the sequential action of renin and ACE. In adult humans,
the effects of angiotensin II are mainly mediated by the
AGTR1, a G-protein-coupled receptor expressed by many
cell types, in particular cardiomyocytes. Each component of
this system constitutes then a candidate for DCM. The
ACE I/D polymorphism was the first genetic factor reported to be associated with nonfamilial IDC (15). However, the association seemed mainly due to a unexpected low
frequency of the DD genotype in controls rather than to an
excess in cases, and this finding failed to be confirmed in
later studies (16 –19). In contrast, the DD genotype was
found associated with poorer survival and reduced left
ventricular performance in idiopathic heart failure and IDC
(17,20).
Angiotensinogen (AGT) is the precursor of angiotensin-I
and its concentration is rate-limiting for the generation of
angiotensin-II. Ever since the initial finding of an association between the M235T and T174M polymorphisms of
the AGT gene and essential hypertension (9), the implication of the AGT locus in the pathogenesis of hypertension
and the regulation of blood pressure has been confirmed in
a large number of studies. A possible involvement of these
two polymorphisms in the susceptibility to IDC was investigated in a Japanese study, which failed to detect any
association with the disease itself or its severity (19).
The AGTR1 has been shown to be selectively downregulated in failing left ventricle from patients with endstage heart failure due to IDC, suggesting that the failing
human heart is exposed to increased concentrations of
angiotensin-II (21). Genetic variation at the AGTR1 locus
might then influence susceptibility to cardiomyopathy or
progression of the disease, although this possibility has not
yet been examined. The selection of the two polymorphisms
investigated in the present study (A-153G and A⫹39C)
was based on the fact that they had been previously
suggested to be involved in susceptibility to myocardial
infarction (10,22) and essential hypertension (23).
Aldosterone, whose production is regulated primarily by
the renin–angiotensin system, may have indirect effects on
cardiac structure and function through its role in blood
pressure regulation (24). In addition, aldosterone has direct
effects on the heart in animal studies, including induction of
myocardial hypertrophy and fibrosis (25,26). The CYP11B2
T-344C polymorphism, which is associated with plasma
JACC Vol. 35, No. 1, 2000
January 2000:29–35
aldosterone levels (27), has been shown in a small study to
strongly affect left ventricular size and mass in young adults
free of clinical heart disease (28).
The TNF gene. The hypertrophic response to myocardial
failure may be considered as a generalized inflammatory
response (29). In this line of evidence, several proinflammatory cytokines have been shown to be increased in the
myocardium of subjects with heart failure, among which one
of the most important by its powerful biological effects is
TNF. Levels of this protein are elevated in the circulation of
patients with congestive heart failure (30 –32) and an
increased expression has been observed in the failing human
heart (33–35). Moreover, in transgenic mice, a cardiac
overexpression of TNF produces heart failure and DCM
(36,37). All these findings concur to suggest that TNF may
be an important mediator of cardiac inflammation evolving
to DCM. The G-308A polymorphism was selected because
it had been shown to affect transcriptional activity (38).
The TGFB1 gene. The TGFB1 is another cytokine that
might play an important role in the immune modulation of
cardiac function. It is a known regulator of cardiac fibroblasts and myocyte function. Its release by activated macrophages stimulates cardiac fibrosis and influences cardiac
remodeling, contributing to impairment of myocardial contractility (39,40). The nonsynonymous TGFB1 R25P polymorphism, which affects TGFB1 production in vitro (41),
has been found associated with several diseases, in particular
hypertension (13,42).
The NOS3 gene. Nitric oxide is a powerful vasoactive
molecule produced from L-arginine by three distinct nitric
oxide synthase enzymes. Two constitutively present enzymes are found in neuronal and endothelial cells, respectively, and the third one is inducible in many cell types after
immunological or inflammatory stimuli. The endothelial
isoform NOS3 is also constitutively expressed in cardiac
myocytes (43). Enhanced basal production of nitric oxide
has been reported in patients with heart failure (44 – 46)
while increased activity of inducible nitric oxide synthase
has been found in cardiac tissue from patients with DCM
(34,47– 49). An explanation for these findings might be that
an excessive production of nitric oxide in cardiomyocytes,
when exerted over long periods, might lead to a depression
of myocardial contractility, an important feature of DCM.
A family study recently demonstrated genetic linkage between the level of plasma metabolites of nitric oxide and
markers located in the region of the NOS3 gene (50). This
result suggests that sequence variation in the NOS3 gene
might influence nitric oxide production, and thereby affect
the risk and/or the progression of DCM.
The BNP gene. Brain natriuretic peptide is mainly produced by the ventricles (51) and its secretion has been found
increased in the failing heart in proportion to the severity of
left-ventricular dysfunction (52). Its expression has been
observed primarily in myocytes in the interstitial fibrous area
Tiret et al.
Dilated Cardiomyopathy and Candidate Genes
33
in DCM (53). Plasma levels of BNP are raised in patients
with heart failure (51,54 –56), left-ventricular dysfunction
(57,58), DCM (59) and have a prognostic role in mortality
of patients with congestive heart failure (60).
Power of the study. The CARDIGENE study, including
more than 400 patients with DCM, is the largest study
conducted so far on this topic. Assuming an additive or a
dominant genetic model, the sample size provided a ⱖ80%
power to detect the effect of any polymorphism having a
frequency ⱖ0.1 and associated with an OR for disease ⱖ1.6.
Under a recessive model, polymorphisms with a frequency
ⱖ0.25 and associated with an OR ⱖ2 could be detected.
The power of the study was then adequate to detect
associations of modest magnitude. Moreover, patients were
selected on strict criteria of disease severity, and both
patients and controls had to fulfill conditions of ethnic
homogeneity. In control subjects, there was no difference of
allele frequencies among the three MONICA regions despite their geographical distance (northern, eastern and
southern France), making unlikely a risk of stratification of
the population for the polymorphisms considered.
Several reasons might explain the negative results. The
first one is that the investigated genes, despite being strong
candidates a priori, do not play any significant role in the
pathogenesis of DCM. A second reason might be that the
polymorphisms selected in each gene were not appropriate
and that there exist other unmeasured polymorphisms of
these genes whose effect on disease could not be detected
through linkage disequilibrium with the polymorphisms
studied. However, this explanation is rather unlikely, given
the strong linkage disequilibrium generally observed within
candidate genes. A third explanation might be related to the
heterogeneity of patients with respect to progression of the
disease. In actuality, the sample included both new and old
patients, some of them being followed up for more than 10
years. If the same genetic factor contributed to both the
susceptibility to disease and its mortality, then mixing new
cases and long-term survivors might mask the genetic effect.
This question would have to be addressed in longitudinal
studies.
APPENDIX
CARDIGENE Project Management Group: M. Desnos, Service de Cardiologie, Hôpital Boucicaut, Paris; R. Dorent,
Service de Chirurgie Cardiaque, Groupe Hospitalier PitiéSalpêtrière, Paris; M. Komajda, Service de Cardiologie,
Groupe Hospitalier Pitié-Salpêtrière, Paris; G. Roizès,
INSERM U249, Montpellier; K. Schwartz, INSERM
U523, Paris; L. Tiret, INSERM U525, Paris, France.
CARDIGENE recruitment centers: CHU Ambroise Paré,
Boulogne Billancourt (O. Dubourg); CHU Henri Mondor,
Créteil (F. Paillart); CHR de Lille (A. Millaire); Hôpital
Louis Pradel, Lyon (X. André-Fouët, J. Beaune, P.
Touboul); CHR de Nancy (Y. Juillière); CHR de Nantes
(J-B. Bouhour, N. Chedru); CHU Pitié-Salpêtrière, Paris
34
Tiret et al.
Dilated Cardiomyopathy and Candidate Genes
(R. Dorent, M. Komajda); Hôpital Boucicaut, Paris (M.
Desnos); Hôpital Bichat, Paris (M-C. Aumont); CHR de
Strasbourg (A. Sacrez).
Acknowledgments
We thank Dominique Arveiler (MONICA Strasbourg),
Philippe Amouyel (MONICA Lille) and Jean-Bernard
Ruidavets (MONICA Toulouse) for providing the control
subjects, and Christiane Souriau for DNA extraction.
Reprint requests and correspondence: Dr. Laurence Tiret,
INSERM U525, 17 rue du Fer à Moulin, 75005 Paris, France.
E-mail: [email protected].
JACC Vol. 35, No. 1, 2000
January 2000:29–35
19.
20.
21.
22.
23.
REFERENCES
24.
1. Report of the 1995 WHO/ISFC Task Force on the Definition and
Classification of Cardiomyopathies. Circulation 1996;93:841–2.
2. Michels VV, Moll PP, Miller FA, et al. The frequency of familial
dilated cardiomyopathy in a series of patients with idiopathic dilated
cardiomyopathy. N Engl J Med 1992;326:77– 82.
3. Keeling P, Gang Y, Smith G, et al. Familial dilated cardiomyopathy in
the United Kingdom. Br Heart J 1995;73:417–21.
4. Olson T, Keating M. Defining the molecular genetic basis of idiopathic dilated cardiomyopathy. Trend Cardiovasc Med 1997;7:60 –3.
5. Cambien F, Poirier O, Mallet C, Tiret L. Coronary heart disease and
genetics: an epidemiologist’s view. Mol Med Today 1997;3:197–202.
6. Lander ES. The new genomics: global views of biology. Science
1996;274:536 –9.
7. Tunstall-Pedoe H, on behalf of the WHO MONICA Project. The
World Health Organization MONICA project (MONItoring trends
and determinants in CArdiovascular disease): a major international
collaboration. J Clin Epidemiol 1988;41:105–14.
8. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P,
Soubrier F. An insertion/deletion polymorphism in the angiotensin
I-converting enzyme gene accounting for half the variance of serum
enzyme levels. J Clin Invest 1990;86:1343– 6.
9. Jeunemaitre X, Soubrier F, Kotelevtsev YV, et al. Molecular basis of
human hypertension: role of angiotensinogen. Cell 1992;71:169 – 89.
10. Poirier O, Georges J, Ricard S, et al. New polymorphisms of the
angiotensin-II type 1 receptor gene and their associations with
myocardial infarction and blood pressure: the ECTIM Study. J Hypertens 1998;16:1443–7.
11. White P, Slutsker L. Haplotype analysis of CYP11B2. Endocr Res
1995;21:437– 42.
12. Herrmann SM, Ricard S, Nicaud V, et al. Polymorphisms of the
tumour necrosis factor-␣ gene, coronary heart disease and obesity. Eur
J Clin Invest 1998;28:59 – 66.
13. Cambien F, Ricard S, Troesch A, et al. Polymorphisms of the
transforming growth factor-␤1 gene in relation to myocardial infarction and blood pressure. Hypertension 1996;28:881–7.
14. Bonnardeaux A, Nadaud S, Charru A, Jeunemaitre X, Corvol P,
Soubrier F. Lack of evidence for linkage of the endothelial cell nitric
oxide synthase gene to essential hypertension. Circulation 1995;91:
96 –102.
15. Raynolds MV, Bristow MR, Bush EW, et al. Angiotensin-converting
enzyme DD genotype in patients with ischaemic or idiopathic dilated
cardiomyopathy. Lancet 1993;342:1073–5.
16. Montgomery HE, Keeling PJ, Goldman JH, Humphries SE, Talmud
PJ, McKenna WJ. Lack of association between the insertion/deletion
polymorphism of the angiotensin-converting enzyme gene and idiopathic dilated cardiomyopathy. J Am Coll Cardiol 1995;25:1627–31.
17. Andersson B, Sylvén C. The DD genotype of the angiotensinconverting enzyme gene is associated with increased mortality in
idiopathic heart failure. J Am Coll Cardiol 1996;28:162–7.
18. Sanderson JE, Young RP, Yu CM, Chan S, Critchley JAJH, Woo KS.
Lack of association between insertion/deletion polymorhism of the
angiotensin-converting enzyme gene and end-stage heart failure due to
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
ischemic or idiopathic dilated cardiomyopathy in the Chinese. Am J
Cardiol 1996;77:1008 –10.
Yamada Y, Ichihara S, Fujimura T, Yokota M. Lack of association of
polymorphisms of the angiotensin-converting enzyme and angiotensinogen genes with nonfamilial hypertrophic or dilated cardiomyopathy. Am J Hypertens 1997;10:921– 8.
Candy G, Skudicky D, Mueller U, et al. Association of left ventricular
systolic performance and cavity size with angiontensin-converting
enzyme genotype in idiopathic dilated cardiomyopathy. Am J Cardiol
1999;83:740 – 4.
Asano K, Dutcher DL, Port JD, et al. Selective downregulation of the
angiotensin II AT1-receptor subtype in failing human ventricular
myocardium. Circulation 1997;95:1193–1200.
Tiret L, Bonnardeaux X, Poirier O, et al. Synergistic effects of
angiotensin-converting enzyme and angiotensin-II type 1 receptor
gene polymorphisms on risk of myocardial infarction. Lancet 1994;
344:910 –3.
Bonnardeaux A, Davies E, Jeunemaitre X, et al. Angiotensin-II type 1
receptor gene polymorphisms in human essential hypertension. Hypertension 1994;24:63–9.
White P. Disorders of aldosterone biosynthesis and action. N Engl
J Med 1994;331:250 – 8.
Brilla C, Matsubara L, Weber K. Anti-aldosterone treatment and the
prevention of myocardial fibrosis in primary and secondary hyperaldosteronism. J Mol Cell Cardiol 1993;25:563–75.
Young M, Fullerton M, Dilley R, Funder J. Mineralocorticoids,
hypertension and cardiac fibrosis. J Clin Invest 1994;93:2578 – 83.
Pojoga L, Gautier S, Blanc H, et al. Genetic determination of plasma
aldosterone levels in essential hypertension. Am J Hypert 1998;11:
856 – 60.
Kupari M, Hautanen A, Lankinen L, et al. Association between
human aldosterone synthase (CYP11B2) gene polymorphism and left
ventricular size, mass and function. Circulation 1998;97:569 –75.
Bristow MR. Tumor necrosis factor-␣ and cardiomyopathy. Circulation 1998;97:1340 –1.
Levine B, Kalman J, Mayer L, Fillit H, Packer M. Elevated circulating
levels of tumor necrosis factor in severe chronic heart failure. N Engl
J Med 1990;223:236 – 41.
Dutka D, Elborn J, Delamere F, Shale D, Morris G. Tumour necrosis
factor-alpha in severe congestive heart failure. Br Heart J 1993;70:
141–3.
Katz S, Rao R, Berman J, et al. Pathophysiological correlates of
increased serum tumor necrosis factor in patients with congestive heart
failure: relation to nitric oxide-dependent vasodilation in the forearm
circulation. Circulation 1994;90:12– 6.
Torre-Amione G, Kapadia S, Lee J, et al. Tumor necrosis factor-␣ and
tumor necrosis factor receptors in the failing human heart. Circulation
1996;93:704 –11.
Habib FM, Springall DR, Davies GJ, Oakley CM, Yacoub MH,
Polak JM. Tumor necrosis factor and inducible nitric oxide synthase in
dilated cardiomyopathy. Lancet 1996;347:1151–5.
Satoh M, Nakamura M, Saitoh H, et al. Tumor necrosis factor-alphaconverting enzyme and tumor necrosis factor-alpha in human dilated
cardiomyopathy. Circulation 1999;99:3260 –5.
Bryant D, Becker L, Richardson J, et al. Cardiac failure in transgenic
mice with myocardial expression of tumor necrosis factor-␣. Circulation 1998;97:1375– 81.
Kubota T, McTiernan C, Frye C, et al. Dilated cardiomyopathy in
transgenic mice with cardiac-specific overexpression of tumor necrosis
factor-␣. Circ Res 1997;81:627–35.
Wilson A, Symons J, McDowell T, McDevitt H, Duff G. Effects of a
polymorphism in the human tumour necrosis factor alpha promoter in
transcriptional activation. Proc Natl Acad Sci U S A 1997;94:3195–9.
Lange L, Schreiner G. Immune mechanisms of cardiac disease.
N Engl J Med 1994;330:1129 –35.
Takahashi N, Calderone A, Izzo N, Mäki TM, Marsh J, Colucci W.
Hypertrophic stimuli induce transforming growth factor-␤1 expression in rat ventricular myocytes. J Clin Invest 1994;94:1470 – 6.
Awad M, El-Game A, Hasleton P, Turner D, Sinnott P, Hutchinson
I. Genotypic variation in the transforming growth factor-beta1 gene:
association with transforming growth factor-beta1 production, fibrotic
lung disease, and graft fibrosis after lung transplantation. Transplantation 1998;66:1014 –20.
Li B, Khanna A, Sharma V, Singh T, Suthanthiran M, August P.
Tiret et al.
Dilated Cardiomyopathy and Candidate Genes
JACC Vol. 35, No. 1, 2000
January 2000:29–35
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
TGF-beta1 DNA polymorphisms, protein levels, and blood pressure.
Hypertension 1999;33:271–5.
Balligand J, Cannon P. Nitric oxide synthases and cardiac muscle.
Autocrine and paracrine influences. Arterioscler Thromb Vasc Biol
1997;17:1846 –58.
Habib F, Dutka D, Crossman D, Oakley CM, Cleland JGF. Enhanced basal nitric oxide production in heart failure: another failed
counter-regulatory vasodilator mechanism? Lancet 1994;344:371–3.
Winlaw DS, Smythe GA, Keogh AM, Schyvens CG, Spratt PM,
Macdonald PS. Increased nitric oxide production in heart failure.
Lancet 1994;344:373– 4.
Drexler H, Hayoz D, Munzel T, Just H, Zelis R, Brunner H.
Endothelial function in congestive heart failure. Am Heart J 1996;
126:761– 4.
de Belder A, Radomski M, Why H, et al. Nitric oxide synthase
activities in human myocardium. Lancet 1993;341:84 –5.
Satoh M, Nakamura M, Tamura G, et al. Inducible nitric oxide
synthase and tumor necrosis factor-alpha in myocardium in human
dilated cardiomyopathy. J Am Coll Cardiol 1997;29:716 –24.
Haywood G, Tsao P, von der Leyen H, et al. Expression of inducible
nitric oxide synthase in human heart failure. Circulation 1996;93:
1087–94.
Wang X, Mahaney M, Sim A, et al. Genetic contribution of the
endothelial constitutive nitric oxide synthase gene to plasma nitric
oxide levels. Arterioscler Thromb Vasc Biol 1997;17:3147–53.
Mukoyama M, Nakao K, Hosoda K, et al. Brain natriuretic peptide as
a novel cardiac hormone in humans: evidence for an exquisite dual
natriuretic peptide system, atrial natriuretic peptide and brain natriuretic peptide. J Clin Invest 1991;87:1402–12.
Yasue H, Yoshimura M, Sumida H, et al. Localization and mechanism
53.
54.
55.
56.
57.
58.
59.
60.
35
of secretion of B-type natriuretic peptide in comparison with those of
A-type natriuretic peptide in normal subjects and patients with heart
failure. Circulation 1994;90:195–203.
Tanaka M, Hiroe M, Nishikawa T, Sato T, Marumo F. Cellular
localization and structural characterization of natriuretic peptideexpressing ventricular myocytes from patients with dilated cardiomyopathy. J Histochem Cytochem 1994;42:1207–14.
Cowie MR, Struthers AD, Wood DA, et al. Value of natriuretic
peptides in assessment of patients with possible new heart failure in
primary care. Lancet 1997;350:1349 –53.
Richards A, Crozier I, Yandle T, Espiner E, Ikram H, Nicholls M.
Brain natriuretic factor: regional plasma concentrations and correlations with haemodynamic state in cardiac disease. Br Heart J 1993;
69:414 –7.
Wei C, Heublein D, Perrella M, et al. Natriuretic peptide system in
human heart failure. Circulation 1993;88:1004 –9.
McDonagh T, Robb S, Murdoch D, et al. Biochemical detection of
left-ventricular systolic dysfunction. Lancet 1998;351:9 –13.
Motwani J, McAlpine H, Kennedy N, Struthers A. Plasma brain
natriuretic peptide as an indicator for angiotensin-converting-enzyme
inhibition after myocardial infarction. Lancet 1993;341:1109 –13.
Yoshimura M, Yasue H, Okumura K, et al. Different secretion
patterns of atrial natriuretic peptide and brain natriuretic peptide in
patients with congestive heart failure. Circulation 1993;87:464 –9.
Tsutamoto T, Atsuyuki W, Maeda K, et al. Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic
heart failure: prognostic role of plasma brain natriuretic peptide
concentration in patients with chronic symptomatic left ventricular
dysfunction. Circulation 1997;96:509 –16.