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Angiotensin I-converting enzyme ID polymorphism and suicidal behaviors.

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Neuropsychiatric Genetics
Angiotensin I-Converting Enzyme I/D Polymorphism
and Suicidal Behaviors
D. Larry Sparks,1 John C. Hunsaker III,2 Philippe Amouyel,3,4* Alain Malafosse,5,6 Franck Bellivier,7,8,9
Marion Leboyer,7,8,9 Philippe Courtet,6,10,11 and Nicole Helbecque3
Sun Health Research Institute, Sun City, Arizona
Division of Medical Examiner’s Services, Kentucky Justice Cabinet, Frankfort, Kentucky
INSERM, U744, Lille, France; Institut Pasteur de Lille, Lille, France; University of Lille 2, Lille, France
Centre Hospitalier et Universitaire de Lille, Lille, France
Department of Medical Genetics and Development, School of Medicine, Geneva, Switzerland
INSERM, U888; University of Montpellier I, Montpellier, France
INSERM, U841; IMRB, Department of Genetics, Psychiatry Genetics, Creteil, France
Universite Paris 12, Faculty of Medicine, IFR10, Creteil, France
AP-HP, Groupe Henri Mondor-Albert Chenevier, Departement Hospitalo-Universitaire de Psychiatrie, Creteil, France
University of Montpellier I, Montpellier, France
Department of Psychological Medicine and Psychiatry, Lapeyronie Hospital, University Hospital of Montpellier, Montpellier, France
Received 27 February 2008; Accepted 28 April 2008
Suicide is one of the ten most common causes of death in Western
countries. It involves genetic vulnerability factors and is often
associated with major depression. A Japanese team reported an
association between the insertion allele of the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism with completed suicide. The ACE I/D polymorphism was
investigated in two independent case-control studies, one involving 64 suicide completers and 90 controls who all underwent
forensic investigations, the second one consisting of 588 suicide
attempters and 639 controls. In the two population samples
studied a statistically significant risk of suicidal behavior was
observed for subjects bearing the DD genotype. These results
suggest a possible role of the renin-angiotensin system in suicidal
behavior. 2008 Wiley-Liss, Inc.
Key words: angiotensin-converting enzyme; association study;
genetics; suicide
In Western countries, suicide is the first cause of death among
people aged 25–34 years and the second cause of death among 15- to
24-year-old and college students. Each year there are 500,000
suicide attempts in the US and 220,000 in France. Worldwide,
1.8% of all deaths are due to suicide and psychiatric illness is
involved in more than 90% of cases [Mann, 2003]. Mood disorders,
more particularly in combination with drug abuse or alcohol, are by
far the most common psychiatric disorders leading to suicide
[Jamison, 2000]. Patients with bipolar disorders, particularly during depressive episodes, have a high risk of committing suicide
[Angst et al., 1999]. For instance among patients with manic
depressive illness the rate of suicide attempts varies between
2008 Wiley-Liss, Inc.
How to Cite this Article:
Sparks DL, Hunsaker JC, Amouyel P,
Malafosse A, Bellivier F, Leboyer M, Courtet
P, Helbecque N. 2009. Angiotensin IConverting Enzyme I/D Polymorphism and
Suicidal Behaviors.
Am J Med Genet Part B 150B:290–294.
24% and 50% [Jamison, 2000]. The treatment of depression usually
involves the classical tricyclic drugs, monoamine oxidase inhibitors, and selective serotonin-reuptake inhibitors. Angiotensinconverting enzyme (ACE) inhibitors have also been reported
effective in the treatment of depression [Bosio et al., 1990; Michalsen et al., 2001; Braszko et al., 2003]. This observation is sustained by
animal models: mice lacking angiotensinogen showed a reduction
of depressive-like behavior [Okuyama et al., 1999].
Affective disorders, particularly bipolar disorders, are linked with
cardiac mortality, suggesting an association between hypertension
Grant sponsor: Suiss National Foundation; Grant number: #32-112084.
*Correspondence to:
Prof. Philippe Amouyel, Service d’Epidemiologie et de Sante Publique,
INSERM, U744, Institut Pasteur de Lille, 1 rue Calmette, BP 245, 59019 Lille
Cedex, France. E-mail:
Published online 2 June 2008 in Wiley InterScience
DOI 10.1002/ajmg.b.30793
and a variety of symptoms, such as anxiety or depression [Rudisch
and Nemeroff, 2003]. Hypertensive subjects receiving ACE inhibitors reported general well-being and increased work performances
after 6 months of treatment, suggesting a possible impact on mood
[Testa et al., 1993]. Conversely other hypotensive drugs did not
exhibit such effects, prompting us to look at possible relationships
between the renin-angiotensin system (RAS) and mood disorders.
ACE belongs to the RAS whose components are detected in
the central nervous system [Phillips et al., 1979]. Previously
angiotensin-receptor blockers were identified as a possible risk
factor for suicide (OR ¼ 3.52) [Callreus et al., 2007]. ACE generates
angiotensin-II, a potent vasoconstrictor, from its precursor angiotensinogen and degrades bradykinin a vasodilator. The circulating
and cellular levels of ACE are partly genetically determined through
an insertion (I)/deletion (D) genetic polymorphism located in
intron 16 of the gene: subjects bearing the D allele have higher
levels of enzyme than the I allele bearers [Rigat et al., 1990]. This
polymorphism has been associated with completed suicide in
Japanese subjects [Hishimoto et al., 2006]. In this work we tested
a possible association of this polymorphism in two independent
population samples, one including 64 suicide completers, the other
dealing with 588 suicide attempters.
Study 1 included 154 subjects selected from a population of
unrelated Americans who all underwent forensic evidences
(Table I). Sixty-four of them committed suicide. Controls
(n ¼ 90) were individuals without cardiovascular problems detected at autopsy. Due to the limited number of subjects who
underwent autopsy, we included subjects aged less than 35 years in
our control population sample, although suicide is rather frequent
in this age range. Suicide attempts were classified as violent according to the criteria proposed by Asberg et al. [1986]. Hanging
attempts, the use of firearms, and drowning were classified as
violent attempts; drug overdoses or poisoning were considered to
be non-violent suicide attempts.
Study 2 included 588 patients consecutively admitted to psychiatric departments after a suicide attempt and 639 healthy controls
without cardiovascular problems recruited in a general population
(Table I). In order to minimize their morbid risk by suicide, only
controls older than 35 years were included. All subjects gave
informed consent. A suicide attempt was defined as intentional
self-harm that was not self-mutilatory in nature and required
medical evaluation and treatment in an emergency or intensive
care unit [Mann, 1998]. Suicide attempts were classified as violent
according to the criteria proposed by Asberg et al. [1986]. For all
TABLE I. Characteristics of the Two Populations Studied
Males (%) Age (years)a Caucasians (%)
Study 1
Controls (n ¼ 90)
Suicide (n ¼ 64)
Study 2
Controls (n ¼ 639)
Suicide (n ¼ 588)
Mean SD.
57 19
41 17
45 5
39 12
patients, we investigated whether there was a past history of violent
suicide attempts. Concerning the control group, no information
concerning psychiatric illness or previous suicide attempts had
been collected. Patients with a history of violent suicide attempts
were classified as violent suicide attempters, regardless of the nature
of the current suicide attempt. All patients were interviewed by
trained psychiatrists or psychologists, using the French version of
the Mini International Neuropsychiatric Interview (MINI). Lifetime diagnosis (DSM-IV-TR) were made by the interviewer and
then blindly rated by an independent psychiatrist according to
medical case notes and MINI. Eighty two percent of the suicide
attempters suffered from depression, 10% from bipolar disorders,
2% from schizophrenia, 2.8% from various psychiatric pathologies,
and 3.2% from none. To minimize population heterogeneity, we
ensured that both the patients and controls were entirely of West
European Caucasian origin for at least two generations. The study
was approved by the institutional ethics committees.
Genomic DNA was extracted from postmortem brain samples
(study 1) using phenol-chloroform or from blood samples collected
into ethylenediaminetetraaceticacid (EDTA)-treated tubes (study
2) using a salt-out procedure [Parra et al., 1992]. All tissues analyzed
in study 1 were collected as part of the routine coroner authorized
autopsy procedure. ACE polymorphism was detected as previously
described, except for addition of dimethylsulfoxide (DMSO) to
enhance amplification of the I allele [Fogarty et al., 1994]. The
laboratory personnel were blind to clinical information concerning
the subjects tested. All gel results were analyzed by two different
Statistical analyses were conducted with the SAS Software release
8.0 (SAS Institute, Inc., Cary, NC). Differences between groups of
suicide victims (or attempters) and control subjects were assessed
using Pearson’ c2 The relationship between suicidal behavior or
completed suicide and ACE genotype was examined using multiple
linear regression models and adjusted systematically for gender and
age (and ethnic origin for study 1). Statistical interactions between
ACE genotype and covariates were systematically explored. The
relative risks were estimated from this multivariate analysis by
the odds ratios (OR) with their 95% confidence intervals. Significance levels were set at P < 0.05.
Table I presents the main characteristics of the two populations
studied and Table II shows the genotype distribution and allele
frequencies of the ACE I/D polymorphism in suicide victims or
suicide attempters and control subjects in the two independent
studies. They were in Hardy–Weinberg equilibrium in all samples.
For study 1 (completed suicide) a weak statistically significant
difference was observed in genotype (P ¼ 0.05) and allele (P ¼ 0.04)
frequencies between cases and controls (Table II). The relative risk
for completed suicide (as expressed by the odds ratio OR) was 2.4
(95% CI ¼ 1.2–4.8) (DD vs. II þ ID bearers) (P ¼ 0.02). After
adjustment for confounding variables (age, gender, and ethnicity
when necessary), the risk of suicide was significant for DD genotype
bearers (Table III). No statistically significant interaction with
covariate was found in this population sample.
For study 2 (suicide attempts) a statistically significant difference
was observed in allele (P ¼ 0.02) frequencies between cases and
controls, whereas there was only a trend for genotype frequencies
(P ¼ 0.06) (Table II). The relative risk for attempting suicide for DD
TABLE II. Distribution of the ACE I/D Polymorphism in Suicide Victims or Suicide Attempters and Control Subjects
Genotypes (n, %)
Study 1
Control subjects
Suicide victims
Violent suicide
Non violent suicide
Caucasian control subjects
Caucasian suicide victims
Study 2
Control subjects
Suicide attempters
Violent suicide
Non violent suicide
Alleles (n, %)
20 (22.2)
26 (40.6)
20 (37.0)
6 (60.0)
19 (23.8)
24 (39.3)
50 (55.6)
27 (42.2)
25 (46.3)
2 (20.0)
43 (53.7)
27 (44.3)
20 (22.2)
11 (17.2)
9 (16.7)
2 (20.0)
18 (22.5)
10 (16.4)
189 (29.6)
209 (35.5)
55 (35.5)
136 (35.4)
315 (49.3)
276 (46.9)
70 (45.2)
184 (47.9)
135 (21.1)
103 (17.5)
30 (19.3)
64 (16.7)
90 (50.0)
79 (61.7)
65 (60.2)
14 (70.0)
81 (50.6)
75 (61.5)
90 (50.0)
49 (38.3)
43 (39.8)
6 (30.0)
79 (49.4)
47 (38.5)
693 (54.2)
694 (59.0)
180 (58.1)
456 (59.4)
585 (45.8)
482 (41.0)
130 (41.9)
312 (40.6)
a 2
c exact test.
genotype bearers was 1.3 (95% CI ¼ 1.0–1.7, P ¼ 0.03). After
adjustment for confounding variables (age and gender), the risk
of suicide was significant for DD genotype bearers (Table III) and
the OR was similar when excluding subjects suffering from schizophrenia, whose genotype distribution differed widely from the
others. No statistically significant interaction with covariate was
From the results presented here dealing with two independent
population samples, Caucasians bearing the ACE DD genotype are
at risk for suicide. This is in accordance with a previous observation
of an increase of ACE activity in the substantia nigra of suicide
completers [Arregui et al., 1980].
The ACE I/D genotype distribution observed in controls from
study 1 is rather unusual, when compared to values previously
published in various population samples. However it did not differ
when excluding black subjects from the sample (Table II) and
remained balanced when taking the same cut-off for controls (35
years) as in study 2 (36 years and over: 18 DD, 40 ID, 17 II). The
statistical power in study 1 was 83.3% to detect an OR of 2.8 (the one
observed after adjustment in the global population in study 1).
When considering only Caucasians in the calculations, the statistical power was 71.2% to detect an OR of 2.5 (the one observed after
adjustment in the Caucasian subsample in study 1). A previous
work reported an impact of the I allele on suicide completion in
Japanese male subjects [Hishimoto et al., 2006], a result opposite to
our findings. The observed discrepancy could be explained (i) by
differences in genotype distribution of the ACE I/D polymorphism
between Japanese and Caucasian populations [Ishigami et al., 1995]
or (ii) by the fact that ACE should be in linkage disequilibrium with
another gene which is truly associated to suicide.
Subjects attempting suicide are usually depressed. Although in
study 2 the ACE genotype distribution in the group of suicide
attempters was similar whatever the psychiatric disease they suffered from (except for schizophrenia), it is interesting to note that
the majority of them (82%) suffered from major depression.
Several hypotheses could explain the observed association between the ACE I/D polymorphism and the risk of suicide. ACE
colocalized with substance P-containing neurons in brain regions
TABLE III. Odds Ratios for the ACE I/D Polymorphism in the Two Populations
Study 1
Violent suicide
Caucasian subjects
Study 2
Violent suicide
Non violent suicide
ID vs. II OR
(95% CI)
D vs. Ia OR
(95% CI)
2.8 (1.3–6.4)b
2.4 (1.0–5.7)b
2.5 (1.1–5.8)c
1.6 (1.0–2.6)
1.5 (0.9–2.5)
1.6 (0.9–2.6)
1.3 (1.0–1.7)c
1.2 (0.8–1.9)c
1.3 (0.9–1.8)c
1.2 (1.0–1.4)
1.2 (0.9–1.5)
1.2 (1.0–1.5)
DD vs. II þ ID OR
(95% CI)
2.8 (1.0–8.2)b
2.6 (0.8–8.0)b
2.8 (0.9–8.5)c
1.5 (1.1–2.1)c
1.1 (0.7–1.9)c
1.6 (1.1–2.4)c
DD vs. II OR
(95% CI)
1.0 (0.4–2.6)b
1.1 (0.4–3.0)b
1.2 (0.4–3.2)c
1.2 (0.9–1.7)c
0.9 (0.5–1.4)c
1.4 (0.9–2.0)c
Due to the low number of subjects, ORs were not calculated in the case of non violent suicide for study 1.
ORs without any adjustment.
ORs are adjusted for age, sex, and ethnicity.
ORs are adjusted for age and sex.
that coordinate stress responses. In guinea pigs and humans
substance P antagonists have been shown to exert antidepressant
effects [Kramer et al., 1998]. An increase in ACE levels associated
with the DD genotype [Arinami et al., 1996] will lead to an increase
in substance P and thus of stress and/or anxiety, possibly increasing
the risk of suicide [Ebner and Singewald, 2006].
Another mechanism involves serotonin, a neurotransmitter
which has been implicated in psychiatric disorders, particularly
mood disorders. Serotonin may also induce vasoconstriction in
patients either directly [Hillis and Lange, 1991] or through amplification of the release and activity of other vasoconstrictors, such as
angiotensin II. Previous reports of an association between suicide
and a functional polymorphism in the regulatory region of the
serotonin transporter gene [Anguelova et al., 2003; Helbecque et al.,
2006], already known to be associated with bipolar disorders, are
in favor of this mechanism, suggesting an association between
depression and/or suicide and vasoconstriction.
Previous investigations have suggested some links between depression and cardiovascular mortality. This hypothesis is sustained
by animal models. ACE-deficient mice have low blood pressure
[Esther et al., 1996] and mice lacking angiotensinogen show a
reduction of depressive-like behavior [Okuyama et al., 1999],
suggesting a possible link between angiotensinogen or its metabolites and depression. Angiotensinogen and ACE are part of the
RAS. In vivo studies in rats have shown that ACE interferes with the
secretion of pituitary hormones such as corticotropin (ACTH) and
potentiates the stimulatory effects of corticotropin releasing hormone (CRH) [Jezova et al., 1998], suggesting that the brain RAS is
involved in the regulation of the hypothalamic-pituitary-adrenal
(HPA) axis [Aguilera et al., 1995]. Dysregulation of the activity of
the HPA system is one of the major neuroendocrine abnormalities
observed in depression. An increase in ACE levels associated with
the DD genotype will lead to an hyperactivation of the HPA axis
response [Baghai et al., 2002]. This in turn could be associated with
a higher risk of suicide as previously suggested by Mann [2003].
In humans, the observed association between the ACE I/D
polymorphism and the risk of suicide could involve angiotensin
itself or the angiotensin type 1 receptor (AGTR1) [Callreus et al.,
2007]. The use of ACE inhibitors may be of benefit as an antidepressant treatment strategy. The antidepressant activity may be
related to reduced angiotensin II activity since ACE inhibitors
which elevate mood in depressed patients reduce angiotensin II
production. A previous study suggested that the ACE D allele,
associated with higher ACE levels, might be associated with a
positive outcome of various antidepressant therapies, at least in
major depressed women [Baghai et al., 2004]. On the other hand
antidepressant drugs induce a reduction of responses to angiotensin II, their effect being at the AGTR1 [Gard et al., 1999]. These
drugs may act either directly or by interference with post-receptor
events. A genetic A1166C polymorphism located in the 30 -nontranslated region of the AGTR1 gene, was associated with hypertension [Baudin, 2005], and subjects bearing the CC genotype
respond better to an antidepressant treatment than the others
[Bondy et al., 2005]. However no significant differences in genotype
or allele frequencies of this polymorphism have been observed
between cases and controls in our population samples (data not
shown), neither in the Japanese study [Hishimoto et al., 2006].
These findings still reinforce the existence of common genetic
factors for depression and cardiovascular disease [Bondy, 2007].
Although the underlying mechanism is still unknown, recent
studies suggest that gene–gene or gene–environment interactions
must be investigated in order to delineate more precisely the impact
of each component.
Our study has several limitations, in particular the small number
of subjects in study 1, due to the difficulty to recruit suicide victims.
However results from this preliminary study were confirmed by
study 2, suggesting a potential role of the ACE DD genotype on
the risk of suicide. Another limitation relies on the fact that
suicide attempters in study 2, although well characterized from a
psychiatric point of view, were not characterized concerning their
cardiovascular status, opposite to the controls in study 2 or to the
whole population in study 1. Nevertheless our results suggest that
the ACE DD genotype bearers have an elevated risk of suicidal
behavior. Further replication studies are needed to confirm this
We thank Mrs V. Codron and Mrs C. Buresi for technical assistance,
and Mrs C. Laurent and Mrs C. Ngo Ton Sang for data collection.
This work was supported by grant from the Suiss National Foundation (# 32-112084 to Pr A. Malafosse).
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