Association Between a Serotonin Transporter Gene Variant and Hopelessness Among Men in the Heart and Soul Study
Kirsten Neudoerffer Kangelaris
1
2
3
4
Eric Vittinghoff
0
2
Christian Otte
2
5
Beeya Na
0
2
Andrew D. Auerbach
1
2
Mary A. Whooley
2
3
6
0
Department of Epidemiology and Biostatistics, University of California
,
San Francisco, San Francisco, CA, USA
1
Division of Hospital Medicine, University of California
,
San Francisco, San Francisco, CA, USA
2
Findings were presented at the Annual Society of General Internal Medicine meeting on May 14
, 2009 in Miami,
Florida
3
Department of Medicine, Division of General Internal Medicine, University of California
,
San Francisco, San Francisco, CA, USA
4
Parnassus Ave UC Hall,
University of California
,
San Francisco, San Francisco, CA, USA
5
Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf
, Hamburg,
Germany
6
Division of General Internal Medicine, Veterans Affairs Medical Center
,
San Francisco, San Francisco, CA, USA
BACKGROUND: Hopelessness is associated with mortality in patients with cardiac disease even after accounting for severity of depression. We sought to determine whether a polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) is associated with increased hopelessness, and whether this effect is modified by sex, age, antidepressant use or depression in patients with coronary heart disease. METHODS: We conducted a cross-sectional study of 870 patients with stable coronary heart disease. Our primary outcomes were hopelessness score (range 0-8) and hopeless category (low, moderate and high) as measured by the Everson hopelessness scale. Analysis of covariance and ordinal logistic regression were used to examine the independent association of genotype with hopelessness. RESULTS: Compared to patients with l/l genotype, adjusted odds of a higher hopeless category increased by 35% for the l/s genotype and 80% for s/s genotype (p-value for trend=0.004). Analysis of covariance demonstrated that the effect of 5-HTTLPR genotype on hopelessness was modified by sex (.04), but not by racial group (p= 0.63). Among men, odds of higher hopeless category increased by 40% for the l/s genotype and by 2.3-fold for s/s genotype (p-value p<0.001), compared to no effect in the smaller female sample (p= 0.42). Results stratified by race demonstrated a similar dose-response effect of the s allele on hopelessness across racial groups. CONCLUSIONS: We found that the 5-HTTLPR is independently associated with hopelessness among men with cardiovascular disease.
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Hopelessness, defined as a sense of futility and negative future
orientation, is associated with worse medical outcomes14.
Among patients with cardiovascular disease, hopelessness
predicts incident myocardial infarction and cardiovascular
mortality2. Although it is widely accepted that hopelessness is a
typical feature of depression5, there is substantial evidence for
the functional independence of hopelessness and depression6,7.
Furthermore, hopelessness is more common than depression1,2,
and the strength of the association between hopelessness and
adverse cardiovascular outcomes has been found to be distinct
from and stronger than that associated with depression1,8.
Several factors impact patients sense of hope, including
socioeconomic status, family support, severity of illness and
comorbidities. Genetic predisposition is also likely to play a role,
and in recent years, there has been increased interest in
investigating the genetic component of both psychiatric
disorders and healthy psychiatric characteristics. A breakthrough
in this research has been the description of the short (s) allele of
5-HTTLPR (serotonin transporter length polymorphic region), a
common functional polymorphism in the promoter region of the
serotonin transporter gene (SLC6A4). Compared to the longer (l)
allele variant, the s allele results in less efficient transcription of
the serotonin transporter gene9,10, increased cardiac
reactivity11, and it has been associated with less resilience to the
depressogenic effects of adverse life events12, poorer response to
selective serotonin reuptake inhibitor (SSRI) antidepressant
therapy13, and with clinical and subclinical depression1423.
Previously, Otte and colleagues found that the short allele of
5-HTTLPR predicted major depressive disorder, higher perceived
stress, and norepinephrine secretion in the Heart and Soul
Study22. However, the association between the 5-HTTLPR
polymorphism and depression has more recently been called
into question, with a meta-analysis demonstrating no evidence
of interaction between the s allele and stressful life events on
development of depression24. Given the heterogeneity of
depression, one possible explanation for these discordant results is
that 5-HTTLPR may be associated with some aspects of
depression, and not with others. For example, Gonda and
colleagues15 recently described an association between the s
allele of 5-HTTLPR and several elements of neuroticism-related
traits including anxiety, depressi (...truncated)