Association Between a Serotonin Transporter Gene Variant and Hopelessness Among Men in the Heart and Soul Study

Journal of General Internal Medicine, Oct 2010

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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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. - 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)


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Kirsten Neudoerffer Kangelaris MD, Eric Vittinghoff PhD, Christian Otte MD, Beeya Na MPH, Andrew D. Auerbach MD, Mary A. Whooley MD. Association Between a Serotonin Transporter Gene Variant and Hopelessness Among Men in the Heart and Soul Study, Journal of General Internal Medicine, 2010, pp. 1030-1037, Volume 25, Issue 10, DOI: 10.1007/s11606-010-1403-0