Length Polymorphisms in the Angiotensin I-Converting Enzyme Gene and the Serotonin-Transporter-Linked Polymorphic Region Constitute a Risk Haplotype for Depression in Patients with Coronary Artery Disease

For The Spirr-Cad Investigators ,Thomas Meyer,Stella V Fangauf,Katja Petrowski,Hans-Christian Deter,Joram Ronel,Matthias Michal,Christian Albus,Isabel Rothe,Julia Staab,Martina De Zwaan,Christoph Herrmann-Lingen,Jana Jünger,Wolfgang Söllner,Stefanie Hamacher,Redford B Williams,Cora Weber,Karl-Heinz Ladwig,Martin Hellmich

doi:10.1007/s10528-020-09967-w

Abstract

Genetic variations affecting the course of depressive symptoms in patients with coronary artery disease (CAD) have not yet been well studied. Therefore, we set out to investigate whether distinct haplotypes of the two insertion/deletion polymorphisms in the serotonin-transporter-linked polymorphic region (5-HTTLPR) and the angiotensin I-converting enzyme (ACE) gene located on chromosome 17 can be identified as risk factors for trajectories of depression. Clinical and genotyping data were derived from 507 depressed CAD patients participating in the randomized, controlled, multicenter Stepwise Psychotherapy Intervention for Reducing Risk in Coronary Artery Disease (SPIRR-CAD) trial, of whom the majority had an acute cardiac event before study inclusion. Depression scores on the Hospital Anxiety and Depression Scale (HADS) were assessed at baseline and at five follow-up time points up to 2 years after study entrance. At baseline, depression scores did not significantly differ between patients carrying the risk haplotype ACE D/D, 5-HTTLPR I/I (n = 46) and the non-risk haplotypes (n = 461, 10.9 ± 2.7 versus 10.4 ± 2.5, p = 0.254). HADS-depression scores declined from study inclusion during the first year irrespective of the genotype. At each follow-up time point, HADS-depression scores were significantly higher in ACE D/D, 5-HTTLPR I/I carriers than in their counterparts. Two years after study inclusion, the mean HADS depression score remained 1.8 points higher in patients with the risk haplotype as compared to subjects not carrying this haplotype (9.9 ± 4.2 versus 8.1 ± 4.0, p = 0.009). In summary, the presence of the ACE D/D, 5-HTTLPR I/I haplotype may be a vulnerability factor for comorbid depressive symptoms in CAD patients.

Highlights

In patients hospitalized for coronary events including acute myocardial infarction, depressive symptoms are common and have been linked to higher mortality (Lichtman et al 2014)
Repeated-measures ANOVA revealed a significant effect of time (p < 0.001), but no significant interaction term between time and risk genotype (p = 0.416). This genetic study assessed the associations between two common functional polymorphisms in genes expressed in the central nervous system and trajectories of depressive symptoms in moderately depressed coronary artery disease (CAD) patients
The length polymorphisms in the serotonin transporter (SERT) and the angiotensin I-converting enzyme (ACE) gene are both located in non-coding gene regions and known to modulate the expression rate of their corresponding gene products

Summary

Introduction

In patients hospitalized for coronary events including acute myocardial infarction, depressive symptoms are common and have been linked to higher mortality (Lichtman et al 2014). Latent class analysis has identified different long-term trajectories of depression in the context of comorbid coronary artery disease (CAD), both following an acute cardiac event and in stable disease (Kaptein et al 2006; Martens et al 2008; Romppel et al 2012). Numerous studies have implicated putative biomarkers in the development of CAD-associated comorbid depression, which have broadened our understanding of the underlying pathophysiological pathways. Genetic variants significantly associated with depressive symptoms in CAD patients include mutations in genes resulting in impaired functioning of the serotoninergic system (Otte et al 2007; Kim et al 2015, 2017)

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Conclusion