Brain‑derived neurotrophic factor gene polymorphisms are associated with coronary artery disease‑related depression and antidepressant response
- Authors:
- Published online on: October 14, 2014 https://doi.org/10.3892/mmr.2014.2638
- Pages: 3247-3253
Abstract
Introduction
Coronary artery disease (CAD) is a leading cause of death in developed countries, with an annual mortality rate of >7 million (1). Up to 20% of patients with CAD meet the Diagnostic and Statistical Manual of Mental Disorders-IV criteria (DSM-IV) for major depression (MD), which is reported to be associated with adverse cardiac outcomes (1,2).
Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family of growth factors, promotes survival, differentiation and maintenance of neurons in the nervous system (3). Previous studies have revealed the importance of BDNF in the development of the cardiac vasculature, including evidence that BDNF promotes angiogenesis (4), enhances vascular flow and regulates revascularization of ischemic tissue (5). Recently, clinical studies have demonstrated that BDNF is associated with coronary atherosclerosis and unstable angina, and experimental studies have revealed that BDNF may contribute to plaque instability in CAD, since it enhances the activity of local nicotinamide adenine dinucleotide (phosphate) oxidase and superoxide production (6). In addition to its association with CAD, BDNF is also reported to be associated with the pathogenesis of MD (7). For example, one study identified that in animal models of depression, the level of BDNF was decreased during hippocampal formation (8). Furthermore, the mRNA level of BDNF is lower in the hippocampus and anterior cingulate cortex in MD patients compared with healthy controls (9).
A number of single nucleotide polymorphisms (SNPs) have been identified in the BDNF gene, including rs13306221 in the promoter region (10), rs56164415 in intron 2 (11), rs6265 in exon 4 (12) and rs16917204 in the 3′-untranslated region (UTR) (13). All of these SNPs are reported to be associated with the expression of the BDNF protein. A recent meta-analysis revealed that the A allele carriers had an increased risk for geriatric depression (14). The putative promoter region contains a SNP rs13306221 (712 bp upstream of the first exon) that is associated with substance dependence (10) and MD patients (15). The rs16917204 polymorphism in the 3′-UTR of BDNF has also been associated with Alzheimer’s disease-related depression (16). Previously, a case-control study demonstrated evidence of an association between the rs6265 polymorphism and coronary artery disease-related depression (CAD-D) (17).
In view of the crucial role of the BDNF gene in CAD and MD, the aim of this study was to elucidate the potential association of seven BDNF polymorphisms with CAD-D and treatment response to selective serotonin reuptake inhibitors (SSRIs).
Materials and methods
Subjects
The subjects were consecutively recruited from The First Hospital Affiliated to Xinxiang Medical College between May 2006 and March 2013, including 616 CAD without depression (CAD-nD) patients (the mean ± SD age, 61.6±5.6 years). The patients with CAD-D were recruited as follows: First, the CAD patients in The First Hospital Affiliated to Xinxiang Medical College received the laboratory examinations including, coronary angiography, electrocardiogram (EKG), blood tests and/or stress tests. The interview and response was also performed on the patients. Coronary angiography was conducted in all patients. Inclusion criteria were as follows: (i) Patients had at least one diseased vessel (≥50% stenosis) in the coronary angiograph; (ii) patients with chronic stable angina pectoris (SAP) had effort ischemic symptoms which lasted for at least three months and a positive stress test; (iii) patients with unstable angina pectoris (UAP) had chest discomfort or other ischemic symptoms at rest or in a progressive crescendo pattern without a rise in biomarkers of myocardial necrosis; (iv) patients presented with transient ST-T segment depression and T-wave inversion, with a typical elevation in biomarkers of myocardial necrosis; (v) patients with acute myocardial infarction (AMI) presented with ischemic symptoms and with ST-segment elevations persistent and ST-segment elevation on EKG. The majority of these patients would exhibit a typical elevation in the biomarkers of myocardial necrosis. Secondly, the MD of the CAD patients was diagnosed with structured clinical interviews, based on DSM-IV criteria for MD. Depressive symptoms were classified using the 24-item Hamilton Depression Rating Scale (HAMD). The patients who had a minimum score of 20 on the HAMD scale were included. Finally, 155 subjects with CAD-D (the mean ± SD age, 62.2±6.8 years) met the DSM-IV criteria. The present study was performed according to the Guidelines of the Medical Ethical Committee of Xinxiang Medical College. Written informed consent was obtained from all individuals involved.
Treatment
The treatment response of patients was evaluated using HAMD. Participants who exhibited at least three symptoms according to the DSM-IV criteria (n=155) received antidepressant treatment with sertraline (150 mg/day for 8 weeks). Five patients did not complete the sertraline treatment. On the contrary, 616 CAD-nD patients received standard care but no antidepressants. Patient response was assessed at the end of the 8 week treatment. The patients with a HAMD score at ≤7 or a 50% improvement were considered to be remittent.
Genotyping
The relative genomic locations of the BDNF gene with a genomic size of 67.2 kb and selected SNPs are illustrated in Fig. 1. Peripheral blood was drawn from a vein into a sterile tube containing ethylenediamine tetraacetic acid (EDTA). Plasma samples were stored at −20°C. Genomic DNA was extracted from the frozen peripheral blood samples using a QIAamp Blood Mini kit (Qiagen Inc., Valencia, CA, USA) according to the manufacturer’s instructions. Genotyping was performed for all SNPs using the MassARRAY platform (Sequenom, San Diego, CA, USA). Primer extension and PCR were conducted according to the manufacturer’s instructions, using iPLEX enzyme (Sequenom) and HotStarTaq DNA polymerase (Qiagen, Hilden, Germany). The resulting spectra were processed with the MassARRAY RT software (version 3.0.0.4) and genotype data was analyzed using the MassARRAY Typer software (version 3.4; Sequenom).
Statistical analysis
The data were analyzed using SPSS 16.0 (SPSS, Inc, Chicago, IL, USA). Hardy-Weinberg equilibrium (HWE) for the distributions of genotypes was estimated by chi-square (χ2) tests. The potential association between CAD-D and each polymorphism was analyzed using Fisher’s exact tests or χ2 tests. The odds ratio (OR) and 95% confidence interval (CI) were used to measure the strength of the association between allele frequencies and the BDNF gene. Bonferroni correction was used in multiple tests and the P-value was divided by the total number of loci or haplotypes. Pair-wise linkage disequilibrium statistics (D′ and r2) and haplotype frequencies were computed using Haploview 4.0 to construct haplotype blocks.
Results
Demographic and clinical characteristics
The demographic and clinical characteristics were compared between the CAD-D participants and CAD-nD participants (Table I). A higher frequency of suicide attempts and increased HAMD scores were observed in CAD-D patients than in CAD-nD participants. LD analyses of the participants and CAD-nD subjects revealed that two SNPs (rs16917204 and rs6265) were located in haplotype block 1 (D′ >0.9; Fig. 2).
 | Table IDemographic and clinical characteristics in CAD-nD patients (n=616) and CAD-D patients (n=155). |
Genotype distribution
The genotype distribution of the seven polymorphisms was consistent with HWE. The genotype distribution and allele frequencies of the seven SNPs are listed in Table II. The distribution of haplotype frequencies is listed in Table III.
| Table IIGenotype and allele frequencies of the BDNF gene polymorphisms in CAD-D patients (n=616) and CAD-nD patients (n=155), and their associated risk. |
| Table IIIBDNF haplotype in block 1 frequencies and the results of their associations with risk of CAD-D. |
The frequency of the A allele of rs6265 was significantly higher in CAD-D patients than in the CAD-nD subjects (χ2=9.634, P=0.002, OR=1.486, 95% CI=1.156–1.910; P<0.007, after Bonferroni correction). Another potential association was observed for rs13306221 (P=0.019, after Bonferroni correction). The CAD-D subjects had a significantly higher frequency of the G allele of rs13306221 but did not pass the threshold value (χ2=5.194, P=0.023, OR=2.139, 95% CI=1.096–4.175). Strong linkage disequilibrium was observed in block 1 (rs16917204, rs6265; D′>0.9). However, significant linkage disequilibrium was not observed between the seven SNPs in the sample population.
Correlation between rs6265 and antidepressant treatment
We further examined the association between rs6265 and response to SSRIs. The rate of remission following the sertraline treatment was significantly higher in the subjects carrying the rs6265 A allele in CAD-D patients (χ2=8.942, P=0.003, OR=2.136, 95%CI=1.293–3.528; Table IV).
| Table IVGenotype and allele frequency of the BDNF gene rs6265 polymorphism responded to sertraline (Rs=105, Non-Rs=45). |
Discussion
Of the 771 CAD participants in this study, 155 (20.10%) had prominent depressive symptoms, a prevalence that is consistent with previous studies (1,2). In the present study, we revealed that the A allele of rs6265 was overexpressed in CAD-D compared with CAD-nD. Following sertraline antidepressant treatment a higher rate of remission was observed in subjects carrying the rs6265 A allele. To the best of our knowledge, this is the first investigation describing evidence for a significant association between rs6265 and treatment response to sertraline in CAD-D.
Several previous studies have indicated that possession of the BDNF rs6265 A allele is a significant risk factor for MD, geriatric depression and Alzheimer’s disease-related depression, and that it may modify the association between stroke and depression (16,18–21). Similarly, a recent study demonstrated that this polymorphism has been associated with CAD-D in an Italian population and that the A allele has been established as a risk factor for CAD-D (17). The present study confirmed the association of this putative functional polymorphism with CAD-D in a Chinese Han population.
The rs6265 (G196A) SNP of the BDNF gene results in the substitution of Val by Met in the 5′-pro-region of the BDNF protein at position 66 (22,23). This substitution may evidently alter the intracellular trafficking and packaging of proBDNF, and activity dependent secretion of BDNF (24). Previous studies have suggested that carriers of the A allele may reduce hippocampal volume and increase the occurrence of MD (25). Similarly, identifying an association between the A allele in the BDNF gene and CAD-D may contribute to further elucidating the role of the BDNF gene in CAD-D.
SSRIs are commonly recommended as the first line treatment for CAD-D (26). It has been demonstrated that sertraline improved endothelial function and reduced inflammatory markers in patients with CAD and symptoms of depression (27). The rs6265 polymorphism in the BDNF gene has also been identified to be associated with the response to antidepressant medications (20). Matrisciano et al also reported that 5-week or 6-month sertraline treatment may increase the serum level of BDNF (28). Consistent with several previous studies (29,30) that reported decreased release of BDNF of the rs6265 A allele, in the present study we observed that CAD-D patients with the A allele exhibited improved responses to sertraline than those with the G allele. This accumulative evidence suggests that the rs6265 functional polymorphism in the BDNF gene is important in the pathogenesis of at least partial CAD-D associated with decreased BDNF levels, since the antidepressant treatment evidently induced BDNF expression.
Analysis using a computational approach has suggested that the sequence of this region is potentially a part of the eukaryotic polymerase II promoter binding site and rs13306221 may disrupt the pattern of recognition, implying that rs13306221 negatively affects transcription of the BDNF gene (10). In the present study, there was a weak correlation between the SNP rs13306221 and CAD-D. The results demonstrated that CAD-D patients had a significantly higher frequency of the A allele of rs13306221 than CAD-nD subjects, although the frequency did not pass the threshold value. Su et al confirmed a statistically significant association between rs13306221 polymorphisms and alcohol dependence-related depression (31). Several other studies revealed that the rs13306221 polymorphism was associated with substance dependence and MD in Chinese Han population (15,32). Therefore, we may reliably conclude that rs13306221 polymorphism may be involved in the pathogenesis of CAD-D by regulating BDNF transcription in our Chinese sample population. The functional importance of this polymorphism, however, requires further investigation.
In summary, genetic variations in the BDNF gene contribute to CAD-D by conferring susceptibility or resistance to antidepressant treatment. The present study further elucidates the pathogenesis of CAD-D and thus will facilitate the development of improved diagnostic and treatment strategies in CAD-D.
Acknowledgements
This study was partially supported by the National Science Foundation of China (no. NSFC31100900).
Abbreviations:
|
BDNF |
brain-derived neurotrophic factor |
|
CAD |
coronary artery disease |
|
CAD-D |
coronary artery disease-related depression |
|
CAD-nD |
CAD without depression |
|
HAMD |
Hamilton Depression Rating Scale |
|
HWE |
Hardy-Weinberg equilibrium |
|
MD |
major depression |
|
SSRIs |
selective serotonin reuptake inhibitors |
|
SNPs |
single nucleotide polymorphisms |
|
UTR |
untranslated region |
References
|
Meijer A, Conradi HJ, Bos EH, Thombs BD, van Melle JP and de Jonge P: Prognostic association of depression following myocardial infarction with mortality and cardiovascular events: a meta-analysis of 25 years of research. Gen Hosp Psychiatry. 33:203–216. 2011. | |
|
Thombs BD, de Jonge P, Coyne JC, Whooley MA, Frasure-Smith N, Mitchell AJ, Zuidersma M, Eze-Nliam C, Lima BB, Smith CG, Soderlund K and Ziegelstein RC: Depression screening and patient outcomes in cardiovascular care: a systematic review. JAMA. 300:2161–2171. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Lewin GR and Barde YA: Physiology of the neurotrophins. Annu Rev Neurosci. 19:289–317. 1996. View Article : Google Scholar | |
|
Donovan MJ, Lin MI, Wiegn P, Ringstedt T, Kraemer R, Hahn R, Wang S, Ibanez CF, Rafii S and Hempstead BL: Brain derived neurotrophic factor is an endothelial cell survival factor required for intramyocardial vessel stabilization. Development. 127:4531–4540. 2000. | |
|
Kermani P, Rafii D, Jin DK, Whitlock P, Schaffer W, Chiang A, Vincent L, Friedrich M, Shido K, Hackett NR, Crystal RG, Rafii S and Hempstead BL: Neurotrophins promote revascularization by local recruitment of TrkB+ endothelial cells and systemic mobilization of hematopoietic progenitors. J Clin Invest. 115:653–663. 2005. View Article : Google Scholar | |
|
Ejiri J, Inoue N, Kobayashi S, Shiraki R, Otsui K, Honjo T, Takahashi M, Ohashi Y, Ichikawa S, Terashima M, Mori T, Awano K, Shinke T, Shite J, Hirata K, Yokozaki H, Kawashima S and Yokoyama M: Possible role of brain-derived neurotrophic factor in the pathogenesis of coronary artery disease. Circulation. 112:2114–2120. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Chen B, Dowlatshahi D, MacQueen GM, Wang JF and Young LT: Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry. 50:260–265. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Angelucci F, Brenè S and Mathé AA: BDNF in schizophrenia, depression and corresponding animal models. Mol Psychiatry. 10:345–352. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Dwivedi Y, Rizavi HS, Conley RR, Roberts RC, Tamminga CA and Pandey GN: Altered gene expression of brain-derived neurotrophic factor and receptor tyrosine kinase B in postmortem brain of suicide subjects. Arch Gen Psychiatry. 60:804–815. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang H, Ozbay F, Lappalainen J, Kranzler HR, van Dyck CH, Charney DS, Price LH, Southwick S, Yang BZ, Rasmussen A and Gelernter J: Brain derived neurotrophic factor (BDNF) gene variants and Alzheimer’s disease, affective disorders, posttraumatic stress disorder, schizophrenia, and substance dependence. Am J Med Genet B Neuropsychiatr Genet. 141B:387–393. 2006. | |
|
Tang J, Xiao L, Shu C, Wang G, Liu Z, Wang X, Wang H and Bai X: Association of the brain-derived neurotrophic factor gene and bipolar disorder with early age of onset in mainland China. Neurosci Lett. 433:98–102. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Hariri AR, Goldberg TE, Mattay VS, Kolachana BS, Callicott JH, Egan MF and Weinberger DR: Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci. 23:6690–6694. 2003. | |
|
Borroni B, Grassi M, Archetti S, Costanzi C, Bianchi M, Caimi L, Caltagirone C, Di Luca M and Padovani A: BDNF genetic variations increase the risk of Alzheimer’s disease-related depression. J Alzheimers Dis. 18:867–875. 2009. | |
|
Pei Y, Smith AK, Wang Y, Pan Y, Yang J, Chen Q, Pan W, Bao F, Zhao L, Tie C, Wang Y, Wang J, Zhen W, Zhou J and Ma X: The brain-derived neurotrophic-factor (BDNF) val66met polymorphism is associated with geriatric depression: a meta-analysis. Am J Med Genet B Neuropsychiatr Genet. 159B:560–566. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Sun RF, Zhu YS, Kuang WJ, Liu Y and Li SB: The G-712A polymorphism of brain-derived neurotrophic factor is associated with major depression but not schizophrenia. Neurosci Lett. 489:34–37. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang L, Fang Y, Zeng Z, Lian Y, Wei J, Zhu H, Jia Y, Zhao X and Xu Y: BDNF gene polymorphisms are associated with Alzheimer’s disease-related depression and antidepressant response. J Alzheimers Dis. 26:523–530. 2011. | |
|
Bozzini S, Gambelli P, Boiocchi C, Schirinzi S, Falcone R, Buzzi P, Storti C and Falcone C: Coronary artery disease and depression: possible role of brain-derived neurotrophic factor and serotonin transporter gene polymorphisms. Int J Mol Med. 24:813–818. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Hwang JP, Tsai SJ, Hong CJ, Yang CH, Lirng JF and Yang YM: The Val66Met polymorphism of the brain-derived neurotrophic-factor gene is associated with geriatric depression. Neurobiol Aging. 27:1834–1837. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Schumacher J, Jamra RA, Becker T, Ohlraun S, Klopp N, Binder EB, Schulze TG, Deschner M, Schmäl C, Höfels S, Zobel A, Illig T, Propping P, Holsboer F, Rietschel M, Nöthen MM and Cichon S: Evidence for a relationship between genetic variants at the brain-derived neurotrophic factor (BDNF) locus and major depression. Biol Psychiatry. 58:307–314. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Choi MJ, Kang RH, Lim SW, Oh KS and Lee MS: Brain-derived neurotrophic factor gene polymorphism (Val66Met) and citalopram response in major depressive disorder. Brain Res. 1118:176–182. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Kim JM, Stewart R, Kim SW, Yang SJ, Shin IS, Kim YH and Yoon JS: BDNF genotype potentially modifying the association between incident stroke and depression. Neurobiol Aging. 29:789–792. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Pröschel M, Saunders A, Roses AD and Müller CR: Dinucleotide repeat polymorphism at the human gene for the brain-derived neurotrophic factor (BDNF). Hum Mol Genet. 1:3531992.PubMed/NCBI | |
|
Lu B, Pang PT and Woo NH: The yin and yang of neurotrophin action. Nat Rev Neurosci. 6:603–614. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, Zaitsev E, Gold B, Goldman D, Dean M, Lu B and Weinberger DR: The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 112:257–269. 2003. View Article : Google Scholar | |
|
Frodl T, Schüle C, Schmitt G, Born C, Baghai T, Zill P, Bottlender R, Rupprecht R, Bondy B, Reiser M, Möller HJ and Meisenzahl EM: Association of the brain-derived neurotrophic factor Val66Met polymorphism with reduced hippocampal volumes in major depression. Arch Gen Psychiatry. 64:410–416. 2007.PubMed/NCBI | |
|
Scherrer JF, Garfield LD, Lustman PJ, Hauptman PJ, Chrusciel T, Zeringue A, Carney RM, Freedland KE, Bucholz KK, Owen R, Newcomer JW and True WR: Antidepressant drug compliance: reduced risk of MI and mortality in depressed patients. Am J Med. 124:318–324. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Paraskevaidis I, Palios J, Parissis J, Filippatos G and Anastasiou-Nana M: Treating depression in coronary artery disease and chronic heart failure: what’s new in using selective serotonin re-uptake inhibitors? Cardiovasc Hematol Agents Med Chem. 10:109–115. 2012. | |
|
Matrisciano F, Bonaccorso S, Ricciardi A, Scaccianoce S, Panaccione I, Wang L, Ruberto A, Tatarelli R, Nicoletti F, Girardi P and Shelton RC: Changes in BDNF serum levels in patients with major depression disorder (MDD) after 6 months treatment with sertraline, escitalopram, or venlafaxine. J Psychiatr Res. 43:247–254. 2009. View Article : Google Scholar | |
|
Chen ZY, Patel PD, Sant G, Meng CX, Teng KK, Hempstead BL and Lee FS: Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci. 24:4401–4411. 2004. View Article : Google Scholar | |
|
Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, Siao CJ, Herrera DG, Toth M, Yang C, McEwen BS, Hempstead BL and Lee FS: Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science. 314:140–143. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Su N, Zhang L, Fei F, Hu H, Wang K, Hui H, Jiang XF, Li X, Zhen HN, Li J, Cao BP, Dang W, Qu Y and Zhou F: The brain-derived neurotrophic factor is associated with alcohol dependence-related depression and antidepressant response. Brain Res. 1415:119–126. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Jia W, Shi JG, Wu B, Ao L, Zhang R and Zhu YS: Polymorphisms of brain-derived neurotrophic factor associated with heroin dependence. Neurosci Lett. 495:221–224. 2011. View Article : Google Scholar : PubMed/NCBI |
