Relationship between major depressive disorder and ACE gene I/D polymorphism in a Turkish population.
Major depressive disorder (MDD) is a common psychiatric disease, often associated with morbidity and mortality. Although many factors were considered as the cause of this disease, its etiology has not been ascertained yet. Studies with families, twins and fosterlings reveal that genetic factors play an important role in its etiology (1). The prevalence of disease varies according to countries and age groups (2). Studies suggest that 10% to 15% of the general population will be exposed to clinical depression during their life (1). Although the etiopathogenesis of the disease is not fully understood yet, it has been estimated that a genetic susceptibility could be effective in the onset of MDD (3). Also, MDD is because of a complex genetic heterogeneity. Recent studies have shown that different genetic variants may contribute to the development of the MDD such as ACE gene polymorphism (4-7).
ACE gene, localized on chromosome 17q23, undergoes a polymorphism deriving from the presence (insertion, I) or absence (deletion, D) within intron 16, of a 287 base pair ALU repeat sequence (8). Although each allele are codominant effect to ACE levels, the homozygosity for I and D alleles have the lowest and highest levels of the enzyme, respectively. Additionally, the heterozygosity have no effect to serum ACE levels (5-9). ACE is also member of the renin-angiotensin system and acts a part in the conversion of angiotensin I to angiotensin II (5). Angiotensin II is a peptide hormone which acts as a stimulator of proinflammatory cytokines and interferes with hypothalamic-pituitary-adrenal (HPA) axis activation in response to stress (5,10). It is mentioned from the effect of the brain renin-angiotensin system in regulation of mood (11). It has been stated that ACE I/D polymorphism may be associated with suicide and MDD5. ACE is responsible for degeneration of neurokinins that play an important role in regulation of emotions. Angiotensin II is both a potent neuropeptide and have essential roles in cognitive processes (12). In some studies, it has been shown that ACE may contribute to the pathophysiology of psychiatric diseases by interacting with central dopamine (7). Therefore, it is important the investigation of ACE gene polymorphisms which are affecting an active to mood and personal stress. This case control study was designed to determine whether the ACE I/D gene polymorphism is related with susceptibility to MDD in Turkish population or not.
Material and methods
In our study, 346 patients diagnosed with MDD (74 male and 272 female) and 210 healthy volunteers (75 male and 134 females as control group) who were recruited to Tokat Gaziosmanpasa University, Department of Psychiatry were included to the study. According to Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria, the patient group comprises individuals diagnosed with major depression. Both the study group and control group were recruited from the Turkish population. Subjects included to the study were greater than 18 years old. Informed written consent was obtained from all patients and subjects before enrollment to the study, according to the ethical guidelines of the 2008 Declaration of Helsinki and the investigation was approved by the ethical, investigation and biosecurity committee of Gaziosmanpasa University Faculty of Medicine.
This study was conducted in Gaziosmanpasa University, Department of Medical Biology and Genetics laboratories. Blood samples were collected from patients and controls. Genomic DNA was isolated from whole venous blood samples using a commercial DNA isolation kit (Sigma-Aldrich, Germany). In addition, after isolated, the DNA should be stored at -20C. ACE gene I/D polymorphism genotypes were determined by polymerase chain reaction (PCR) using the primers and conditions described earlier (8,11). Reactions were performed with 10 pmol of each primer: sense oligo, 5'-CTG GAG ACC ACT CCC ATC CTT TCT-3, and antisense oligo, 5'-GAT GTG GCC ATC ACA TTC GTC AAG T-3'. Amplification was performed in a thermal cycler for 30 cycles with denaturation at 94[degrees]C for 40 s, annealing at 56[degrees]C for 40 s and extension at 72[degrees]C for 40 s, followed by a final extension at 72[degrees]C for 10 min. PCR products were analyzed on 2% agarose gels after staining with ethidium bromide and were visualized using a UV transilluminator. The polymorphisms detected by PCR were evident as an approximately 490-bp fragment in the presence of the insertion (I) allele and as an approximately 190-bp fragment in the absence of insertion (D) allele. In heterozygous samples, two bands (490 and 190 bp) were detected. In order to confirm the accuracy and reproducibility of this method, each PCR reaction included internal controls for each genotype. Second PCR was performed to confirm samples whose results were not clear.
All statistical analyses of data were performed using the computer software SPSS version 15.0 for Windows and OpenEpi Info software package program. Genotype distribution of the ACE gene and allele frequency between MDD patients and controls were compared by Chi-Square test. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated. Hardy-Weinberg equation was applied to the genotypes of the patients and controls. P values 0.05 or less were considered statistically significant.
Demographic variables and baseline characteristics of patients were presented in Table 1. The mean age [+ or -] standard deviation (SD) was 38.12 [+ or -] 12.74 years in patients and 36.47 [+ or -] 9.33 years in control group. There were 74 (21.4%) males, 272 (78.6%) females and 75 (35.7%) males, 134 (63.8%) females in patient and control groups, respectively. The observed and expected frequencies of the polymorphism in both patient and control group were in Hardy-Weinberg equilibrium. It is determined that there was no statistical significant difference in the allele and genotype frequencies of ACE I/D polymorphism in patients and control groups (p > 0.05, OR 1.18, 95 % CI 0.91-1.51) (Table 2). Agarose gel electrophoresis patterns of ACE gene I/D polymorphisms were represented in Figure 1.
In this study we assessed the association of ACE I/D polymorphism in patients with MDD. When we consider prevalence and etiologies of MDD, we think that the genetic background of MDD should be investigated. In this study, it was not found any association between patient and control groups in Turkish MDD population in terms of ACE I/D polymorphism. ACE, membrane-bound endopeptidase, is expressed in many tissues including brain (13). It is reported that ACE in neuroepithelial cells degrades neurotransmitters such as substance P, which has a role in depression (14) and that angiotensin II interacts with dopamine in some specific parts of brain (15). Angiotensin II, acting as a stimulator of proinflammatory cytokines, makes changes on the hypothalamic-pituitary-adrenal (HPA) axis activation that develops in response to stress. ACE gene variations play a significant role in the HPA axis hyperactivity in depression. It has shown that variations in the ACE gene have an important impact on the HPA axis hyperactivity found in depression (16). Captopril, an ACE inhibitor, is proved to have an antidepressant effect (17). The fact that ACE gene variations affect serum enzyme level causes functional changes. ACE I/D polymorphism has been the subject of association studies related to various physiopathological conditions including mood disorder. It was reported that the depressive symptoms in schizophrenics was clearly associated with ACE I allele in the Chinese population (7) and that D allele had a protective effect for schizophrenia in the Spanish population (18). The researchers were also interested in whether ACE gene polymorphism affected the responses to therapeutic agents. It was reported that high activity of ACE genotype was associated with unfavorable response to conventional therapy in schizophrenic patients (19). Kucukali et al. indicated that there was an association between D/D genotype and bipolar disorder in patients order and their first-degree relatives (20). On the other hand, data collected previously suggested that ACE I/D polymorphism could possibly be a biological marker of depression (21-24). On the basis of these findings, the studies related to the genetic background of the MDD patients will make an important contribution to the clarification of the relationship between ACE gene and MDD.
A meta-analysis evaluating the data of several studies indicated that there was no association between schizophrenia and ACE I/D polymorphism (25), and the same result was supported in a study with the Croatian population (26), in consistent with our study results. While it was reported that bipolar disorder was not associated with I/D polymorphism (27), another study suggested that it was associated with I/D genotype in the Asian race (28). ACE gene polymorphism was reported not to be related to panic disorder (29,30), although the frequency of I allele is higher in men than women (31). Another study stated that there was an association between ACE gene polymorphism and MDD only in female patients (32), as consistent to our results. Arinami et al. found that D/D genotype increased sensitivity to affective disorder (33). However, mood disorders that started in childhood were reported not to be associated with ACE polymorphism (34). Studies conducted to examine the association between MDD and ACE did not show any link with ACE I/D polymorphism (14,35-39). The same result was supported in Chinese population where it was reported that ACE gene polymorphism did not affect response to the treatment (13). Also, Zill et al. suggest that aberrations in ACE promoter DNA methylation may be an underlying cause of MD (40). Depression were also significantly associated with an increase in cortisol secretion and, it is stated that ACE gene rs4295, rs4311, rs4343, rs4291, rs4333 and rs4351 variations influence cortisol secretion41. ACE gene A2350G polymorphism was closely associated with MDD among Iranian population (12). Stewart et al. reported that there was no difference between MDD and control groups with regard to allele and genotype (42). Considering this informations, we think that ACE I/D polymorphism was not related to the development of MDD in Turkish patients. Because the number of studies performed on the association of the ACE gene with Turkish MDD is limited, we think that the present study provides an important contribution to the literature.
In the present study, we not found a significant association between the ACE gene I/D polymorphism and MDD in Turkish population. The results cannot explain the role of ACE I/D polymorphism in the development of MDD. This polymorphism is not a susceptibility factor to MDD in the Turkish population. Although the present study does not provide any difference between the groups, we believe that there is a need for more comprehensive studies in different populations.
Conflict of interest
The authors declare no conflict of interest.
(1.) Lohoff FW. Overview of the genetics of major depressive disorder. Curr Psychiatry Rep. 2010;12(6):539-46.
(2.) Prina AM, Cosco TD, Dening T, Beekman A, Brayne C, Huisman M. The association between depressive symptoms in the community, non-psychiatric hospital admission and hospital outcomes: a systematic review. J Psychosom Res. 2015;78(1):25-33.
(3.) Lopizzo N, Bocchio Chiavetto L, Cattane N, Plazzotta G, Tarazi FI, Pariante CM, et al. Gene-environment interaction in major depression: focus on experience-dependent biological systems. Front Psychiatry. 2015;6:68.
(4.) Hou Z, Yuan Y, Zhang Z, Hou G, You J, Bai F. The D-allele of ACE insertion/deletion polymorphism is associated with regional white matter volume changes and cognitive impairment in remitted geriatric depression. Neurosci Lett. 2010;479(3):262-6.
(5.) Wu Y, Wang X, Shen X, Tan Z, Yuan Y. The I/D polymorphism of angiotensin-converting enzyme gene in major depressive disorder and therapeutic outcome: a case-control study and meta-analysis. J Affect Disord. 2012;136(3):971-8.
(6.) Zill P, Baghai TC, Schule C, Born C, Frustuck C, Buttner A, et al. DNA methylation analysis of the angiotensin converting enzyme (ACE) gene in major depression. PLoS One. 2012;7(7):1-11.
(7.) Hui L, Wu JQ, Ye MJ, Zheng K, He JC, Zhang X, et al. Association of angiotensin-converting enzyme gene polymorphism with schizophrenia and depressive symptom severity in a Chinese population. Hum Psychopharmacol. 2015;30(2):100-7.
(8.) Inanir A, Yigit S, Tural S, Ozturk SD, Akkanet S, Habiboglu A. Significant association between insertion/deletion polymorphism of the angiotensin-convertig enzyme gene and ankylosing spondylitis. Mol Vis. 2012;18:2107-13.
(9.) Zintzaras E, Raman G, Kitsios G, Lau J. Angiotensin-converting enzyme insertion/deletion gene polymorphic variant as a marker of coronary artery disease: a meta-analysis. Arch Intern Med. 2008;168(10):1077-89.
(10.) Ising M, Holsboer F. Genetics of stress response and stress-related disorders. Dialogues Clin Neurosci. 2006;8(4):433-44.
(11.) Inanir A, Yigit S, Tekcan A, Pinarli FA, Inanir S, Karakus N. Angiotensin converting enzyme and methylenetetrahydrofolate reductase gene variations in fibromyalgia syndrome. Gene. 2015;564(2):188-92.
(12.) Firouzabadi N, Shafiei M, Bahramali E, Ebrahimi SA, Bakhshandeh H, Tajik N. Association of angiotensin-converting enzyme (ACE) gene polymorphism with elevated serum ACE activity and major depression in an Iranian population. Psychiatry Res. 2012;200(2-3):336-42.
(13.) Wu Y, Wang X, Shen X, Tan Z, Yuan Y. The I/D polymorphism of angiotensin-converting enzyme gene in major depressive disorder and therapeutic outcome: a case-control study and meta-analysis. J Affect Disord. 2012;136(3):971-8.
(14.) Hong CJ, Wang YC, Tsai SJ. Association study of angiotensin I-converting enzyme polymorphism and symptomatology and antidepressant response in major depressive disorders. J Neural Transm. 2002;109(9):1209-14.
(15.) Angunsri R, Sritharathikhun T, Suttirat S, Tencomnao T. Association of angiotensin-converting enzyme gene promoter single nucleotide polymorphisms and haplotype with major depression in a northeastern Thai population. J Renin Angiotensin Aldosterone Syst. 2009;10(3):179-84.
(16.) Baghai TC, Schule C, Zwanzger P, Minov C, Zill P, Ella R, et al. Hypothalamic-pituitary-adrenocortical axis dysregulation in patients with major depression is influenced by the insertion/deletion polymorphism in the angiotensin I-converting enzyme gene. Neurosci Lett. 2002;328(3):299-303.
(17.) Vuckovic A, Cohen BM, Zubenko GS. The use of captopril in treatment-resistant depression: an open trial. Clin Psychopharmacol. 1991;11(6):395-6.
(18.) Crescenti A, Gasso P, Mas S, Abellana R, Deulofeu R, Parellada E, et al. Insertion/deletion polymorphism of the angiotensin-converting enzyme gene is associated with schizophrenia in a Spanish population. Psychiatry Res. 2009;165(1-2):175-80.
(19.) Illi A, Kampman O, Anttila S, Roivas M, Mattila KM, Lehtimaki T, et al. Interaction between angiotensin-converting enzyme and catechol-O-methyltransferase genotypes in schizophrenics with poor response to conventional neuroleptics. Eur Neuropsychopharmacol. 2003;13(3):147-51.
(20.) Kucukali CI, Aydin M, Ozkok E, Bilge E, Zengin A, Cakir U, et al. Angiotensin-converting enzyme polymorphism in schizophrenia, bipolar disorders, and their first-degree relatives. Psychiatr Genet. 2010;20(1):14-9.
(21.) Kara M, Kara B, Erol D, Yuce H, Atmaca M, Tekederli I. The insertion/deletion of angiotensin converting enzyme is associated with major depression. Firat Medical Journal. 2012;17(3):153-5.
(22.) Baghai TC, Schule C, Zwanzger P, Zill P, Ella R, Eser D, et al. Influence of a functional polymorphism within the angiotensin I-converting enzyme gene on partial sleep deprivation in patients with major depression. Neurosci Lett. 2003;339(3):223-6.
(23.) Baghai TC, Binder EB, Schule C, Salyakina D, Eser D, Lucae S, et al. Polymorphisms in the angiotensin-converting enzyme gene are associated with unipolar depression, ACE activity and hypercortisolism. Mol Psychiatry. 2006;11(11):1003-15.
(24.) Ancelin ML, Carriere I, Scali J, Ritchie K, Chaudieu I, Ryan J. Angiotensin-converting enzyme gene variants are associated with both cortisol secretion and late-life depression. Transl Psychiatry. 2013;3:e322.
(25.) Song GG, Lee YH. The insertion/deletion polymorphism in the angiotensin-converting enzyme and susceptibility to schizophrenia or Parkinson's disease: A meta-analysis. J Renin Angiotensin Aldosterone Syst. 2015;16(2):434-42.
(26.) Nadalin S, Buretic-Tomljanovic A, Rubesa G, Jonovska S, Tomljanovic D, Ristic S. Angiotensin-converting enzyme gene insertion/deletion polymorphism is not associated with schizophrenia in a Croatian population. Psychiatr Genet. 2012;22(5):267-8.
(27.) Meira-Lima IV, Pereira AC, Mota GF, Krieger JE, Vallada H. Angiotensinogen and angiotensin converting enzyme gene polymorphisms and the risk of bipolar affective disorder in humans. Neurosci Lett. 2000;293(2):103-6.
(28.) Zou YF, Wang F, Feng XL, Li WF, Pan FM, Huang F. Meta-analysis of ACE gene I/D polymorphism and bipolar disorder susceptibility. Nord J Psychiatry. 2011;65(4):276-82.
(29.) Shimizu E, Hashimoto K, Kobayashi K, Mitsumori M, Ohgake S, Koizumi H, et al. Lack of association between angiotensin I-converting enzyme insertion/deletion gene functional polymorphism and panic disorder in humans. Neurosci Lett. 2004;363(1):81-3.
(30.) Olsson M, Annerbrink K, Westberg L, Melke J, Baghaei F, Rosmond R, et al. Angiotensin-related genes in patients with panic disorder. Am J Med Genet B Neuropsychiatr Genet. 2004;127B(1):81-4.
(31.) Bayoglu B, Cengiz M, Karacetin G, Uysal O, Kocabasoglu N, Bayar R, et al. Genetic polymorphism of angiotensin I-converting enzyme (ACE), but not angiotensin II type I receptor (ATr1), has a gender-specific role in panic disorder. Psychiatry Clin Neurosci. 2012;66(2):130-7.
(32.) Baghai TC, Schule C, Zill P, Deiml T, Eser D, Zwanzger P, et al. The angiotensin I converting enzyme insertion/deletion polymorphism influences therapeutic outcome in major depressed women, but not in men. Neurosci Lett. 2004;363(1):38-42.
(33.) Arinami T, Li L, Mitsushio H, Itokawa M, Hamaguchi H, Toru M. An insertion/deletion polymorphism in the angiotensin converting enzyme gene is associated with both brain substance P contents and affective disorders. Biol Psychiatry. 1996;40(11):1122-7.
(34.) Dempster EL, Kiss E, Kapornai K, Daroczi G, Mayer L, Baji I, et al.; International Consortium for Childhood-Onset Mood Disorders. No evidence of an association between two genes, EDN1 and ACE, and childhood-onset mood disorders. Am J Med Genet B Neuropsychiatr Genet. 2010;153B(1):341-6.
(35.) Segman RH, Shapira Y, Modai I, Hamdan A, Zislin J, Heresco-Levy U, et al. Angiotensin converting enzyme gene insertion/deletion polymorphism: case-control association studies in schizophrenia, major affective disorder, and tardive dyskinesia and a family-based association study in schizophrenia. Am J Med Genet. 2002;114(3):310-4.
(36.) Pauls J, Bandelow B, Ruther E, Kornhuber J. Polymorphism of the gene of angiotensin converting enzyme: lack of association with mood disorder. J Neural Transm. 2000;107U1):1361-6.
(37.) Furlong RA, Keramatipour M, Ho LW, Rubinsztein JS, Michael A, Walsh C, et al. No association of an insertion/deletion polymorphism in the angiotensin I converting enzyme gene with bipolar or unipolar affective disorders. Am J Med Genet. 2000;96(6):733-5.
(38.) Saab YB, Gard PR, Yeoman MS, Mfarrej B, El-Moalem H, Ingram MJ. Renin-angiotensin-system gene polymorphisms and depression. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31(5):1113-8.
(39.) Lopez-Leon S, Janssens AC, Hofman A, Claes S, Breteler MM, Tiemeier H, et al. No association between the angiotensin-converting enzyme gene and major depression: a case-control study and meta-analysis. Psychiatr Genet. 2006;16(6):225-6.
(40.) Zill P, Baghai TC, Schule C, Born C, Frustuck C, Buttner A, et al. DNA methylation analysis of the angiotensin converting enzyme (ACE) gene in major depression. PLoS One. 2012;7(7):e40479.
(41.) Ancelin ML, Carriere I, Scali J, Ritchie K, Chaudieu I, Ryan J. Angiotensin-converting enzyme gene variants are associated with both cortisol secretion and late-life depression. Transl Psychiatry. 2013;3:322.
(42.) Stewart JA, Kampman O, Huuhka M, Anttila S, Huuhka K, Lehtimaki T, Leinonen E. ACE polymorphism and response to electroconvulsive therapy in major depression. Neurosci Lett. 2009 ; 458(3): 122-5.
Sema Inanir , Serbulent Yigit , Feryal Cam Celikel , Omer Ates , Serap Erdogan Taycan , Ayse Feyda Nursal , Akin Tekcan , Aydin Rustemoglu , Gul Dursun , Ahmet Inanir 
 Gaziosmanpasa University, Faculty of Medicine, Department of Psychiatry, Tokat, Turkey.
 Gaziosmanpasa University, Faculty of Medicine, Department of Medical Biology, Tokat, Turkey.
 Giresun University, Faculty of Medicine, Department of Medical Genetics, Giresun, Turkey.
 Ahi Evran University, School of Health, Kirsehir, Turkey.
 Gaziosmanpasa University, Faculty of Medicine, Department of Physical Medicine and Rehabilitation, Tokat, Turkey.
Received: 11/9/2015--Accepted: 4/7/2016
Address for correspondence: Akin Tekcan. Ahi Evran University, School of Health, Kirsehir, Turkey. Phone: +905055719646. E-mail: firstname.lastname@example.org
Caption: Figure 1. Agarose gel electrophoresis patterns for I/D genotypes and genetic variations of ACE gene.
Table 1. Clinical and demographic characteristics of the patients with MDD and healthy controls Characteristics Control group, n (%) Gender, male/female 75/134 (35.7/63.8) Age, mean [+ or -] SD, years 36.47 [+ or -] 9.33 Weight, mean [+ or -] SD, years BMI, mean [+ or -] SD, years Age of onset Disease duration Civil status Single/Married Background of psychological disorders No/Yes Family history No/Yes Depression score Anxiety score Pain score Characteristics Study group, n (%) Gender, male/female 74/272 (21.4/78.6) Age, mean [+ or -] SD, years 38.12 [+ or -] 12,74 Weight, mean [+ or -] SD, years 70.97 [+ or -] 10.54 BMI, mean [+ or -] SD, years 26.51 [+ or -] 3.78 Age of onset 33.81 [+ or -] 12.25 Disease duration 4.75 [+ or -] 5.12 Civil status Single/Married 73/165 (30.7/69.3) Background of psychological disorders No/Yes 148/90 (62.2/37.8) Family history No/Yes 150/88 (63.0/37.0) Depression score 19.22 [+ or -] 11.22 Anxiety score 22.07 [+ or -] 14.48 Pain score 19.62 [+ or -] 11.30 BMI: body mass index. Table 2. Genotype and allele frequencies of ACE gene polymorphisms In MDD patient and control groups Gene MDD patients Healthy p OR (CI 95%) n = 346 controls n = 210 ACE (I/D) Genotypes I/I 44 (12.7%) 34 (16.19%) I/D 163 (47.1%) 101 (48.09%) 0.40 D/D 139 (40.1%) 75 (35.71%) II: ID+DD 44:302 34:176 > 0.05 0.75 (0.46-1.23) II+ID:DD 207:139 135:75 > 0.05 0.77 (0.53-1.10) Alleles I 251 (36.2%) 169 (40.23%) 0.18 1.18 (0.91-1.51) D 441 (63.7%) 251 (59.76%)
|Printer friendly Cite/link Email Feedback|
|Title Annotation:||Original article|
|Author:||Inanir, Sema; Yigit, Serbulent; Celikel, Feryal Cam; Ates, Omer; Taycan, Serap Erdogan; Nursal, Ayse|
|Publication:||Archives of Clinical Psychiatry|
|Date:||Mar 1, 2016|
|Previous Article:||Frontal electroencephalographic (EEG) activity and mediumship: a comparative study between spiritist mediums and controls.|
|Next Article:||Changing negative core beliefs with trial-based thought record.|