Back
 JBM  Vol.6 No.2 , February 2018
Association of Bax and Bcl-2 Functional Polymorphisms and Protein Levels with Posttraumatic Stress Disorder
Abstract: Background: Posttraumatic stress disorder (PTSD) is an anxiety disease influenced by both environmental and genetic factors, which affects a patient’s quality of life and social stability. Recent studies have shown that the pathogenesis of PTSD is associated with apoptosis; however, the molecular mechanisms that cause such damage are not well-understood. Also it is unclear whether these pathologic alterations are genetically determined or caused by other factors. The aim of this study was to investigate the genetic association of functional polymorphisms in genes coding for apoptosis-related Bcl-2 and Bax proteins with PTSD as well as proteins levels in the blood of affected subjects. Methods: The study groups consisted of 200 combat veterans with PTSD and an equal number of healthy subjects with no family- or past-history of any psychiatric disorders. Bax and Bcl-2 proteins levels in blood were measured by ELISA. DNA samples were genotyped for SNPs using PCR-SSP. Results: According to our results, PTSD patients are characterized by increased levels of apoptotic proteins and the imbalance in the Bax/Bcl-2 ratio compared to healthy subjects. Our results also demonstrate that rs956572*A minor allele of the BCL2 gene was overrepresented in patients with PTSD compared to healthy subjects. Conclusions: The results implicate Bcl-2 and Bax in pathogenesis of PTSD on genetic and protein levels, though further studies on enlarged cohort and in different populations are required.
Cite this paper: Avetyan, D. , Arakelyan, A. and Mkrtchyan, G. (2018) Association of Bax and Bcl-2 Functional Polymorphisms and Protein Levels with Posttraumatic Stress Disorder. Journal of Biosciences and Medicines, 6, 23-32. doi: 10.4236/jbm.2018.62003.
References

[1]   ICD-10-CM (2016) The International Statistical Classification of Diseases and Related Health Problems. 10th Edition, World Health Organization, Geneva.

[2]   DSM-V (2013) Diagnostic and Statistical Manual of Mental Disorders by the American Psychiatric Association. 5th Edition, American Psychiatric Association Publishing.

[3]   American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association.

[4]   Blake, D.D., Weathers, F.W., Nagy, L.M., Kaloupek, D.G., Gusman, F.D., Charney, D.S. and Keane, T.M. (1995) The Development of a Clinician Administered PTSD Scale. Journal of Traumatic Stress, 8, 75-90.
https://doi.org/10.1002/jts.2490080106

[5]   Afifi, T.O., Asmundson, G.J., Taylor, S. and Jang K.L. (2010) The Role of Genes and Environment on Trauma Exposure and Post-Traumatic Stress Disorder Symptoms: A Review of Twin Studies. Clinical Psychology Review, 30, 101-112.
https://doi.org/10.1016/j.cpr.2009.10.002

[6]   Cornelis, M.C., Nugent, N.R., Amstadter, A.B. and Koenen, K.C. (2010) Genetics of Post-Traumatic Stress Disorder: Review and Recommendations for Genome-Wide Association Studies. Current Psychiatry Reports, 12, 313-326.
https://doi.org/10.1007/s11920-010-0126-6

[7]   Boyajyan, A., Avetyan, D., Hovhannisyan, L. and Mkrtchyan, G. (2015) Genetics of Posttraumatic Stress Disorder: Candidate Genes and Their Implication in the Disease-Associated Molecular Pathomechanisms. In: Durbano, F., Ed., A Fresh Look at Anxiety Disorders, InTech., London, 65-88.
https://doi.org/10.5772/60443

[8]   Shin, L.M., Rauch, S.L. and Pitman R.K. (2006) Amygdala, Medial Prefrontal Cortex, and Hippocampal Function in PTSD. Annals of the New York Academy of Sciences, 1071, 67-79.
https://doi.org/10.1196/annals.1364.007

[9]   Roozendaal, B., Griffith, Q.K., Buranday, J., De Quervain, D.J. and McGaugh, J.L. (2003) The Hippocampus Mediates Glucocorticoid Induced Impairment of Spatial Memory Retrieval: Dependence on the Basolateral Amygdale. Proceedings of the National Academy of Sciences of the United States of America, 100, 1328-1333.
https://doi.org/10.1073/pnas.0337480100

[10]   Bonne, O., Brandes, D., Gilboa, A., Gomori, J.M., Shenton, M.E., Pitman, R.K. and Shalev, A.Y. (2001) Longitudinal MRI Study of Hippocampal Volume in Trauma Survivors with PTSD. American Journal of Psychiatry, 158, 1248-1251.
https://doi.org/10.1176/appi.ajp.158.8.1248

[11]   Kitayama, N., Vaccarino, V., Kutner, M., Weiss, P. and Bremner, J.D. (2005) Magnetic Resonance Imaging [MRI] Measurement of Hippocampal Volume in Posttraumatic Stress Disorder: A Meta-Analysis. Journal of Affective Disorders, 88, 79-86.
https://doi.org/10.1016/j.jad.2005.05.014

[12]   Skommer, J., Wlodkowic, D. and Deptala, A. (2007) Larger than Life: Mitochondria and the Bcl-2 Family. Leukemia Research, 31, 277-286.
https://doi.org/10.1016/j.leukres.2006.06.027

[13]   Guicciardi, M.E. and Gores, G.J. (2009) Life and Death by Death Receptors. THE FASEB Journal, 23, 1625-1627.
https://doi.org/10.1096/fj.08-111005

[14]   Waldmeier, P.C. and Tatton, W.G. (2004) Interrupting Apoptosis in Neurodegenerative Disease: Potential for Effective Therapy? Drug Discovery Today, 9, 210-208.
https://doi.org/10.1016/S1359-6446(03)03000-9

[15]   Bremner, J.D. (2006) Stress and Brain Atrophy. CNS & Neurological Disorders-Drug Targets, 5, 503-512.
https://doi.org/10.2174/187152706778559309

[16]   Shishkina, G.T., Kalinina, T.S., Berezova, I.V., Bulygina, V.V. and Dygalo, N.N. (2010) Resistance to the Development of Stress-Induced Behavioral Despair in the Forced Swim Test Associated with Elevated Hippocampal Bcl-xl Expression. Behavioural Brain Research, 213, 218-224.
https://doi.org/10.1016/j.bbr.2010.05.003

[17]   Panaretakis, T., Pokrovskaja, K., Shoshan, M.C. and Grandér, D. (2002) Activation of Bak, Bax, and BH3-Only Proteins in the Apoptotic Response to Doxorubicin. The Journal of Biological Chemistry, 277, 44317-44326.
https://doi.org/10.1074/jbc.M205273200

[18]   Sun, F., Akazawa, S., Sugahara, K., Kamihira, S., Kawasaki, E., Eguchi, K. and Koji, T. (2002) Apoptosis in Normal Rat Embryo Tissues during Early Organogenesis: The Possible Involvement of Bax and Bcl-2. Archives of Histology and Cytology, 65, 145-157.
https://doi.org/10.1679/aohc.65.145

[19]   Li, X., Han, F., Liu, D. and Shi, Y. (2010) Changes of Bax, Bcl-2 and Apoptosis in Hippocampus in the Rat Model of Posttraumatic Stress Disorder. Neurological Research, 32, 579-586.
https://doi.org/10.1179/016164110X12556180206194

[20]   Li, X., Han, F. and Shi, Y. (2013) Increased Neuronal Apoptosis in Medial Prefrontal Cortex Is Accompanied with Changes of Bcl-2 and Bax in a Rat Model of Post-Traumatic Stress Disorder. Journal of Molecular Neuroscience, 51, 127-137.
https://doi.org/10.1007/s12031-013-9965-z

[21]   Miller, S.A., Dykes, D.D. and Polesky, H.F. (1988) A Simple Salting out Procedure for Extracting DNA from Human Nucleated Cells. Nucleic Acids Research, 16, 1215. https://doi.org/10.1093/nar/16.3.1215

[22]   Bunce, M., Procter, J. and Welsh, K.I. (1999) A DNA Based Detection and Screening System for Identifying HLA Class I Expression Variants by Sequence-Specific Primers. Tissue Antigens, 53, 498-506.
https://doi.org/10.1034/j.1399-0039.1999.530506.x

[23]   Strasser, A., O’Conner, L. and Dixit, V.M. (2000) Apoptosis Signaling. International Journal of Cancer, 69, 217-245.
https://doi.org/10.1146/annurev.biochem.69.1.217

[24]   Li, X.M., Han, F., Liu, J.D. and Shi, Y. (2010) Single-Prolonged Stress Induced Mitochondrial Dependent Apoptosis in Hippocampus in the Rat Model of Post-Traumatic Stress Disorder. Journal of Chemical Neuroanatomy, 40, 248-255.
https://doi.org/10.1016/j.jchemneu.2010.07.001

[25]   Alani, B., Maghsoudi, N., Khatibi, A., Noureddini, M., Asefifar, F. and Shams, J. (2013) Study of the Variations in Apoptotic Factors in Hippocampus of Male Rats with Posttraumatic Stress Disorder. Advanced Biomedical Research, 2, 42.
https://doi.org/10.4103/2277-9175.109757

[26]   Mkrtchian, G.M., Boiadzhian, A.S., Avetian, D.G. and Sukiasian, S.G. (2013) The Involvement of Abnormal Apoptosis in the Disturbance of Synaptic Plasticity in Posttraumatic Stress Disorder. Zhurnal Nevrologii I Psikhiatrii Imeni S.S. Korsakova, 113, 26-29.

[27]   Salvadore, G., Nugent, A.C., Chen, G., Akula, N., Yuan, P., Cannon, D.M., Zarate, C.A. Jr., McMahon, F.J., Manji, H.K. and Drevets, W.C. (2009) Bcl-2 Polymorphism Influences Gray Matter Volume in the Ventral Striatum in Healthy Humans. Biological Psychiatry, 66, 804-807.
https://doi.org/10.1016/j.biopsych.2009.05.025

[28]   Yuan, P., Baum, A.E., Zhou, R., Wang, Y., Laje, G. and McMahon, F.J. (2008) Bcl-2 Polymorphisms Associated with Mood Disorders and Antidepressant-Responsiveness Regulate Bcl-2 Gene Expression and Cellular Resilience in Human Lymphoblastoid Cell Lines. Biological Psychiatry, 63, 63S.

[29]   Soeiro-de-Souza, M.G., Salvadore, G., Moreno, R.A., Otaduy, M.C., Chaim, K.T., Gattaz, W.F., Zarate, C.A. and Machado-Vieira, R. (2013) Bcl-2 rs956572 Polymorphism Is Associated with Increased Anterior Cingulate Cortical Glutamate in Euthymic Bipolar I Disorder. Neuropsychopharmacology, 38, 468-475.
https://doi.org/10.1038/npp.2012.203

[30]   Uemura, T., Green, M., Corson, T.W., Perova, T., Li, P.P. and Warsh, J.J. (2011) Bcl-2 SNP rs956572 Associates with Disrupted Intracellular Calcium Homeostasis in Bipolar I Disorder. Bipolar Disorder, 13, 41-51.
https://doi.org/10.1111/j.1399-5618.2011.00897.x

 
 
Top