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Vol.1 , No. 1, Publication Date: Jul. 7, 2014, Page: 28-34
 family proteins among which Bcl-2 proper is a major anti-apoptotic protein, and Bcl-2-associated X protein (Bax) is pro-apoptotic death promoter. Postmortem studies demonstrated the increased expression level of Bax encoding gene and high Bax/Bcl-2 proteins ratio in schizophrenia. However, it is yet unclear whether these alterations are genetically determined or caused by other factors. In the present study we, for the first, time evaluated the association of single nucleotide polymorphisms (SNPs) rs1057369 (A>G) and rs956572 (G>A), rs1801018 (A>G) of Bax and Bcl-2 encoding genes, BAX and BCL2, respectively, with schizophrenia in Armenian population using polymerase chain reaction with sequence-specific primers. BAX rs1057369 SNP was found negatively associated with this disorder; the presence of BAX rs1057369*G minor allele, especially in homozygous form, was associated with decreased risk of developing schizophrenia, whereas no association between schizophrenia and BCL2 rs956572 and rs1801018 polymorphisms was revealed. Based on the obtained results we concluded that the rs1057369*G minor allele of BAX may have a protective effect relative to schizophrenia, and that this effect is most pronounced in individuals with GG homozygous genotype&picture=http://www.aascit.org/aascit/decorators/img/journal/903.jpg)
| [1] | Kristina Pirumyan , Department of Molecular and Applied Biology, Institute of Molecular Biology, National Academy of Sciences of the Republic of Armenia (NAS RA), Yerevan, Armenia. |
| [2] | Anna Boyajyan , Department of Molecular and Applied Biology, Institute of Molecular Biology, National Academy of Sciences of the Republic of Armenia (NAS RA), Yerevan, Armenia. |
It is proposed that both pre- and postnatal as well as genetically determined abnormalities of the apoptotic processes are among factors responsible for the development of schizophrenia. The ultimate vulnerability of cells to diverse apoptotic stimuli is determined by the relative ratio of various pro-apoptotic and anti-apoptotic members of the B-cell lymphoma 2 (Bcl-2) family proteins among which Bcl-2 proper is a major anti-apoptotic protein, and Bcl-2-associated X protein (Bax) is pro-apoptotic death promoter. Postmortem studies demonstrated the increased expression level of Bax encoding gene and high Bax/Bcl-2 proteins ratio in schizophrenia. However, it is yet unclear whether these alterations are genetically determined or caused by other factors. In the present study we, for the first, time evaluated the association of single nucleotide polymorphisms (SNPs) rs1057369 (A>G) and rs956572 (G>A), rs1801018 (A>G) of Bax and Bcl-2 encoding genes, BAX and BCL2, respectively, with schizophrenia in Armenian population using polymerase chain reaction with sequence-specific primers. BAX rs1057369 SNP was found negatively associated with this disorder; the presence of BAX rs1057369*G minor allele, especially in homozygous form, was associated with decreased risk of developing schizophrenia, whereas no association between schizophrenia and BCL2 rs956572 and rs1801018 polymorphisms was revealed. Based on the obtained results we concluded that the rs1057369*G minor allele of BAX may have a protective effect relative to schizophrenia, and that this effect is most pronounced in individuals with GG homozygous genotype
Keywords
Schizophrenia, Apoptosis, BAX, BCL2, Single Nucleotide Polymorphisms, Genotyping
Reference
| [01] | Perälä J, Suvisaari J, Saarni SI, Kuoppasalmi K, Isometsä E, Pirkola S, et al. Tuulio-Henriksson A, Hintikka J, Kieseppä T, Härkänen T, Koskinen S, Lönnqvist J, Lifetime prevalence of psychotic and bipolar I disorders in a general population. Arch Gen Psychiatry.2007;64:19-28. |
| [02] | Lublin H, Cognitive dysfunction in schizophrenia, Acta Psychiatr Scand Suppl.2001;104(408):5-9. |
| [03] | Matza LS, Buchanan R, Purdon S, Brewster-Jordan J, Zhao Y, Revicki DA, Measuring changes in functional status among patients with schizophrenia: the link with cognitive impairment. Schizophr Bull.2006;32(4):666-78. |
| [04] | van Os J, Rutten BP, Poulton R, Gene-environment interactions in schizophrenia: review of epidemiological findings and future directions. Schizophr Bull.2008;34(6):1066-82. |
| [05] | Zahir FR, Brown CJ, Epigenetic impacts on neurodevelopment: pathophysiological mechanisms and genetic modes of action. Pediatr Res.2011;69(5 Pt 2):92R-100R. |
| [06] | Holcik M, Apoptosis in Health and Disease: Clinical and Therapeutic Aspects. Cambridge: Cambridge University Press,;2005. |
| [07] | Olney JW, Excitotoxicity, apoptosis and neuropsychiatric disorders. Curr Opin Pharmacol.2003;3(1):101-9. |
| [08] | Burek MJ, Oppenheim RW, Programmed cell death in the developing nervous system. Brain Pathol.1996;6(4):427-46. |
| [09] | Mattson MP, Keller JN, Begley JG, Evidence for synaptic apoptosis. Exp Neurol.1998;153(1):35-48. |
| [10] | Jarskog LF, Glantz LA, Gilmore JH, Lieberman JA, Apoptotic mechanisms in the pathophysiology of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry.2005;29(5):846-58. |
| [11] | Jarskog LF, Apoptosis in schizophrenia: pathophysiologic and therapeutic considerations. Curr Opin Psychiatry.2006;19(3):307-12. |
| [12] | Pantelis C, Yücel M, Wood SJ, Velakoulis D, Sun D, Berger G, et al. Structural brain imaging evidence for multiple pathological processes at different stages of brain development in schizophrenia. Schizophr Bull.2005;31(3):672-96. |
| [13] | Benes FM, Walsh J, Bhattacharyya S, Sheth A, Berretta S, DNA fragmentation decreased in schizophrenia but not in bipolar disorder. Arch Gen Psychiatry.2003;60(4):359-64. |
| [14] | Glantz LA, Gilmore JH, Overstreet DH, Salimi K, Lieberman JA, Jarskog LF, Pro-apoptotic Par-4 and dopamine D2 receptor in temporal cortex in schizophrenia, bipolar disorder and major depression. Schizophr Res.2010;118(1-3):292-9. |
| [15] | Djordjević VV, Ristić T, Lazarević D, Cosić V, Vlahović P, Djordjević VB, Schizophrenia is associated with increased levels of serum Fas and FasL. Clin Chem Lab Med.2012;50(6):1049-54. |
| [16] | Boyajyan A, Zakharyan R, Khoyetsyan A, Chapter XI. Molecular and genetic indicators of aberrant immunity and apoptosis in schizophrenia. In: Sumiyoshi T editor: Schizophrenia Research: Recent Advances. New York: Nova Science Publishers Inc;2012:p.183-240. |
| [17] | Boyajyan AS, Chavushyan AS, Zakharyan RV, Mkrtchyan GM, Markers of apoptotic dysfunctions in schizophrenia. Molecular Biology (Moscow).2013;47(4):587-91. |
| [18] | Fatemi SH, Folsom TD, The neurodevelopmental hypothesis of schizophrenia, revisited. Schizophr Bull.2009;35(3):528-48. |
| [19] | Glantz LA, Gilmore JH, Lieberman JA, Jarskog LF, Apoptotic mechanisms and the synaptic pathology of schizophrenia. Schizophr Res.2006;81(1):47-63. |
| [20] | Pérez-Neri I, Ramírez-Bermúdez J, Montes S, Ríos C, Possible mechanisms of neurodegeneration in schizophrenia. Neurochem Res.2006;31(10):1279-94. |
| [21] | Rothermundt M, Arolt V, Bayer TA, Review of immunological and immunopathological findings in schizophrenia. Brain Behav Immun.2001;15(4):319-39. |
| [22] | Müller N, Schwarz MJ, Immune system and schizophrenia,. Curr Immunol Rev.2010;6(3):213-20. |
| [23] | Haanen C, Vermes I, Apoptosis and inflammation. Mediators Inflamm.1995;4(1):5-15. |
| [24] | Mahoney JA, Rosen A, Apoptosis and autoimmunity. Curr Opin Immunol.2005;17(6):583-8. |
| [25] | Otani S, Prefrontal cortex: from synaptic plasticity to cognition. Kluwer Academic Publishers Group, Dordrecht.2004. |
| [26] | Cunningham C, Campion S, Lunnon K, Murray CL, Woods JF, Deacon RJ, et al. Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol Psychiatry.2009;65(4):304-12. |
| [27] | Oliva CA, Vargas JY, Inestrosa NC, Wnts in adult brain: from synaptic plasticity to cognitive deficiencies. Front Cell Neurosci.2013;7:224. |
| [28] | Yasuda T, Nakata Y, Choong CJ, Mochizuki H, Neurodegenerative changes initiated by presynaptic dysfunction. Transl Neurodegener.2013;2(1):16. |
| [29] | Lim L, Lippe S, Silverman E, Effect of autoimmune diseases on cognitive function. Handb Clin Neurol.2013;112:1275-83. |
| [30] | Roset R, Ortet L, Gil-Gomez G, Role of Bcl-2 family members on apoptosis: what we have learned from knock-out mice. Front Biosci.2007;12:4722-30. |
| [31] | Youle RJ, Strasser A, The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 2008;9(1):47-59. |
| [32] | Korsmeyer SJ, Shutter JR, Veis DJ, Merry DE, Oltvai ZN, Bcl2/Bax: a rheostat that regulates an anti-oxidant pathway and cell death. Semin Cancer Biol.1993;4(6):327-32. |
| [33] | Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, et al. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science.1997;275(5303):1129-32. |
| [34] | Chen G, Manji HK, The extracellular signal-regulated kinase pathway: An emerging promising target for mood stabilizers. Curr Opin Psychiatry.2006;19:313-23. |
| [35] | Chen DF, Schneider GE, Martinou JC, Tonegawa S, Bcl-2 promotes regeneration of severed axons in mammalian CNS. Nature.1997;385:435-9. |
| [36] | Jonas E, Bcl-xl regulates synaptic plasticity. Mol Interv.2006;6:208-22. |
| [37] | Oltwai ZN, Milliman CL, Korsemeyer SJ, Bcl2 heterodimers in vivo with a conserved homolog Bax, that accelerates programmed cell death. Cell.1993;74:609-19. |
| [38] | Surhone LM, Tennoe MT, Henssonow SF, Bcl-2-associated X Protein. Beau Bassin: Betascript Publishing;2011. |
| [39] | Jarskog LF, Selinger ES, Lieberman JA, Gilmore JH, Cortical Bcl2 protein expression and apoptotic regulation in schizophrenia. Biol Psychiatry.2000;48:641-50. |
| [40] | Jarskog LF, Selinger ES, Lieberman JA, Gilmore JH, Apoptotic proteins in the temporal cortex in schizophrenia: high Bax/Bcl2 ratio without caspase-3 activation. Am J Psychiatry.2004;161:109-15. |
| [41] | World Health Organization, The International Statistical Classification of Diseases and Related Health Problems (10th edition). Geneva:World Health Organization;1992. |
| [42] | American Psychiatric Association Diagnostic and Statistical Manual of mental disorders, (4th edition, text revised), Arlington (VA):American Psychiatric Publishing;2000. |
| [43] | First MB, Spitzer RL, Gibbon M, Williams JB, SCID-I/NP: Structured Clinical Interview for DSM-IV-TR Axis I Disorders (research version, non-patient edition). New York: Biometrics Research, New York State Psychiatric Institute;2002. |
| [44] | Sambrook J, Russell DW, Molecular Cloning: A Laboratory Manual (3rd edition). New York: Cold Spring Harbor Laboratory Press;2001. |
| [45] | Bunce M, O’Neil CM, Barnado MC, Krausa P, Browning MJ, Morris PJ, et al. Phototyping: comprehensive DNA typing for HLA-A, B, C, DRB3, DRB4, DRB5 & DQB1 by PCR with 144 primer mixes utilizing sequence-specific primers (PCR-SSP). Tissue Antigens.1995;46:355-67. |
| [46] | Rice TK, Schork NJ, Rao DC, Methods for handling multiple testing. Adv Genet.2008;60:293-308. |
| [47] | Lalouel JM, Rohrwasser A, Power and replication in case-control studies. Am J Hypertens.2002;15(2):201-5. |
| [48] | Milani L, Gupta M, Andersen M, Dhar S, Fryknäs M, Isaksson A, et al. Allelic imbalance in gene expression as a guide to cis-acting regulatory single nucleotide polymorphisms in cancer cells. Nucleic Acids Res.2007;35(5):34. |
| [49] | Kim DH, Xu W, Ma C, Liu X, Siminovitch K, Messner HA, et al. Genetic variants in the candidate genes of the apoptosis pathway and susceptibility to chronic myeloid leukemia. Blood.2009;113(11):2517-25. |
| [50] | Eun YG, Hong IK, Kim SK, Park HK, Kwon S, Chung DH, et al. Polymorphism (rs1801018, Thr7Thr) of BCL2 is associated with papillary thyroid cancer in Korean population. Clin Exp Otorhinolaryngol.2011;4(3):149-54. |
| [51] | Gu S, Wu Q, Zhao X, Wu W, Gao Z, Tan X, et al. Association of CASP3 polymorphism with hematologic toxicity in patients with advanced non-small-cell lung carcinoma treated with platinum-based chemotherapy. Cancer Sci.2012;103(8):1451-9. |
| [52] | Hoh NZ, Wagner AK, Alexander SA, Clark RB, Beers SR, Okonkwo DO, et al. BCL2 genotypes: functional and neurobehavioral outcomes after severe traumatic brain injury. J Neurotrauma.2010;27(8):1413-27. |
| [53] | Manji HK, Bcl-2: A key regulator of affective resilience in the pathophysiology and treatment of severe mood disorders. Biol Psychiatry.2008;63(suppl 1):243S. |
| [54] | Yuan P, Baum AE, Zhou R, Wang Y, Laje G, McMahon FJ, et al. Bcl-2 polymorphisms associated with mood disorders and antidepressant-responsiveness regulate Bcl-2 gene expression and cellular resilience in human lymphoblastoid cell lines. Biol Psychiatry.2008;63(suppl 1):63S. |
| [55] | Salvadore G, Nugent AC, Chen G, Akula N, Yuan P, Cannon DM, et al. Bcl-2 polymorphism influences gray matter volume in the ventral striatum in healthy humans. Biol Psychiatry.2009;66(8):804-7. |
| [56] | Liu ME, Huang CC, Hwang JP, Yang AC, Tu PC, Yeh HL, et al. Effect of Bcl-2 rs956572 SNP on regional gray matter volumes and cognitive function in elderly males without dementia. Age (Dordr).2013;35(2):343-52. |
| [57] | Soeiro-de-Souza MG, Salvadore G, Moreno RA, Otaduy MC, Chaim KT, Gattaz WF, et al. Bcl-2 rs956572 polymorphism is associated with increased anterior cingulate cortical glutamate in euthymic bipolar I disorder. Neuropsychopharmacology.2013;38(3):468-75. |
| [58] | Uemura T, Green M, Corson TW, Perova T, Li PP, Warsh JJ, Bcl-2 SNP rs956572 associates with disrupted intracellular calcium homeostasis in bipolar I disorder. Bipolar Disord.2011;13(1):41-51. |
| [59] | Machado-Vieira R, Pivovarova NB, Stanika RI, Yuan P, Wang Y, Zhou R, et al. The Bcl-2 gene polymorphism rs956572AA increases inositol 1,4,5-trisphosphate receptor-mediated endoplasmic reticulum calcium release in subjects with bipolar disorder. Biol Psychiatry.2011;69(4):344-52. |
