5-HTTLPR与抑郁相关性的研究动态

摘要/Abstract

摘要：

摘要 5-HTTLPR是5-羟色胺转运蛋白基因启动子区域上的多态性位点，对其转录效率具有调节作用。5-HTTLPR基因型与抑郁存在相关，但必须把二者的关系置于一个多基因与环境交互作用的框架下考察。一方面，环境因素的作用不容忽视：S等位基因携带者暴露于负性生活事件时，表现出更多情绪问题，更易发生抑郁。另一方面，CYP2C9、BDNF等基因与5-HTTLPR有交互作用，共同影响抑郁的发生。此外，年龄、性别等因素会对研究结果造成混淆。未来研究应侧重于对机制的探讨。

关键词: 5-HTTLPR, 抑郁, 交互作用, 生活事件

Abstract:

Abstract: A regulatory variation in the serotonin transporter gene promoter region (5-HTTLPR) is considered to be related to depression. However, the effects of environmental factors and other genes could not be ignored. On one hand, 5-HTTLPR interacts with risk environmental factors: S-allele carriers would be at higher risk of depression or other emotion disorders when exposed to negative life events. On the other hand, other genes, such as CYP2C9 and BDNF gene, interact with 5-HTTLPR, accounting for the development of depression. In addition, gender and age may be potential confounding factors, and should be well controlled. Future work should highlight the mechanisms how 5-HTTLPR, risk environment factors and other genes interact with each other, enhancing the depression level of human and laboratory animals.

Key words: 5-HTTLPR, depression, interaction, life events

张俊先陈杰李新影. 5-HTTLPR与抑郁相关性的研究动态[J]. 心理科学, 2012, 35(1): 226-232.

参考文献

Barr, C. S., Newman, T. K., Becker, M. L., Parker, C. C., Champoux, M., ＆ Lesch, K. P., et al. (2003). The utility of the non-human primate model for studying gene by environment interactions in behavioral research. Genes, Brain and Behavior, 2, 336–340. Barr, C. S., Newman, T. K., Shannon, C., Parker, C., Dvoskin, R. L., ＆ Becker, M. L., et al. (2004). Rearing condition and rh5-HTTLPR interact to influence limbic-hypothalamic-pituitary-adrenal axis response to stress in infant macaques. Biol Psychiatry ,55, 733–738. Beck, A. T. (1987). Cognitive models of depression. Journal of Cognitive Psychotherapy, 1, 5–38. Bennett, A. J., Lesch, K. P., Heils, A., Long, J. C., Lorenz, J. G., ＆ Shoaf, S. E., et al. (2002). Early experience and serotonin transporter gene variation interact to influence primate CNS function. Molecular Psychiatry,7,118–122. Brummett, B. H., Boyle, S. H., Siegler, I. C., Kuhn, C. M., Ashley-Koch. A., ＆ Jonassaint, C. R., et al. (2008). Effects of environmental stress and gender on associations among symptoms of depression and the serotonin transporter gene linked polymorphic region (5-HTTLPR). Behav Genet, 38, 34–43. Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., ＆ Harrington, H., et al. (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science, 301, 386–389. Cervilla, J. A., Rivera, M., Molina, E., Torres-González, F., Bellón, J. A., ＆ Moreno, B., et al. (2006). The 5-HTTLPR s/s genotype at the serotonin transporter gene (SLC6A4) increases the risk for depression in a large cohort of primary care attendees: the PREDICT-Genestudy. Neuropsychiatric Genetics, 141(B), 912–917. Champoux, M., Bennett, A., Shannon, C., Higley, J. D., Lesch, K. P., ＆ Suomi1, S. J. (2002). Serotonin transporter gene polymorphism, differential early rearing, and behavior in rhesus monkey neonates. Molecular Psychiatry, 7, 1058–1063. Dorado, P., Pe?as-LLedó, E. M., González, A. P., Cáceres, M. C., Cobaleda, J., ＆ Llerena, A. (2007). Increased risk for major depression associated with the short allele of the serotonin transporter promoter region (5-HTTLPR-S) and the CYP2C9*3 allele. Fundamental & Clinical Pharmacology, 21, 451–453. Eley, T. C., Sugden, K., Corsico, A., Gregory, A. M., Sham, P., ＆ McGuffin, P., et al. (2004). Gene–environment interaction analysis of serotonin system markers with adolescent depression. Mol Psychiatry, 9, 908–915. Gershon, E. S., Hamovit, J., Guroff, J. J., Dibble, E., Leckman, J. F., ＆ Sceery, W., et al. (1982). A family study of schizoaffective, bipolar I, bipolar II, unipolar, and normal control probands. Achieves of General Psychiatry, 39, 1157–1167. Gervasini, G., Mart??nez, C., Agu? ndez, J. A. G., Garc??a-Gamito, F. J., ＆ Ben??tez, J. (2001). Inhibition of cytochrome P450 2C9 activity in vitro by 5-hydroxytryptamine and adrenaline. Pharmacogenetics, 11, 29–37. Gillespie, N. A., Whitfield, J. B., Williams, B., Heath, A. C., ＆ Martin, N. G. (2005). The relationship between stressful life events, the serotonin transporter (5-HTTLPR) genotype and major depression. Psychological Medicine, 35, 101–111. Gonda, X., Fountoulakis, K. N., Juhasz, G., Rihmer, Z., Lazary, J., ＆ Laszik, A., et al. (2009). Association of the s allele of the 5-HTTLPR with neuroticism-related traits and temperaments in a psychiatrically healthy population. Eur Arch Psychiatry Clin Neurosci, 259, 106–113. Gotlib, L. H., Joormann, J., Minor, K. L., ＆ Hallmayer, J. (2008). HPA axis reactivity:a mechanism underlying the associations among 5-HTTLPR, stress, and depression. Biol Psychiatry, 63, 847–851. Grabe, H. J., Lange, M., Wolff, B., V?lzke, H., Lucht, M., ＆ Freyberger, H. J., et al. (2005). Mental and physical distress is modulated by a polymorphism in the 5-HT transporter gene interacting with social stressors and chronic disease burden. Mol Psychiatry, 10, 220–224. Heils, A., Teufel, A., Petri, S., Stober, G.., Riederer, P., ＆ Bengel, D., et al. (1996). Allelic variation of human serotonin transporter gene expression. J.Neurochem, 66, 2621-2624. Hoefgen, B., Schulze, T. G., Ohlraun, S., Widdern, O. V., H?fels, S., ＆ Gross, M., et al. (2005). The power of sample size and homogenous sampling: association between the 5-HTTLPR serotonin transporter polymorphism and major depressive disorder. Biol Psychiatry, 57, 247–251. Holmes, A., Murphy, D. L., ＆ Crawley, J. N. (2003). Abnormal behavioral phenotypes of serotonin transporter knockout mice: parallels with human anxiety and depression. Biol Psychiatry, 54, 953–959. Holmes, A., Yang, R. J., Lesch, K. P., Crawley, J. N., ＆ Murphy, D. L. (2003). Mice lacking the serotonin transporter exhibit 5-HT1A receptor-mediated abnormalities in tests for anxiety-like behavior. Neuropsychopharmacology, 28, 2077–2088. Jabbi, M., Korf, J., Kema, I. P., Hartman, C., van der Pompe, G., ＆ Minderaa, R. B., et al. (2007). Convergent genetic modulation of the endocrine stress response involves polymorphic variations of 5-HTT, COMT and MAOA. Mol Psychiatry, 12(5), 483-490. Jacobs, N., Kenis, C., Peeters, F., Derom, C., Vlietinck, R., ＆ Os, J. V. (2006). Stress-related negative affectivity and genetically altered serotonin transporter function. Arch Gen Psychiatry, 63, 989–996. Jennings, K. A., Loder, M. K., Sheward, W. J., Pei, Q., Deacon, R. M. J., ＆ Benson, M. A., et al. (2006). Increased expression of the 5-HT transporter confers a low-anxiety phenotype linked to decreased 5-HT transmission. The Journal of Neuroscience, 26(35), 8955–8964. Kaufman, J., Yang, B. Z., Douglas-Palumberi, H., Grasso, D., Lipschitz, D., Houshyar, S., ＆Krystal, J. H., et al. (2006). Brain-derived neurotrophic factor–5-HTTLPR gene interactions and environmental modifiers of depression in children. Biol Psychiatry, 59, 673–680. Kaufman, J., Yang, B. Z., Douglas-Palumberi, H., Houshyar, S., Lipschitz, D., ＆ Krystal, J. H.,et al. (2004). Social supports and serotonin transporter gene moderate depression in maltreated children. Proc Natl Acad Sci USA, 101, 17316–17321. Kendler, K. S., Kuhn, J. W., Vittum, J., Prescott, C. A., ＆ Riley, B. (2005). The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression. Arch Gen Psychiatry, 62, 529–535. Kim, J. M., Stewart, R., Kim, S. W., Shin, I. S., Yang, S. J., ＆ Yoon, J. S. (2009). Cholesterol and serotonin transporter polymorphism interactions in late-life depression. Neurobiology of Aging, (in press). Kim, J. M., Stewart, R., Kim, S. W., Yang, S. J., Shin, I. S., ＆ Kim, Y. H., et al. (2007). Interactions between life stressors and susceptibility genes (5-HTTLPR and BDNF) on depression in Korean elders. Biol Psychiatry, 62, 423–428. Laucht, M., Treutlein, J., Blomeyer, D., Buchmann, A. F., Schmid, B., ＆ Becker, K., et al. (2009). Interaction between the 5-HTTLPR serotonin transporter polymorphism and environmental adversity for mood and anxiety psychopathology: evidence from a high-risk community sample of young adults. International Journal of Neuropsychopharmacology, 1–11. Lesch, K. P., Bengel, D., Heils, A., Sabol, S. Z., Greenberg, B. D., ＆ Petri, S., et al. (1996). Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science, 274, 1527–1531. Levinson, D. F. (2006). The genetics of depression: a review. Biol Psychiatry, 60, 84–92. LLerena, A., Berecz, R., Dorado, P., González, A. P., Pe?as-LLedó, E. M., ＆Rubia, A. De. la. (2003). CYP2C9 gene and susceptibility to major depressive disorder. The Pharmacogenomics Journal , 3, 300–302. Maier, W., Lichtermann, D., Minges, J., Heun, R., Hallmayer, J., ＆ Benkert, O. (1992). Schizoaffective disorder and affective disorders with mood-incongruent psychotic features: Keep separate or combine? Evidence from a family study. American Journal of Psychiatry, 149, 1666 –1673. Malberg, J. E., Eisch, A. J., Nestler, E. J., ＆ Duman, R. S. (2000). Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci, 20, 9104–9110. Martinowich, K., ＆ Lu, B. (2008). Interaction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology REVIEWS, 33, 73–83. Monroe, S. M., ＆ Simons, A. D.(1991). Diathesis-Stress Theories in the context of life stress research: implications for the depressive disorders. Psychological Bulletin, 110(3), 406–425. Neumeister, A., Konstantinidis, A., Stastny, J., Schwarz, M. J., Vitouch, O., ＆ Willeit, M., et al. (2002). Association between serotonin transporter gene promoter polymorphism (5-HTTLPR) and behavioral responses to tryptophan depletion in healthy women with and without family history of depression. Arch Gen Psychiatry, 59, 613–620. Power, T., Stewart, R., Ancelin, M. L., Jaussent, I., Malafosse, A., ＆ Ritchie, K. (2008). 5-HTTLPR genotype, stressful life events and late-life depression: No evidence of interaction in a French population. Neurobiology of Aging. (in press). Ramamoorthy, S., Baumant, A. L., Mooret, K. R., Han, H., Yang-Feng, T., ＆ Chang, A. S., et al. (1993). Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proc. Natl. Acad. Sci. USA, 90, 2542–2546. Rosemary, J., ＆ Adithan, C. (2007). The pharmacogenetics of CYP2C9 and CYP2C19: ethnic variation and clinical significance. Current Clinical Pharmacology, 2, 93–109. Serretti, A., Lilli, R., Lorenzi, C., Lattuada, E., Cusin, C., ＆ Smeraldi, E. (2002). Serotonin transporter gene (5-HTTLPR) and major psychoses. Mol Psychiatry, 7, 95–99. Sj?berg, R. L., Nilsson, K. W., Nordquist, N., ?hrvik, J., Leppert, J., ＆ Lindstr?m, L., et al. (2006). Development of depression: sex and the interaction between environment and a promoter polymorphism of the serotonin transporter gene. Int J Neuropsychopharmacol, 9, 443–449. Smeraldi, E., Zanardi, R., Benedetti, F., Bella, D. D., Perez, J., ＆ Catalano, M. (1998). Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Molecular Psychiatry, 3, 508–511. Surtees, P. G., Wainwright, N. W. J., Willis-Owen, S. A. G., Luben, R., Day, N. E., ＆ Flint, J. (2006). Social adversity, the serotonin transporter (5-HTTLPR) polymorphism and major depressive disorder. Biol Psychiatry, 59, 224–229. Taylor, S. E., Way, B. M., Welch, W. T., Hilmert, C. J., Lehman, B. J., ＆ Eisenberger, N. I. (2006). Early family environment,current adversity, the serotonin transporter promoter polymorphism, and Depressive symptomatology. Biol Psychiatry, 60, 671–676. Uher, R., ＆ McGuffin, P. (2007). The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis. Mol Psychiatry, 1–16. Veletza, S., Samakouri, M., Emmanouil, G., Trypsianis, G., Kourmouli, N., ＆ Livaditis, M. (2009). Psychological vulnerability differences in students-carriers or not of the serotonin transporter promoter allele S: effect of adverse experiences. Synapse, 63, 193–200. Weissman, M. M., Gershon, E. S., Kidd, K. K., Prusoff, B. A., Leckman, J. F., ＆ Dibble, E., et al. (1984). Psychiatric disorders in the relatives of probands with affective disorders: The Yale NIMH collaborative family study. Achieves of General Psychiatry, 41, 13–21. Wellman, C. L., Izquierdo, A., Garrett, J. E., Martin, K. P., Carroll, J., ＆ Millstein, R., et al. (2007). Impaired stress-coping and fear extinction and abnormal corticolimbic morphology in serotonin transporter knock-out mice. The Journal of Neuroscience, 27(3), 684–691. Wilhelm, K., Mitchell, P. B., Niven, H., Finch, A., Wedgwood, L., ＆ Scimone, A., et al. (2006). Life events, first depression onset and the serotonin transporter gene. British Journal of Psychiatry, 188, 210–215. Willis-Owen, S. A. G., Turri, M. G., Munafò, M. R., Surtees, P. G., Wainwright, N. W. J., ＆Brixey, R. D., et al. (2005). The serotonin transporter length polymorphism, neuroticism, and depression: a comprehensive assessment of association. Biol Psychiatry, 58, 451–456. Wüst, s., Kumsta, R., Treutlein, J., Frank, J., Entringer, S., ＆ Schulze, T. G., et al. (2009). Sex-specific association between the 5-HTT gene-linked polymorphic region and basal cortisol secretion. Psychoneuroendocrinology, 34, 972–982. Zhang, K., Xu, Q., Xu, Y., Yang, H., Luo, J., ＆ Sun, Y., et al. (2009). The combined effects of the 5-HTTLPR and 5-HTR1A genes modulates the relationship between negative life events and major depressive disorder in a Chinese population. Journal of Affective Disorders, 114, 224–231.

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