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A longitudinal study of the association between the GNB3 C825T polymorphism and metabolic disturbance in bipolar II patients treated with valproate

The Pharmacogenomics Journal volume 17, pages 155–161 (2017)Cite this article

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Abstract

This longitudinal study aimed to investigate the associations between the polymorphisms of guanine nucleotide-binding protein subunit β-3 (GNB3) C825T and metabolic disturbance in bipolar II disorder (BP-II) patients being treated with valproate (VPA). A 100 BP-II patients received a 12-week course of VPA treatment, and their body weight and metabolic indices were measured. At baseline, the GNB3 C825T polymorphisms were associated with the triglyceride level (P=0.032) in BP-II patients. During the VPA treatment course, the polymorphisms were not only associated with body mass index (BMI) and waist circumference (P-values=0.009 and 0.001, respectively), but also with total cholesterol, triglyceride, low-density lipoprotein and leptin levels (P-values=0.004, 0.002, 0.031 and 0.015, respectively). Patients with the TT genotype had a lower BMI, smaller waist circumference, and lower levels of lipids and leptin than those with the CT or CC genotypes undergoing the VPA treatment course.

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References

  1. Osby U, Brandt L, Correia N, Ekbom A, Sparen P . Excess mortality in bipolar and unipolar disorder in Sweden. Arch Gen Psychiatry 2001; 58: 844–850.

    Article  CAS  PubMed  Google Scholar 

  2. Keck PJ, McElroy S, Arnold L . Bipolar disorder. Med Clin North Am 2001; 85: 6455–6661.

    Article  Google Scholar 

  3. Das AK, Olfson M, Gameroff MJ, Pilowsky DJ, Blanco C, Feder A et al. Screening for bipolar disorder in a primary care practice. JAMA 2005; 293: 956–963.

    Article  CAS  PubMed  Google Scholar 

  4. Judd LL, Akiskal HS, Schettler PJ, Endicott J, Leon AC, Solomon DA et al. Psychosocial disability in the course of bipolar I and II disorders: a prospective, comparative, longitudinal study. Arch Gen Psychiatry 2005; 62: 1322–1330.

    Article  PubMed  Google Scholar 

  5. Lu RB, Chen SL, Lee SY, Chang YH, Chen SH, Chu CH et al. Neuroprotective and neurogenesis agent for treating bipolar II disorder: add-on memantine to mood stabilizer works. Med Hypotheses 2012; 79: 280–283.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lee SY, Chen SL, Chang YH, Chen PS, Huang SY, Tzeng NS et al. Add-on memantine to valproate treatment increased HDL-C in bipolar II disorder. J Psychiatr Res 2013; 47: 1343–1348.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Vieta E, Gasto C, Otero A, Nieto E, Vallejo J . Differential features between bipolar I and bipolar II disorder. Compr Psychiatry 1997; 38: 98–101.

    Article  CAS  PubMed  Google Scholar 

  8. Judd LL, Akiskal HS, Schettler PJ, Coryell W, Endicott J, Maser JD et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry 2003; 60: 261–269.

    Article  PubMed  Google Scholar 

  9. Pallanti S, Quercioli L, Pazzagli A, Rossi A, Dell'Osso L, Pini S et al. Awareness of illness and subjective experience of cognitive complaints in patients with bipolar I and bipolar II disorder. Am J Psychiatry 1999; 156: 1094–1096.

    CAS  PubMed  Google Scholar 

  10. Akiskal HS . The bipolar spectrum: research and clinical perspectives. Encephale 1995; 21: 3–11.

    PubMed  Google Scholar 

  11. Akiskal HS, Pinto O . The evolving bipolar spectrum. Prototypes I, II, III, and IV. Psychiatr Clin North Am 1999; 22: 517–534, vii.

    Article  CAS  PubMed  Google Scholar 

  12. Angst J, Gamma A, Benazzi F, Ajdacic V, Eich D, Rossler W . Toward a re-definition of subthreshold bipolarity: epidemiology and proposed criteria for bipolar-II, minor bipolar disorders and hypomania. J Affect Disord 2003; 73: 133–146.

    Article  PubMed  Google Scholar 

  13. Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Beaulieu S, Alda M et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013. Bipolar Disord 2013; 15: 1–44.

    Article  CAS  PubMed  Google Scholar 

  14. Grunze H, Vieta E, Goodwin GM, Bowden C, Licht RW, Moller HJ et al. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2012 on the long-term treatment of bipolar disorder. World J Biol Psychiatry 2013; 14: 154–219.

    Article  PubMed  Google Scholar 

  15. Winsberg ME, DeGolia SG, Strong CM, Ketter TA . Divalproex therapy in medication-naive and mood-stabilizer-naive bipolar II depression. J Affect Disord 2001; 67: 207–212.

    Article  CAS  PubMed  Google Scholar 

  16. Wang PW, Nowakowska C, Chandler RA, Hill SJ, Nam JY, Culver JL et al. Divalproex extended-release in acute bipolar II depression. J Affect Disord 2010; 124: 170–173.

    Article  CAS  PubMed  Google Scholar 

  17. Rosenberg G . The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees? Cell Mol Life Sci 2007; 64: 2090–2103.

    Article  CAS  PubMed  Google Scholar 

  18. Hunsberger J, Austin DR, Henter ID, Chen G . The neurotrophic and neuroprotective effects of psychotropic agents. Dialogues Clin Neurosci 2009; 11: 333–348.

    PubMed  PubMed Central  Google Scholar 

  19. Chen G, Hasanat KA, Bebchuk JM, Moore GJ, Glitz D, Manji HK . Regulation of signal transduction pathways and gene expression by mood stabilizers and antidepressants. Psychosom Med 1999; 61: 599–617.

    Article  CAS  PubMed  Google Scholar 

  20. Hahn CG, Umapathy, Wang HY, Koneru R, Levinson DF, Friedman E . Lithium and valproic acid treatments reduce PKC activation and receptor-G protein coupling in platelets of bipolar manic patients. J Psychiatr Res 2005; 39: 355–363.

    Article  PubMed  Google Scholar 

  21. Martini JS, Raake P, Vinge LE, DeGeorge BR Jr, Chuprun JK, Harris DM et al. Uncovering G protein-coupled receptor kinase-5 as a histone deacetylase kinase in the nucleus of cardiomyocytes. Proc Natl Acad Sci USA 2008; 105: 12457–12462.

    Article  CAS  PubMed  Google Scholar 

  22. Beaulieu JM, Caron MG . Beta-arrestin goes nuclear. Cell 2005; 123: 755–757.

    Article  CAS  PubMed  Google Scholar 

  23. Chang HH, Chou CH, Chen PS, Gean PW, Huang HC, Lin CY et al. High prevalence of metabolic disturbances in patients with bipolar disorder in Taiwan. J Affect Disord 2009; 117: 124–129.

    Article  CAS  PubMed  Google Scholar 

  24. Chang HH, Yang YK, Gean PW, Huang HC, Chen PS, Lu RB . The role of valproate in metabolic disturbances in bipolar disorder patients. J Affect Disord 2010; 124: 319–323.

    Article  CAS  PubMed  Google Scholar 

  25. Brown R, Imran SA, Ur E, Wilkinson M . Valproic acid and CEBPalpha-mediated regulation of adipokine gene expression in hypothalamic neurons and 3T3-L1 adipocytes. Neuroendocrinology 2008; 88: 25–34.

    Article  CAS  PubMed  Google Scholar 

  26. Kannel WB, D'Agostino RB, Cobb JL . Effect of weight on cardiovascular disease. Am J Clin Nutr 1996; 63: 419S–422S.

    Article  CAS  PubMed  Google Scholar 

  27. Verrotti A, D'Egidio C, Mohn A, Coppola G, Chiarelli F . Weight gain following treatment with valproic acid: pathogenetic mechanisms and clinical implications. Obes Rev 2011; 12: e32–e43.

    Article  CAS  PubMed  Google Scholar 

  28. Wood JR, Nelson-Degrave VL, Jansen E, McAllister JM, Mosselman S, Strauss JF 3rd . Valproate-induced alterations in human theca cell gene expression: clues to the association between valproate use and metabolic side effects. Physiol Genomics 2005; 20: 233–243.

    Article  CAS  PubMed  Google Scholar 

  29. Siffert W . G protein beta 3 subunit 825 T allele, hypertension, obesity, and diabetic nephropathy. Nephrol Dial Transplant 2000; 15: 1298–1306.

    Article  CAS  PubMed  Google Scholar 

  30. Siffert W, Rosskopf D, Siffert G, Busch S, Moritz A, Erbel R et al. Association of a human G-protein beta3 subunit variant with hypertension. Nat Genet 1998; 18: 45–48.

    Article  CAS  PubMed  Google Scholar 

  31. Brand E, Wang JG, Herrmann SM, Staessen JA . An epidemiological study of blood pressure and metabolic phenotypes in relation to the Gbeta3 C825 T polymorphism. J Hypertens 2003; 21: 729–737.

    Article  CAS  PubMed  Google Scholar 

  32. Chang HH, Gean PW, Chou CH, Yang YK, Tsai HC, Lu RB et al. C825T polymorphism of the GNB3 gene on valproate-related metabolic abnormalities in bipolar disorder patients. J Clin Psychopharmacol 2010; 30: 512–517.

    Article  CAS  PubMed  Google Scholar 

  33. Chi MH, Chang HH, Tzeng N-S, Huang S-Y, Chou K-R, Tsai HC et al. The prevalence of metabolic syndrome in drug-naïve bipolar II disorder patients before and after twelve week pharmacological intervention. J Affect Disord 2013; 146: 79–83.

    Article  CAS  Google Scholar 

  34. Huang CC, Chang YH, Lee SY, Chen SL, Chen SH, Chu CH et al. The interaction between BDNF and DRD2 in bipolar II disorder but not in bipolar I disorder. Am J Med Genet B Neuropsychiatr Genet 2012; 159B: 501–507.

    Article  PubMed  Google Scholar 

  35. Hu Q, Zhang SY, Liu F, Zhang XJ, Cui GC, Yu EQ et al. Influence of GNB3 C825T polymorphism on the efficacy of antidepressants in the treatment of major depressive disorder: a meta-analysis. J Affect Disord 2014; 172C: 103–109.

    Google Scholar 

  36. Milaneschi Y, Lamers F, Mbarek H, Hottenga JJ, Boomsma DI, Penninx BW . The effect of FTO rs9939609 on major depression differs across MDD subtypes. Mol Psychiatry 2014; 19: 960–962.

    Article  CAS  PubMed  Google Scholar 

  37. Uher R, Mors O, Hauser J, Rietschel M, Maier W, Kozel D et al. Body weight as a predictor of antidepressant efficacy in the GENDEP project. J Affect Disord 2009; 118: 147–154.

    Article  CAS  PubMed  Google Scholar 

  38. Kloiber S, Ising M, Reppermund S, Horstmann S, Dose T, Majer M et al. Overweight and obesity affect treatment response in major depression. Biol Psychiatry 2007; 62: 321–326.

    Article  PubMed  Google Scholar 

  39. Opel N, Redlich R, Grotegerd D, Dohm K, Heindel W, Kugel H et al. Obesity and major depression: body-mass index (BMI) is associated with a severe course of disease and specific neurostructural alterations. Psychoneuroendocrinology 2015; 51: 219–226.

    Article  PubMed  Google Scholar 

  40. Rivera M, Cohen-Woods S, Kapur K, Breen G, Ng MY, Butler AW et al. Depressive disorder moderates the effect of the FTO gene on body mass index. Mol Psychiatry 2012; 17: 604–611.

    Article  CAS  PubMed  Google Scholar 

  41. Bornstein SR, Schuppenies A, Wong ML, Licinio J . Approaching the shared biology of obesity and depression: the stress axis as the locus of gene-environment interactions. Mol Psychiatry 2006; 11: 892–902.

    Article  CAS  PubMed  Google Scholar 

  42. Lee SY, Chen SL, Chang YH, Chen PS, Huang SY, Tzeng NS et al. Correlation of plasma brain-derived neurotrophic factor and metabolic profiles in drug-naive patients with bipolar II disorder after a twelve-week pharmacological intervention. Acta Psychiatr Scand 2015; 131: 120–128.

    Article  CAS  PubMed  Google Scholar 

  43. Ernst C, Marshall CR, Shen Y, Metcalfe K, Rosenfeld J, Hodge JC et al. Highly penetrant alterations of a critical region including BDNF in human psychopathology and obesity. Arch Gen Psychiatry 2012; 69: 1238–1246.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Ma XY, Qiu WQ, Smith CE, Parnell LD, Jiang ZY, Ordovas JM et al. Association between BDNF rs6265 and obesity in the Boston Puerto Rican Health Study. J Obes 2012; 2012: 102942.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Schwartz E, Mobbs CV . Hypothalamic BDNF and obesity: found in translation. Nat Med 2012; 18: 496–497.

    Article  CAS  PubMed  Google Scholar 

  46. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS . Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 2001; 276: 36734–36741.

    Article  CAS  PubMed  Google Scholar 

  47. Leng Y, Liang MH, Ren M, Marinova Z, Leeds P, Chuang DM . Synergistic neuroprotective effects of lithium and valproic acid or other histone deacetylase inhibitors in neurons: roles of glycogen synthase kinase-3 inhibition. J Neurosci 2008; 28: 2576–2588.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Christensen DP, Dahllof M, Lundh M, Rasmussen DN, Nielsen MD, Billestrup N et al. Histone deacetylase (HDAC) inhibition as a novel treatment for diabetes mellitus. Mol Med 2011; 17: 378–390.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Crunkhorn S . Metabolic disease: new role for HDACs in glucose homeostasis. Nat Rev Drug Discov 2011; 10: 492.

    Article  CAS  PubMed  Google Scholar 

  50. Karpac J, Jasper H . Metabolic homeostasis: HDACs take center stage. Cell 2011; 145: 497–499.

    Article  CAS  PubMed  Google Scholar 

  51. Schroeder FA, Lewis MC, Fass DM, Wagner FF, Zhang YL, Hennig KM et al. A selective HDAC 1/2 inhibitor modulates chromatin and gene expression in brain and alters mouse behavior in two mood-related tests. PLoS One 2013; 8: e71323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Siffert W, Forster P, Jockel KH, Mvere DA, Brinkmann B, Naber C et al. Worldwide ethnic distribution of the G protein beta3 subunit 825T allele and its association with obesity in Caucasian, Chinese, and Black African individuals. J Am Soc Nephrol 1999; 10: 1921–1930.

    CAS  PubMed  Google Scholar 

  53. Rosskopf D, Manthey I, Siffert W . Identification and ethnic distribution of major haplotypes in the gene GNB3 encoding the G-protein beta3 subunit. Pharmacogenetics 2002; 12: 209–220.

    Article  CAS  PubMed  Google Scholar 

  54. Klenke S, Kussmann M, Siffert W . The GNB3 C825T polymorphism as a pharmacogenetic marker in the treatment of hypertension, obesity, and depression. Pharmacogenet Genomics 2011; 21: 594–606.

    Article  CAS  PubMed  Google Scholar 

  55. Hsiao T-J, Hwang Y, Liu C-H, Chang H-M, Lin E . Association of the C825T polymorphism in the GNB3 gene with obesity and metabolic phenotypes in a Taiwanese population. Genes Nutr 2013; 8: 137–144.

    Article  CAS  PubMed  Google Scholar 

  56. Andersen G, Overgaard J, Albrechtsen A, Glümer C, Borch-Johnsen K, Jørgensen T et al. Studies of the association of the GNB3 825C>T polymorphism with components of the metabolic syndrome in white Danes. Diabetologia 2006; 49: 75–82.

    Article  CAS  PubMed  Google Scholar 

  57. Wang YC, Bai YM, Chen JY, Lin CC, Lai IC, Liou YJ . C825T polymorphism in the human G protein beta3 subunit gene is associated with long-term clozapine treatment-induced body weight change in the Chinese population. Pharmacogenet Genomics 2005; 15: 743–748.

    Article  CAS  PubMed  Google Scholar 

  58. Souza RP, De Luca V, Muscettola G, Rosa DVF, de Bartolomeis A, Romano Silva M et al. Association of antipsychotic induced weight gain and body mass index with GNB3 gene: a meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 1848–1853.

    Article  CAS  PubMed  Google Scholar 

  59. Martin CK, Han H, Anton SD, Greenway FL, Smith SR . Effect of valproic acid on body weight, food intake, physical activity and hormones: results of a randomized controlled trial. J Psychopharmacol 2009; 23: 814–825.

    Article  CAS  PubMed  Google Scholar 

  60. Kanemura H, Sano F, Maeda Y-i, Sugita K, Aihara M . Valproate sodium enhances body weight gain in patients with childhood epilepsy: a pathogenic mechanisms and open-label clinical trial of behavior therapy. Seizure 2012; 21: 496–500.

    Article  PubMed  Google Scholar 

  61. Lee SY, Chen SL, Chang YH, Chen SH, Chu CH, Huang SY et al. Genotype variant associated with add-on memantine in bipolar II disorder. Int J Neuropsychopharmacol 2014; 17: 189–197.

    Article  PubMed  Google Scholar 

  62. Shinozaki G, Potash JB . New developments in the genetics of bipolar disorder. Curr Psychiatry Rep 2014; 16: 493.

    Article  PubMed  Google Scholar 

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Acknowledgements

This study was financially supported by the National Science Council of Taiwan (NSC 100-2627-B-006-012, NSC 101-2314-B-006-064-MY3, and MOST 104-2320-B-006-024). We thank Mr Chien Ting Lin for his administrative support. The funding institutions of this study had no further role in the study design; collection, analysis and interpretation of data; writing of this article; or the decision to submit for publication.

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Authors and Affiliations

  1. Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    P S Chen, C-C Huang, Y K Yang & R-B Lu

  2. Addiction Research Center, National Cheng Kung University, Tainan, Taiwan

    P S Chen, Y K Yang & R-B Lu

  3. Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    H H Chang & C C Lee

  4. School of Pharmacy, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    H H Chang

  5. Department of Psychiatry, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

    S-Y Lee

  6. Department of Neurology, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    S-L Chen

  7. Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

    S-Y Huang

  8. Department of Psychiatry, National Cheng Kung University Hospital, Dou-Liou Branch, Yunlin, Taiwan

    Y K Yang

  9. Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan

    Y K Yang

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Chen, P., Chang, H., Huang, CC. et al. A longitudinal study of the association between the GNB3 C825T polymorphism and metabolic disturbance in bipolar II patients treated with valproate. Pharmacogenomics J 17, 155–161 (2017). https://doi.org/10.1038/tpj.2015.96

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