Bipolar bozukluk hastalarında beyin kökenli nörotrofik faktör (BDNF) geni Val66Met ve Val66Val polimorfizmi ile hastalık özellikleri ve obsesif kompulsif belirti ilişkisi
Amaç: Bu çalışmada bipolar bozukluk (BB) hastalarında beyin kökenli nörotrofik faktör (brain-derived neuro- trophic factor-BDNF) geni Val66Met ve Val66Val polimorfizmi ile hastalık özellikleri ve obsesif kompulsif belirtiler arasındaki ilişkinin araştırılması amaçlanmıştır. Yöntem: Çalışmamıza klinik görüşme sonucunda DSM-IV-TR tanı ölçütlerine göre BB tanısı konan 106 gönüllü hasta alındı. Tüm katılımcılara Sosyodemografik ve Hastalık Bilgi Formu verildi ve DSM-IV Eksen I Bozuklukları için Yapılandırılmış Klinik Görüşme (Structured Clinical Interview for DSM-IV Axis Disorders-SCID-I), Maudsley Obsesif Kompulsif Soru Listesi, Beck Depresyon Ölçeği ve Beck Anksiyete Ölçeği uygulandı. Hastaların venöz kan örneklerinden DNA izolasyonu yapıldı, elde edilen DNAlar üzerinde PCR-RFLP yöntemi ile BDNF gen polimorfizmine bakıldı. Sonuçlar: Çalışmamızın sonucunda 78 hasta- da BDNF Val66Val, 28 hastada Val66Met polimorfizminin olduğu belirlendi. Val66Val grubundaki hastalarda BB başlama yaşının Val66Met grubundaki hastalara göre daha erken olduğu ve Val66Met grubundaki hastalar ara- sında antidepresan ile tetiklenen mani atağına istatistiksel olarak anlamlı ölçüde daha fazla rastlandığı belirlendi. Obsesif kompulsif bozukluk belirtilerinin varlığı açısından iki grup arasında istatistiksel anlamlılığa sahip bir fark saptanamadı. Tartışma: BBnin bazı özelliklerinin BDNF geni Val66Val/Met polimorfizmi ile ilişkili olduğu düşünül- mektedir. Araştırmamız bu görüşü destekler nitelikte olup daha geniş örneklemlerle yapılacak çalışmalara gerek- sinme vardır.
The relationship between disease characteristics, obsessive compulsive symptoms and brain derived neurotrophic factor (BDNF) gene Val66Met and Val66Val polymorphism in patients with bipolar disorder
Objective: The aim of this study is to investigate the association between brain-derived neurotrophic factor (BDNF) val66met, val66val gene polymorphism and the characteristics of bipolar disorder (BD), obsessive com- pulsive symptoms within patients of BD. Methods: One hundred and six patients, diagnosed with BD according to the DSM-IV-TR criteria, were included in the study. All participants completed a sociodemographic questionnaire and they went through Structured Clinical Interview for DSM-IV Axis Disorders (SCID-I), Maudsley Obsessional Compulsive Questionnaire, Beck Depression Inventory and Beck Anxiety Inventory. DNA isolation was made from patients venous blood samples and on these DNAs BDNF gene polymorphism investigated by PCR-RFLP method. Results: Our results showed that 78 patients had BDNF val66val while 28 patients had val66met poly- morphism. It was found that the patient group with val66val had an earlier age of onset of BD; moreover, in the val66met group, antidepressant induced mania episodes were significantly more frequent. No statistically signify- cant difference was found between the two polymorphism groups with respect to obsessive compulsive symp- toms. Discussion: It has been thought that some characteristics of BD maybe related with the BDNF gene Val66Val/Met polymorphism. Our research partially supports this notion and more studies with larger samples are needed.
___
- 1. Tsuang MT, Faraone SV. The genetics of mood disorders. The Johns Hopkins series in contem- porary medicine and public health. Baltimore, MD, US: Johns Hopkins University Press. 1990.
- 2. Birmaher B, Axelson D, Pavuluri M. Bipolar disor- der. M Andres, RV Fred (Eds.), Lewiss Child and Adolescent Psychiatry A Comprehensive Text- book, fourth ed., 2007, p.513-528.
- 3. Dick DM, Foroud T, Flury L, Bowman ES, Miller MJ, Rau NL et al. Genomewide linkage analyses of bipolar disorder: a new sample of 250 pedigrees from the National Institute of Mental Health Genetics Initiative. Am J Hum Genet 2003; 73:979.
- 4. Sklar P, Gabriel SB, McInnis MG, Bennett P, Lim YM, Tsan G, et al. Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Brain-derived neurotrophic factor. Mol Psychiatry 2002; 7:579- 593.
- 5. McInnes LA, Escamilla MA, Service SK, Reus VI, Leon P, Silva S, et al. A complete genome screen for genes predisposing to severe bipolar disorder in two Costa Rican pedigrees. Proc Natl Acad Sci U S A. 1996; 93:13060-13065.
- 6. Detera-Wadleigh SD, Badner JA, Berrettini WH, Yoshikawa T, Goldin LR, Turner G, et al. A high- density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2. Proc Natl Acad Sci USA 1999; 96:5604-5609.
- 7. Muller DJ, de Luca V, Sicard T, King N, Strauss J, Kennedy JL. Brain-derived neurotrophic factor (BDNF) gene and rapid-cycling bipolar disorder: family-based association study. Br J Psychiatry 2006; 189:317-323.
- 8. Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, Kennedy JL. The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study. Am J Hum Genet 2002; 71:651-655.
- 9. Geller B, Badner JA, Tillman R, Christian SL, Bolhofner K, Cook EH. Linkage disequilibrium of the brain-derived neurotrophic factor Val66Met polymorphism in children with a prepubertal and early adolescent bipolar disorder phenotype. Am J Psychiatry 2004; 161:1698-1700.
- 10. Hong CJ, Huo SJ, Yen FC, Tung CL, Pan GM, Tsai SJ. Association study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal be- havior. Neuropsychobiology. 2003; 48:186-189.
- 11. Nakata K, Ujike H, Sakai A, Uchida N, Nomura A, Imamura T, et al. Association study of the brain-derived neurotrophic factor (BDNF) gene with bipolar disorder. Neurosci Let 2003; 337:17- 20.
- 12. Kunugi H, Iijima Y, Tatsumi M, Yoshida M, Hashimoto R, Kato T, et al. No association be- tween the Val66Met polymorphism of the brain- derived neurotrophic factor gene and bipolar disorder in a Japanese population: a multicenter study. Biol Psychiatry. 2004; 56:376-378.
- 13. Oswald P, Del-Favero J, Massat I, Souery D, Claes S, Van Broeckhoven C, et al. Non-repli- cation of the brain-derived neurotrophic factor (BDNF) association in bipolar affective disorder: a Belgian patient-control study. Am J Med Genet B Neuropsychiatr Genet 2004; 129:34-35.
- 14. Neves-Pereira M, Cheung JK, Pasdar A, Zhang F, Breen G, Yates P, et al. BDNF gene is a risk factor for schizophrenia in a Scottish population. Mol Psychiatry 2005; 10:208-212.
- 15. Hall D, Dhilla A, Charalambous A, Gogos JA, Karayiorgou M. Sequence variants of the brain- derived neurotrophic factor (BDNF) gene are strongly associated with obsessive-compulsive disorder. Am J Hum Genet 2003; 73:370-376.
- 16. Hemmings SM, Kinnear CJ, Van der Merwe L, Lochner C, Corfield VA, Moolman-Smook JC, et al. Investigating the role of the brain-derived neurotrophic factor (BDNF) val66met variant in obsessive-compulsive disorder (OCD). World J Biol Psychiatry 2008; 9:126-134.
- 17. Rocha FF, Malloy-Diniz L, Lage NV, Correa H. Positive association between MET allele (BDNF Val66Met polymorphism) and obsessive-compul- sive disorder. Rev Bras Psiquiatr 2010; 32:323- 324.
- 18. Katerberg H, Lochner C, Cath DC, de Jonge P, Bochdanovits Z, Moolman-Smook JC, et al. The role of the brain-derived neurotrophic factor (BDNF) val66met variant in the phenotypic expression of obsessive-compulsive disorder (OCD). Am J Med Genet B Neuropsychiatr Genet 2009; 150:1050-1062.
- 19. Chen YW, Dilsaver SC. Comorbidity of panic dis- order in bipolar illness: evidence from the Epi- demiologic Catchment Area Survey. Am J Psychiatry 1995; 152:280-282.
- 20. Tamam L. Bipolar bozukluk ile anksiyete bozuk- luğu birlikteliği: Bir gözden geçirme. Türk Psiki- yatri Dergisi 2007; 18:59-71.
- 21. Hantouche EG, Angst J, Demonfaucon C, Perugi G, Lancrenon S, Akiskal HS. Cyclothymic OCD: a distinct form? J Affect Disord 2003; 75:1-10.
- 22. Shimizu E, Hashimoto K, Iyo M. Ethnic difference of the BDNF 196G/A (val66met) polymorphism frequencies: the possibility to explain ethnic mental traits. Am J Med Genet B Neuropsychiatr Genet 2004; 126:122-123.
- 23. Gratacos M, Gonzalez JR, Mercader JM, de Cid R, Urretavizcaya M, Estivill X. Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disor- ders, eating disorders, and schizophrenia. Biol Psychiatry 2007; 61:911-922.
- 24. Strauss J, Barr CL, George CJ, Devlin B, Vetro A, Kiss E, et al. Brain-derived neurotrophic factor variants are associated with childhood-onset mood disorder: confirmation in a Hungarian sample. Mol Psychiatry 2005; 10:861-867.
- 25. Skibinska M, Hauser J, Czerski PM, Leszc- zynska-Rodziewicz A, Kosmowska M, Kapelski P, et al. Association analysis of brain-derived neurotrophic factor (BDNF) gene Val66Met poly- morphism in schizophrenia and bipolar affective disorder. World J Biol Psychiatry 2004; 5:215- 220.
- 26. Rybakowski JK, Borkowska A, Czerski PM, Skibinska M, Hauser J. Polymorphism of the brain-derived neurotrophic factor gene and per- formance on a cognitive prefrontal test in bipolar patients. Bipolar disord. 2003; 5:468-472.
- 27. Zai G, Mundo E, Strauss J, Wong GW, Kennedy JL. Brain-derived neurotrophic factor (BDNF) gene not associated with antidepressant-induced mania. Bipolar Disord 2007; 9:521-525.
- 28. Tsai SJ. Is mania caused by overactivity of central brain-derived neurotrophic factor? Med Hypotheses 2004; 62:19-22.
- 29. Gallinat J, Schubert F, Bruhl R, Hellweg R, Klar AA, Kehrer C, et al. Met carriers of BDNF Val66Met genotype show increased N-acetyl- aspartate concentration in the anterior cingulate cortex. Neuroimage 2010; 49:767-771.
- 30. Hashimoto K. Brain-derived neurotrophic factor as a biomarker for mood disorders: an historical overview and future directions. Psychiatry Clin Neurosci 2010; 64:341-357.
- 31. Kim B, Kim CY, Hong JP, Kim SY, Lee C, Joo YH. Brain-derived neurotrophic factor Val/Met polymorphism and bipolar disorder. Association of the Met allele with suicidal behavior of bipolar patients. Neuropsychobiology 2008; 58:97-103.
- 32. Vincze I, Perroud N, Buresi C, Baud P, Bellivier F, Etain B, et al. Association between brain- derived neurotrophic factor gene and a severe form of bipolar disorder, but no interaction with the serotonin transporter gene. Bipolar disord. 2008; 10:580-587.
- 33. Zutshi A, Reddy YC, Thennarasu K, Chandras- hekhar CR. Comorbidity of anxiety disorders in patients with remitted bipolar disorder. Eur Arch Psychiatry Clin Neurosci. 2006; 256:428-436.
- 34. Green EK, Raybould R, Macgregor S, Hyde S, Young AH, O'Donovan MC, et al. Genetic varia- tion of brain-derived neurotrophic factor (BDNF) in bipolar disorder: case-control study of over 3000 individuals from the UK. Br J Psychiatry 2006; 188:21-25.