Advertisement

BDNF rs6265 (Val66Met) Polymorphism as a Risk Factor for Blepharospasm

  • Vasileios Siokas
  • Dimitrios Kardaras
  • Athina-Maria Aloizou
  • Ioannis Asproudis
  • Konstadinos G. Boboridis
  • Eleni Papageorgiou
  • Georgios M. Hadjigeorgiou
  • Evangelia E. Tsironi
  • Efthimios Dardiotis
Original Paper

Abstract

A few genetic variants are implicated in the development of blepharospasm (BSP). The precise role of the rs6265 on the brain-derived neurotrophic factor (BDNF) gene on BSP remains controversial. The effect of rs6265 on BSP was evaluated. 206 patients with BSP and 206 healthy controls were recruited and genotyped for the rs6265. We also performed a meta-analysis, by pooling our results with those from previous studies. A significant effect of rs6265 on the risk of BSP was found in the dominant model of inheritance [odds ratio (OR) (95% confidence interval (CI) 1.52 (1.01–2.29), p = 0.044]. Mutational load analysis of rs6265 in the risk of BSP using the ORG revealed that higher load of the “A” allele of rs6265 denotes higher probability of a subject to develop BSP (ORG 1.48; 95% CI 1.00–2.19). Finally, pooled results from the meta-analysis revealed that the rs6265 is associated with an increased risk of BSP in the dominant model [OR 1.26; 95% CI 1.02–1.55, pz = 0.03]. Also, higher load of the “A” allele of rs6265 denotes higher probability of a subject to develop BSP (ORG 1.26; 95% CI 1.04–1.53). The present study provides additional evidence to the existing knowledge concerning the contribution of the rs6265 BDNF on the risk of developing BSP. While the pathophysiology and genetic susceptibility in BSP and focal dystonia are only partially understood, it seems that BDNF and rs6265 may constitute one essential risk factor that is heavily involved.

Keywords

BDNF Blepharospasm Focal dystonia Polymorphism SNP 

Notes

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

12017_2018_8519_MOESM1_ESM.docx (14 kb)
Supplementary File 1 The complete search algorithm. (DOCX 13 KB)
12017_2018_8519_MOESM2_ESM.doc (31 kb)
Supplementary File 2 Flow chart presenting the selection of eligible studies. (DOC 31 KB)
12017_2018_8519_MOESM3_ESM.doc (63 kb)
Supplementary File 3 PRISMA 2009 Checklist. (DOC 63 KB)
12017_2018_8519_MOESM4_ESM.docx (21 kb)
Supplementary Table 1—Characteristics of the studies included in the meta-analysis. Supplementary Table 2—Quantitate measures of genetic risk (individual study estimates and pooled effects), for the rs6265 and the BSP risk, with the generalized odds ratio (ORG). (DOCX 20 KB)
12017_2018_8519_MOESM5_ESM.tif (55 kb)
Supplementary Figure 1 Funnel plots assessing evidence of publication bias in overall studies for BDNF rs6265 included in meta-analysis for BSP group. SE, standard error; OR, odds ratio. (TIF 55 KB)
12017_2018_8519_MOESM6_ESM.tif (205 kb)
Supplementary Figure 2 Funnel plots assessing evidence of publication bias in studies with Caucausian/European cohorts for BDNF rs6265 included in meta-analysis for BSP group. SE, standard error; OR, odds ratio (TIF 205 KB)
12017_2018_8519_MOESM7_ESM.tif (339 kb)
Supplementary Figure 3 Forest plots assessing odds ratios of BSP associated with rs6265 BDNF polymorphism in overall studies included in meta-analysis (TIF 338 KB)
12017_2018_8519_MOESM8_ESM.tif (320 kb)
Supplementary Figure 4 Forest plots assessing odds ratios of BSP associated with rs6265 BDNF polymorphism in studies with Caucasian/European Cohorts included in meta-analysis. (TIF 320 KB)

References

  1. Albanese, A., Bhatia, K., Bressman, S. B., Delong, M. R., Fahn, S., Fung, V. S., et al. (2013). Phenomenology and classification of dystonia: A consensus update. Movement Disorder, 28(7), 863–873.  https://doi.org/10.1002/mds.25475.CrossRefGoogle Scholar
  2. Anastasia, A., & Hempstead, B. L. (2014). BDNF function in health and disease (Poster). Nature Reviews Neuroscience, 15(2). https://www.nature.com/nrn/posters/bdnf/index.html.
  3. Belviranli, M., & Okudan, N. (2018). Exercise training protects against aging-induced cognitive dysfunction via activation of the hippocampal PGC-1alpha/FNDC5/BDNF pathway. Neuromolecular Medicine.  https://doi.org/10.1007/s12017-018-8500-3.CrossRefPubMedGoogle Scholar
  4. Cattaneo, A., Cattane, N., Begni, V., Pariante, C. M., & Riva, M. A. (2016). The human BDNF gene: Peripheral gene expression and protein levels as biomarkers for psychiatric disorders. Translational Psychiatry, 6(11), e958.  https://doi.org/10.1038/tp.2016.214.CrossRefPubMedCentralPubMedGoogle Scholar
  5. Charlesworth, G., Bhatia, K. P., & Wood, N. W. (2013). The genetics of dystonia: New twists in an old tale. Brain, 136(Pt 7), 2017–2037.  https://doi.org/10.1093/brain/awt138.CrossRefPubMedCentralPubMedGoogle Scholar
  6. Chen, Y., Song, W., Yang, J., Chen, K., Huang, R., Zhao, B., et al. (2013). Association of the Val66Met polymorphism of the BDNF gene with primary cranial-cervical dystonia patients from South-west China. Parkinsonism & Related Disorders, 19(11), 1043–1045.  https://doi.org/10.1016/j.parkreldis.2013.06.004.CrossRefGoogle Scholar
  7. Cramer, S. C., Sampat, A., Haske-Palomino, M., Nguyen, S., Procaccio, V., & Hermanowicz, N. (2010). Increased prevalence of val(66)met BDNF genotype among subjects with cervical dystonia. Neuroscience Letters, 468(1), 42–45.  https://doi.org/10.1016/j.neulet.2009.10.059.CrossRefPubMedGoogle Scholar
  8. Dardiotis, E., Siokas, V., Sokratous, M., Tsouris, Z., Michalopoulou, A., Andravizou, A., et al. (2018). Genetic polymorphisms in amyotrophic lateral sclerosis: Evidence for implication in detoxification pathways of environmental toxicants. Environment International, 116, 122–135.  https://doi.org/10.1016/j.envint.2018.04.008.CrossRefPubMedGoogle Scholar
  9. Defazio, G., Abbruzzese, G., Livrea, P., & Berardelli, A. (2004). Epidemiology of primary dystonia. The Lancet Neurology, 3(11), 673–678.  https://doi.org/10.1016/s1474-4422(04)00907-x.CrossRefPubMedGoogle Scholar
  10. Defazio, G., Hallett, M., Jinnah, H. A., Conte, A., & Berardelli, A. (2017). Blepharospasm 40 years later. Movement Disorders, 32(4), 498–509.  https://doi.org/10.1002/mds.26934.CrossRefPubMedCentralPubMedGoogle Scholar
  11. Defazio, G., Hallett, M., Jinnah, H. A., Stebbins, G. T., Gigante, A. F., Ferrazzano, G., et al. (2015). Development and validation of a clinical scale for rating the severity of blepharospasm. Movement Disorders, 30(4), 525–530.  https://doi.org/10.1002/mds.26156.CrossRefPubMedCentralPubMedGoogle Scholar
  12. Defazio, G., Matarin, M., Peckham, E. L., Martino, D., Valente, E. M., Singleton, A., et al. (2009). The TOR1A polymorphism rs1182 and the risk of spread in primary blepharospasm. Movement Disorders, 24(4), 613–616.  https://doi.org/10.1002/mds.22471.CrossRefPubMedCentralPubMedGoogle Scholar
  13. DerSimonian, R., & Laird, N. (1986). Meta-analysis in clinical trials. Controlled Clinical Trials, 7(3), 177–188.CrossRefPubMedGoogle Scholar
  14. Egger, M., Davey Smith, G., Schneider, M., & Minder, C. (1997). Bias in meta-analysis detected by a simple, graphical test. Bmj, 315(7109), 629–634.CrossRefPubMedCentralPubMedGoogle Scholar
  15. Gomez-Garre, P., Huertas-Fernandez, I., Caceres-Redondo, M. T., Alonso-Canovas, A., Bernal-Bernal, I., Blanco-Ollero, A., et al. (2014). BDNF Val66Met polymorphism in primary adult-onset dystonia: A case-control study and meta-analysis. Movement Disorders, 29(8), 1083–1086.  https://doi.org/10.1002/mds.25938.CrossRefPubMedGoogle Scholar
  16. Groen, J. L., Ritz, K., Tanck, M. W., van de Warrenburg, B. P., van Hilten, J. J., Aramideh, M., et al. (2013). Is TOR1A a risk factor in adult-onset primary torsion dystonia? Movement Disorders, 28(6), 827–831.  https://doi.org/10.1002/mds.25381.CrossRefPubMedGoogle Scholar
  17. Groen, J. L., Ritz, K., Velseboer, D. C., Aramideh, M., van Hilten, J. J., Boon, A. J., et al. (2012). Association of BDNF Met66Met polymorphism with arm tremor in cervical dystonia. Movement Disorders, 27(6), 796–797.  https://doi.org/10.1002/mds.24922.CrossRefPubMedGoogle Scholar
  18. Hempstead, B. L. (2015). Brain-derived neurotrophic factor: Three ligands, many actions. Transactions of the American Clinical and Climatological Association, 126, 9–19.PubMedCentralPubMedGoogle Scholar
  19. Jankovic, J., Tsui, J., & Bergeron, C. (2007). Prevalence of cervical dystonia and spasmodic torticollis in the United States general population. Parkinsonism & Related Disorders, 13(7), 411–416.  https://doi.org/10.1016/j.parkreldis.2007.02.005.CrossRefGoogle Scholar
  20. Kojovic, M., Parees, I., Kassavetis, P., Palomar, F. J., Mir, P., Teo, J. T., et al. (2013). Secondary and primary dystonia: Pathophysiological differences. Brain, 136(Pt 7), 2038–2049.  https://doi.org/10.1093/brain/awt150.CrossRefPubMedGoogle Scholar
  21. Liu, M. E., Huang, C. C., Chen, M. H., Yang, A. C., Tu, P. C., Yeh, H. L., et al. (2014). Effect of the BDNF Val66Met polymorphism on regional gray matter volumes and cognitive function in the Chinese population. Neuromolecular Medicine, 16(1), 127–136.  https://doi.org/10.1007/s12017-013-8265-7.CrossRefPubMedGoogle Scholar
  22. Lohmann, K., & Klein, C. (2017). Update on the genetics of dystonia. Current Neurology and Neuroscience Reports, 17(3), 26.  https://doi.org/10.1007/s11910-017-0735-0.CrossRefPubMedGoogle Scholar
  23. Lohmann, K., Schmidt, A., Schillert, A., Winkler, S., Albanese, A., Baas, F., et al. (2014). Genome-wide association study in musician’s dystonia: A risk variant at the arylsulfatase G locus? Movement Disorders, 29(7), 921–927.  https://doi.org/10.1002/mds.25791.CrossRefPubMedGoogle Scholar
  24. Ma, L., Chen, Y., Wang, L., Yang, Y., Cheng, F., Tian, Y., et al. (2013). Brain-derived neurotrophic factor Val66Met polymorphism is not associated with primary dystonia in a Chinese population. Neuroscience Letters, 533, 100–103.  https://doi.org/10.1016/j.neulet.2012.11.037.CrossRefPubMedGoogle Scholar
  25. Mantel, N., & Haenszel, W. (1959). Statistical aspects of the analysis of data from retrospective studies of disease. Journal of the National Cancer Institute, 22(4), 719–748.PubMedGoogle Scholar
  26. Martino, D., Muglia, M., Abbruzzese, G., Berardelli, A., Girlanda, P., Liguori, M., et al. (2009). Brain-derived neurotrophic factor and risk for primary adult-onset cranial-cervical dystonia. European Journal of Neurology, 16(8), 949–952.  https://doi.org/10.1111/j.1468-1331.2009.02633.x.CrossRefPubMedGoogle Scholar
  27. Misbahuddin, A., Placzek, M. R., Chaudhuri, K. R., Wood, N. W., Bhatia, K. P., & Warner, T. T. (2002). A polymorphism in the dopamine receptor DRD5 is associated with blepharospasm. Neurology, 58(1), 124–126.CrossRefPubMedGoogle Scholar
  28. Mok, K. Y., Schneider, S. A., Trabzuni, D., Stamelou, M., Edwards, M., Kasperaviciute, D., et al. (2014). Genomewide association study in cervical dystonia demonstrates possible association with sodium leak channel. Movement Disorders, 29(2), 245–251.  https://doi.org/10.1002/mds.25732.CrossRefPubMedGoogle Scholar
  29. Newman, J. R., Sutherland, G. T., Boyle, R. S., Limberg, N., Blum, S., O’Sullivan, J. D., et al. (2012). Common polymorphisms in dystonia-linked genes and susceptibility to the sporadic primary dystonias. Parkinsonism & Related Disorders, 18(4), 351–357.  https://doi.org/10.1016/j.parkreldis.2011.11.024.CrossRefGoogle Scholar
  30. Notaras, M., Hill, R., & van den Buuse, M. (2015). The BDNF gene Val66Met polymorphism as a modifier of psychiatric disorder susceptibility: Progress and controversy. Molecular Psychiatry, 20(8), 916–930.  https://doi.org/10.1038/mp.2015.27.CrossRefPubMedGoogle Scholar
  31. Pruunsild, P., Kazantseva, A., Aid, T., Palm, K., & Timmusk, T. (2007). Dissecting the human BDNF locus: Bidirectional transcription, complex splicing, and multiple promoters. Genomics, 90(3), 397–406.  https://doi.org/10.1016/j.ygeno.2007.05.004.CrossRefPubMedCentralPubMedGoogle Scholar
  32. Quartarone, A., Morgante, F., Sant’angelo, A., Rizzo, V., Bagnato, S., Terranova, C., et al. (2008). Abnormal plasticity of sensorimotor circuits extends beyond the affected body part in focal dystonia. Journal of Neurology, Neurosurgery & Psychiatry, 79(9), 985–990.  https://doi.org/10.1136/jnnp.2007.121632.CrossRefGoogle Scholar
  33. Sako, W., Murakami, N., Izumi, Y., & Kaji, R. (2015). Val66Met polymorphism of brain-derived neurotrophic factor is associated with idiopathic dystonia. Journal of Clinical Neuroscience, 22(3), 575–577.  https://doi.org/10.1016/j.jocn.2014.08.014.CrossRefPubMedGoogle Scholar
  34. Siokas, V., Dardiotis, E., Sokolakis, T., Kotoula, M., Tachmitzi, S. V., Chatzoulis, D. Z., et al. (2017a). Plasminogen activator inhibitor type-1 tag single-nucleotide polymorphisms in patients with diabetes mellitus type 2 and diabetic retinopathy. Current Eye Research, 42(7), 1048–1053.  https://doi.org/10.1080/02713683.2016.1276197.CrossRefPubMedGoogle Scholar
  35. Siokas, V., Dardiotis, E., Tsironi, E. E., Tsivgoulis, G., Rikos, D., Sokratous, M., et al. (2017b). The role of TOR1A polymorphisms in dystonia: A systematic review and meta-analysis. PLoS ONE, 12(1), e0169934.  https://doi.org/10.1371/journal.pone.0169934.CrossRefPubMedCentralPubMedGoogle Scholar
  36. Siokas, V., Fotiadou, A., Dardiotis, E., Kotoula, M. G., Tachmitzi, S. V., Chatzoulis, D. Z., et al. (2017c). SLC2A1 tag SNPs in Greek patients with diabetic retinopathy and nephropathy. Ophthalmic Research.  https://doi.org/10.1159/000480241.CrossRefPubMedGoogle Scholar
  37. Skol, A. D., Scott, L. J., Abecasis, G. R., & Boehnke, M. (2006). Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nature Genetics, 38(2), 209–213.  https://doi.org/10.1038/ng1706.CrossRefPubMedGoogle Scholar
  38. Sole, X., Guino, E., Valls, J., Iniesta, R., & Moreno, V. (2006). SNPStats: A web tool for the analysis of association studies. Bioinformatics, 22(15), 1928–1929.  https://doi.org/10.1093/bioinformatics/btl268.CrossRefPubMedGoogle Scholar
  39. Svetel, M. V., Djuric, G., Novakovic, I., Dobricic, V., Stefanova, E., Kresojevic, N., et al. (2013). A common polymorphism in the brain-derived neurotrophic factor gene in patients with adult-onset primary focal and segmental dystonia. Acta Neurologica Belgica, 113(3), 243–245.  https://doi.org/10.1007/s13760-013-0183-9.CrossRefPubMedGoogle Scholar
  40. Theuns, J., Verstraeten, A., Sleegers, K., Wauters, E., Gijselinck, I., Smolders, S., et al. (2014). Global investigation and meta-analysis of the C9orf72 (G4C2)n repeat in Parkinson disease. Neurology, 83(21), 1906–1913.  https://doi.org/10.1212/wnl.0000000000001012.CrossRefPubMedCentralPubMedGoogle Scholar
  41. Tian, J., Vemula, S. R., Xiao, J., Valente, E. M., Defazio, G., Petrucci, S., et al. (2018). Whole-exome sequencing for variant discovery in blepharospasm. Molecular Genetics & Genomic Medicine.  https://doi.org/10.1002/mgg3.411.CrossRefGoogle Scholar
  42. Valls-Sole, J., & Defazio, G. (2016). Blepharospasm: Update on epidemiology, clinical aspects, and pathophysiology. Front Neurol. 7, 45.  https://doi.org/10.3389/fneur.2016.00045.CrossRefPubMedCentralPubMedGoogle Scholar
  43. Weiss, E. M., Hershey, T., Karimi, M., Racette, B., Tabbal, S. D., Mink, J. W., et al. (2006). Relative risk of spread of symptoms among the focal onset primary dystonias. Movement Disorders, 21(8), 1175–1181.  https://doi.org/10.1002/mds.20919.CrossRefPubMedGoogle Scholar
  44. Xiromerisiou, G., Dardiotis, E., Tsironi, E. E., Hadjigeorgiou, G., Ralli, S., Kara, E., et al. (2013). THAP1 mutations in a Greek primary blepharospasm series. Parkinsonism & Related Disorders, 19(3), 404–405.  https://doi.org/10.1016/j.parkreldis.2012.08.015.CrossRefGoogle Scholar
  45. Xiromerisiou, G., Houlden, H., Scarmeas, N., Stamelou, M., Kara, E., Hardy, J., et al. (2012). THAP1 mutations and dystonia phenotypes: Genotype phenotype correlations. Movement Disorders, 27(10), 1290–1294.  https://doi.org/10.1002/mds.25146.CrossRefPubMedCentralPubMedGoogle Scholar
  46. You, H. J., Park, J. H., Pareja-Galeano, H., Lucia, A., & Shin, J. I. (2016). Targeting MicroRNAs involved in the BDNF signaling impairment in neurodegenerative diseases. Neuromolecular Medicine, 18(4), 540–550.  https://doi.org/10.1007/s12017-016-8407-9.CrossRefPubMedGoogle Scholar
  47. Zintzaras, E. (2010). The generalized odds ratio as a measure of genetic risk effect in the analysis and meta-analysis of association studies. Statistical Applications in Genetics and Molecular Biology.  https://doi.org/10.2202/1544-6115.1542.CrossRefPubMedGoogle Scholar
  48. Zintzaras, E. (2012). The power of generalized odds ratio in assessing association in genetic studies with known mode of inheritance. Journal of Applied Statistics, 39(12), 2569–2581.  https://doi.org/10.1080/02664763.2012.722611.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Vasileios Siokas
    • 1
  • Dimitrios Kardaras
    • 2
  • Athina-Maria Aloizou
    • 1
  • Ioannis Asproudis
    • 3
  • Konstadinos G. Boboridis
    • 4
  • Eleni Papageorgiou
    • 2
  • Georgios M. Hadjigeorgiou
    • 1
    • 5
  • Evangelia E. Tsironi
    • 2
  • Efthimios Dardiotis
    • 1
  1. 1.Laboratory of Neurogenetics, Department of Neurology, University Hospital of LarissaUniversity of ThessalyLarissaGreece
  2. 2.Department of Ophthalmology, University Hospital of LarissaUniversity of ThessalyLarissaGreece
  3. 3.Department of OphthalmologyUniversity of IoanninaIoanninaGreece
  4. 4.3rd University Department of OphthalmologyAristotle University of ThessalonikiThessalonikiGreece
  5. 5.Department of Neurology, Medical SchoolUniversity of CyprusNicosiaCyprus

Personalised recommendations