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Gamma-aminobutyric acid (GABA) receptors genes polymorphisms and risk for restless legs syndrome

The Pharmacogenomics Journal volume 18, pages 565–577 (2018)Cite this article

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Abstract

The possible role of gammaaminobutyric acid (GABA) in the pathophysiology of restless legs syndrome (RLS) is suggested by the symptomatic improvement achieved with GABAergic drugs. Thalamic GABA levels have shown positive correlation with periodic limb movements indices and with RLS severity. We tried to investigate the possible association between the most common single nucleotide polymorphisms (SNPs) in the GABA receptors (GABR) genes rho1, 2, and 3 (GABRR1, GABRR2, GABRR3), alpha4 (GABRA4), epsilon (GABRE), and theta (GABRQ) with the risk of developing RLS. We studied the genotype and allelic variant frequencies of the most common SNPs in the GABRR1(rs12200969, rs1186902), GABRR2(rs282129), GABRR3(rs832032), GABRA4(rs2229940), GABRE(rs1139916), and GABRQ(rs3810651) genes in 205 RLS patients and 230 age- and gender-matched healthy controls using specific TaqMan assays. The frequencies of the GABRR3 rs832032TT genotype and the allelic variant GABRR3 rs832032T were significantly higher in RLS patients than in controls (odds ratio [95% confidence intervals] 7.08[1.48–46.44] and 1.66[1.16–2.37], respectively), although only the higher frequency of the rs832032T allele remained as significant after multiple comparison analysis, both in the whole series and in the female gender. The frequencies of the other genotypes of allelic variants did not differ significantly between RLS patients and controls. RLS patients carrying the GABRA4 rs2229940TT genotype showed a significantly younger age at onset of RLS symptoms than those with the other two genotypes. These results suggest association between GABRR3rs832032 polymorphism and the risk for RLS, and a modifier effect of GABRA4 rs2229940 on the age of onset of RLS.

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References

  1. Jiménez-Jiménez FJ, Alonso-Navarro H, García-Martín E, Agúndez JAG. Genetics of restless legs syndrome: an update. Sleep Med Rev. 2018;39:108–21.

    Article  PubMed  Google Scholar 

  2. Schormair B, Zhao C, Bell S, Tilch E, Salminen AV, Pütz B, et al. Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis. Lancet Neurol. 2017;16:898–907.

    Article  PubMed  PubMed Central  Google Scholar 

  3. García-Martín E, Jiménez-Jiménez FJ, Alonso-Navarro H, Martínez C, Zurdo M, Turpín-Fenoll L, et al. Heme oxygenase-1 and 2 common genetic variants and risk for restless Legs Syndrome. Medicine 2015;94:e1448.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Jiménez-Jiménez FJ, García-Martín E, Alonso-Navarro H, Martínez C, Zurdo M, Turpín-Fenoll L, et al. Association between vitamin D receptor rs731236 (Taq1) polymorphism and risk for restless Legs Syndrome in the Spanish Caucasian Population. Medicine. 2015;94:e2125.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Jiménez-Jiménez FJ, Gómez-Tabales J, Alonso-Navarro H, Zurdo M, Turpín-Fenoll L, Millán-Pascual J, et al. Association between the rs1229984 polymorphism in the alcohol dehydrogenase 1B gene and risk for restless Legs Syndrome. Sleep. 2017;40. https://doi.org/10.1093/sleep/zsx174.

  6. Jiménez-Jiménez FJ, Alonso-Navarro H, García-Martín E, Agúndez JAG. Neurochemistry of idiopathic restless legs syndrome. Eur Neurol Rev. 2015;10:35–44. http://www.touchneurology.com/articles/neurochemistry-idiopathic-restless-legs-syndrome

    Article  Google Scholar 

  7. Jiménez-Jiménez FJ, Alonso-Navarro H, García-Martín E, Agúndez JAG. Treatment options for idiopathic restless legs syndrome. Eur Neurol Rev. 2015;10:45–55. http://www.touchneurology.com/articles/treatment-options-idiopathic-restless-legs-syndrome

    Article  Google Scholar 

  8. Winkelman JW, Schoerning L, Platt S, Jensen JE. Restless legs syndrome and central nervous system gamma-aminobutyric acid: preliminary associations with periodic limb movements in sleep and restless leg syndrome symptom severity. Sleep Med. 2014;15:1225–30.

    Article  PubMed  Google Scholar 

  9. IUPHAR DATABASE. Nomenclature of ligand-gates ion channels. Available at http://www.iuphar-db.org/LGIICNomenclature.jsp.

  10. Olsen RW, Sieghart W. International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update Pharmacol Rev. 2008;60:243–60.

    Article  PubMed  CAS  Google Scholar 

  11. Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J. Restless Legs Syndrome diagnosis and epidemiology workshop at the National Institutes of Health; International Restless Legs Syndrome Study Group. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology: a report from the restless legs syndrome diagnosis and epidemiology work shop at the National Institute of Health. Sleep Med. 2003;4:101–19.

    Article  PubMed  Google Scholar 

  12. Allen RP, Picchietti DL, Garcia-Borreguero D, Ondo WG, Walters AS, Winkelman JW. et al.International Restless Legs Syndrome Study Group 2014 Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria - history, rationale, description, and significance. Sleep Med. 2014;15:860–73.

    Article  PubMed  Google Scholar 

  13. Roco A, Jiménez-Jiménez FJ, Alonso-Navarro H, Martínez C, Zurdo M, Turpín-Fenoll L, et al. MAPT1 gene rs1052553 variant is unrelated with the risk for restless legs syndrome. J Neural Transm. 2013;120:463–7.

    Article  PubMed  CAS  Google Scholar 

  14. Jiménez-Jiménez FJ, Alonso-Navarro H, Martínez C, Zurdo M, Turpín-Fenoll L, Millán J, et al. Dopamine Receptor D3 (DRD3) gene rs6280 variant and risk for restless legs syndrome. Sleep Med. 2013;14:382–4.

    Article  PubMed  Google Scholar 

  15. Jiménez-Jiménez FJ, Alonso-Navarro H, Martínez C, Zurdo M, Turpín-Fenoll L, Millán J, et al. The solute carrier family 1 (glial high affinity glutamate transporter), member 2 gene, SLC1A2, rs3794087 variant and assessment risk for restless legs syndrome. Sleep Med. 2014;15:266–8.

    Article  PubMed  Google Scholar 

  16. Jiménez-Jiménez FJ, Alonso-Navarro H, Martínez C, Zurdo M, Turpín-Fenoll L, Millán J, et al. Neuronal nitric oxide synthase (nNOS, NOS1) rs693534 and rs7977109 variants and risk for restless legs syndrome. J Neural Transm. 2015;122:819–23.

    Article  PubMed  CAS  Google Scholar 

  17. Jiménez-Jiménez FJ, García-Martín E, Alonso-Navarro H, Martínez C, Zurdo M, Turpín-Fenoll L, et al. Thr105Ile (rs11558538) polymorphism in the histamine-1-methyl- transferase (HNMT) gene and risk for restless legs syndrome. J Neural Transm. 2017;124:285–291.

    Article  PubMed  CAS  Google Scholar 

  18. Walters AS, LeBrocq C, Dhar A, Hening W, Rosen R, Allen RP, et al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med. 2003;4:121–32.

    Article  PubMed  Google Scholar 

  19. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Stat Soc Ser B. 1995;1:289–300.

    Google Scholar 

  21. Daly AK, Day CP. Candidate gene case-control association studies: advantages and potential pitfalls. Br J Clin Pharmacol. 2001;52:489–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Pértegas Díaz S, Pita Fernández S. Cálculo del poder estadístico de un estudio. Cad Aten Prima. 2003;10:59–63.

    Google Scholar 

  23. Altman DG, Bland JM. Diagnostic tests 2: Predictive values. BMJ. 1994;309:102.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Martínez C, Molina JA, Alonso-Navarro H, Jiménez-Jiménez FJ, Agúndez JA, García-Martín E. Two common nonsynonymous paraoxonase 1 (PON1) gene polymorphisms and brain astrocytoma and meningioma. BMC Neurol. 2010;10:71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. García Martín E, Ramos MI, Cornejo-García JA, Galván S, Perkins JR, Rodríguez-Santos L, et al. Missense gamma-aminobutyric acid receptor polymorphisms are associated with reaction time, motor time, and ethanol effects in vivo. Front Cell Neurosci. 2018;12:10. https://doi.org/10.3389/fncel.2018.00010

    Article  PubMed  PubMed Central  Google Scholar 

  26. Bustamante MF, Morcillo-Suárez C, Malhotra S, Rio J, Leyva L, Fernández O, et al. Pharmacogenomic study in patients with multiple sclerosis: Responders and nonresponders to IFN-β. Neurol Neuroimmunol Neuroinflamm. 2015;2:e154.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Agrawal A, Pergadia ML, Saccone SF, Hinrichs AL, Lessov-Schlaggar CN, Saccone NL, et al. Gamma-aminobutyric acid receptor genes and nicotine dependence: evidence for association from a case-control study. Addiction. 2008;103:1027–38.

    Article  PubMed  Google Scholar 

  28. García-Martín E, Martínez C, Alonso-Navarro H, Benito-León J, Lorenzo-Betancor O, Pastor P, et al. Gamma-aminobutyric acid (GABA) receptor rho (GABRR) polymorphisms and risk for essential tremor. J Neurol. 2011;258:203–11.

    Article  PubMed  CAS  Google Scholar 

  29. García-Martín E, Martínez C, Alonso-Navarro H, Benito-León J, Lorenzo-Betancor O, Pastor P, et al. Gamma-aminobutyric acid GABRA4, GABRE, and GABRQ receptor polymorphisms and risk for essential tremor. Pharm Genom. 2011;21:436–9.

    Article  CAS  Google Scholar 

  30. García Martín E, Martínez C, Serrador M, Alonso-Navarro H, Navacerrada F, Esguevillas G, et al. Gamma-aminobutyric acid (GABA) receptors rho (GABRR) gene polymorphisms and risk for migraine. Headache. 2016;57:1118–35.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported in part by Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Madrid, Spain (Grants PI15/00303 and RETICS ARADyAL RD16/0006/0004), Junta de Extremadura, Mérida, Spain (Grants GR15026 and IB16170), Fundesalud, Mérida, Spain (Grant PRIS10016), and Spanish Ministry of Science and Innovation (Grants SAF2006-10126 and SAF2010-22329-C02-01). Partially funded with FEDER funds.

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Authors and Affiliations

  1. Section of Neurology, Hospital Universitario del Sureste, Arganda del Rey (Madrid), Madrid, Spain

    Félix Javier Jiménez-Jiménez, Hortensia Alonso-Navarro, Francisco Navacerrada, Marisol Calleja, José Francisco Plaza-Nieto, Belén Pilo-de-la-Fuente & Margarita Arroyo-Solera

  2. Department of Medicine-Neurology, Hospital “Príncipe de Asturias”, Universidad de Alcalá, Alcalá de Henares (Madrid), Madrid, Spain

    Félix Javier Jiménez-Jiménez, Hortensia Alonso-Navarro, Ana Rojo-Sebastián, Lluisa Rubio & Esteban García-Albea

  3. University Institute of Molecular Pathology Biomarkers, UNEx. ARADyAL Instituto de Salud Carlos III, Cáceres, Spain

    Gara Esguevillas, Gemma Amo, José A. G. Agúndez & Elena García-Martín

  4. Section of Neurology, Hospital Virgen del Puerto, Plasencia (Cáceres), Spain

    Martín Zurdo

  5. Section of Neurology, Hospital La Mancha-Centro, Alcázar de San Juan (Ciudad Real), Ciudad Real, Spain

    Laura Turpín-Fenoll & Jorge Millán-Pascual

  6. Unit of Neurology, Hospital Recoletas, Zamora, Spain

    Teresa Adeva-Bartolomé

  7. Section of Neurology, Hospital Universitario de Burgos, Burgos, Spain

    Esther Cubo

  8. Fundació per la Recerca Biomèdica i Social Mútua de Terrassa, Terrassa, Barcelona, Spain

    Mónica Díez-Fairén & Pau Pastor

  9. Memory and Movement Disorders Units, Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain

    Mónica Díez-Fairén & Pau Pastor

  10. CIBERNED, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain

    Pau Pastor

  11. Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, Universidad de Navarra, Pamplona, Spain

    Pau Pastor

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  1. Félix Javier Jiménez-Jiménez
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Correspondence to Félix Javier Jiménez-Jiménez.

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Jiménez-Jiménez, F.J., Esguevillas, G., Alonso-Navarro, H. et al. Gamma-aminobutyric acid (GABA) receptors genes polymorphisms and risk for restless legs syndrome. Pharmacogenomics J 18, 565–577 (2018). https://doi.org/10.1038/s41397-018-0023-7

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