Objective: To analyze the association between ADORA2A-rs2298383 and levodopa induced dyskinesias (LID) in a cohort of Latin American Parkinson’s disease patients.

Background: Previous evidence has demonstrated associations between variants in the ADORA2A gene and LID. This gene encodes the adenosine A2A receptor, whose expression has been found to be increased in the striatum and external globus pallidus of animal models with LID, as well as in the brains of post-mortem PD patients who presented this motor complication [1,2]. Specifically, rs2298383 (C>T) has been associated with an increased odds of developing LID in Brazilian populations [3,4]; however, this association has not been studied in other Latin American countries.

Method: Data from the Latin American Research consortium on the Genetics of Parkinson’s Disease (LARGE-PD) was used [5]. Participants were divided into two groups based on their LID status. Clinical and demographic data were collected. All participants were genotyped utilizing the Neurobooster Array [6]. Multiple logistic regressions were performed to evaluate the association between rs2298383 and LID, analyzing the SNP under both additive and dominant models, adjusting for clinical (age at onset, levodopa therapy duration) and demographic (sex) confounders.

Results: A total of 1,165 participants from six Latin American countries (Argentina, Colombia, Chile, Mexico, Peru, Puerto Rico) were divided by LID status (yes, n=259; no, n=906).  In the logistic regression model, rs2298383 showed a trend toward increased LID occurrence. Specifically, under the additive model, CT (OR = 1.41, 95% CI: 0.95–2.10, p = 0.084) and TT (OR = 1.49, 95% CI: 0.97–2.28, p = 0.068) carriers had increased odds of LID compared to CC. In the dominant model (CT+TT vs. CC), the minor allele showed a similar trend toward higher odds of LID (OR = 1.44, 95%CI: 1.00 – 2.10, p = 0.054). Younger age at onset (p < 0.001) and longer levodopa therapy (p < 0.001) were significant predictors of LID, while sex was not associated.

Conclusion: These findings suggest a possible genetic influence of rs2298383 on LID susceptibility, aligning with previous evidence regarding its role in LID occurrence. Larger studies, accounting for additional variants in ADORA2A, could further enhance our understanding of this gene’s role in the pathophysiology and prediction of LID.

References: [1] Tomiyama M, Kimura T, Maeda T, Tanaka H, Kannari K, Baba M. Upregulation of striatal adenosine A2A receptor mRNA in 6-hydroxydopamine-lesioned rats intermittently treated with L-DOPA. Synapse 2004;52:218–22. https://doi.org/10.1002/syn.20011.

[2] Calon F, Dridi M, Hornykiewicz O, Bédard PJ, Rajput AH, Di Paolo T. Increased adenosine A2A receptors in the brain of Parkinson’s disease patients with dyskinesias. Brain 2004;127:1075–84. https://doi.org/10.1093/brain/awh128.

[3] Rieck M, Schumacher-Schuh AF, Callegari-Jacques SM, Altmann V, Schneider Medeiros M, Rieder CR, et al. Is there a role for ADORA2A polymorphisms in levodopa-induced dyskinesia in Parkinson’s disease patients? Pharmacogenomics 2015;16:573–82. https://doi.org/10.2217/pgs.15.23.

[4] Santos-Lobato BL, Schumacher-Schuh AF, Rieder CRM, Hutz MH, Borges V, Ferraz HB, et al. Diagnostic prediction model for levodopa-induced dyskinesia in Parkinson’s disease. Arq Neuropsiquiatr 2020;78:206–16. https://doi.org/10.1590/0004-282X20190191.

[5] Zabetian CP, Mata IF, Latin American Research Consortium on the Genetics of PD (LARGE-PD). LARGE-PD: Examining the genetics of Parkinson’s disease in Latin America. Mov Disord 2017;32:1330–1. https://doi.org/10.1002/mds.27081.

[6] Bandres-Ciga S, Faghri F, Majounie E, Koretsky MJ, Kim J, Levine KS, et al. NeuroBooster Array: A Genome-Wide Genotyping Platform to Study Neurological Disorders Across Diverse Populations. Mov Disord 2024;39:2039–48. https://doi.org/10.1002/mds.29902.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/assessing-the-potential-association-of-rs2298383-in-adora2a-as-a-predictor-of-levodopa-induced-dyskinesia-in-latin-american-parkinsons-disease-patients/