Catechol-O-methyltransferase Val158Met and the Risk of Dyskinesias in Parkinson’s Disease Lonneke M.L. de Lau, MD, PhD, 1,2 * Dagmar Verbaan, PhD, 1 Johan Marinus, PhD, 1 Peter Heutink, PhD, 3 and Jacobus J. van Hilten, MD, PhD 1 1 Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands; 2 Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands; 3 Section of Medical Genomics, Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands ABSTRACT Background: The A-allele of the catechol-O-methyl- transferase (COMT) Val158Met polymorphism is associ- ated with decreased enzymatic activity and higher dopamine availability. Methods: We studied 219 patients with PD who were free of dyskinesias at baseline and underwent thorough annual examinations. Results: The A-allele of the COMT Val158Met polymor- phism was related to an increased risk of developing dyskinesias during follow-up, in a dose-dependent man- ner (adjusted hazard ratios for the AG and AA genotypes [compared to GG]: 2.09 [95% confidence interval (CI), 1.07–4.06] and 2.81 [CI, 1.43–5.54], respectively). Conclusions: This finding suggests that genetic factors may affect susceptibility to dyskinesias in PD. V C 2011 Movement Disorder Society Key Words: Parkinson’s disease; dyskinesia; genet- ics; COMT Catechol-O-methyltransferase (COMT) is an enzyme that degrades catecholamines, including levo- dopa (L-dopa) and dopamine. The human COMT gene on chromosome 22q11 contains a common func- tional polymorphism, producing a substitution of valine to methionine at codon 158. This Val158Met polymorphism influences the thermostability and enzy- matic activity of the COMT protein. The methionine- encoding A allele is associated with decreased enzy- matic activity, resulting in higher bioavailability of L- dopa and higher synaptic dopamine levels. 1 It has been hypothesized that the low-activity genotype of the COMT Val158Met polymorphism may lead to a sustained therapeutic response to L-dopa and increased sensitivity to motor complications of dopaminergic ther- apy in patients with PD. 2–4 Dyskinesias (i.e., abnormal involuntary movements) are a common, potentially dis- abling motor complication affecting 30% to 40% of PD patients treated with Ldopa. 5,6 Previous studies on the relationship between the COMT Val158Met polymor- phism and dyskinesias in PD yielded inconsistent results, and longitudinal studies are lacking. 2–4,7 We evaluated the association between the COMT Val158Met poly- morphism and the development of dyskinesias in a pro- spective cohort study among hospital-based PD patients without dyskinesias at baseline. Patients and Methods This work was carried out within the ‘‘PROfiling PARKinson’s disease’’ (PROPARK) study, a longitudi- nal cohort study of patients with PD with extensive annual evaluation of different clinical domains. All patients fulfilled the United Kingdom Parkinson’s Dis- ease Society Brain Bank criteria for idiopathic PD. 8 The recruitment procedure has been described in detail elsewhere. 9 The medical ethical committee of the Lei- den University Medical Center approved the study, and all patients gave written informed consent. At baseline (May 2003–September 2005) and at five annual follow-up visits (final visit between April 2008 and July 2010), all patients received a standardized assessment comprising an evaluation of demographic and clinical characteristics including disease severity (Hoehn and Yahr scale score), and medication use (duration and daily dose of antiparkinsonian medica- tion), and evaluation of different clinical domains, using measurement instruments and scales that have been found valid and reliable in PD. 9 At baseline and at each follow-up visit, patients were evaluated for the presence and severity of dyskinesias using the Motor Complications section of the Short Parkinson’s ------------------------------------------------------------ *Correspondence to: Lonneke M.L. de Lau, Department of Neurology, K5Q-92, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands; l.delau@erasmusmc.nl Funding agencies: This work was supported by grants from the van Alkemade-Keuls Foundation and the Dutch Parkinson’s Disease Society (to J.J.v.H.). These funding sources had no role in the study design, collection, analysis, and interpretation of data, or writing of the report. Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 6 December 2010; Revised: 8 April 2011; Accepted: 28 April 2011 Published online 14 November 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.23805 BRIEF REPORTS 132 Movement Disorders, Vol. 27, No. 1, 2012