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Association of Common Genetic Variants of HOMER1 Gene with Levodopa Adverse Effects in Parkinson’S Disease Patients

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Association of Common Genetic Variants of HOMER1 Gene with Levodopa Adverse Effects in Parkinson’S Disease Patients The Pharmacogenomics Journal (2014) 14, 289–294 & 2014 Macmillan Publishers Limited All rights reserved 1470-269X/14 www.nature.com/tpj ORIGINAL ARTICLE Association of common genetic variants of HOMER1 gene with levodopa adverse effects in Parkinson’s disease patients AF Schumacher-Schuh1,2, V Altmann1, M Rieck1, L Tovo-Rodrigues1, TL Monte2, SM Callegari-Jacques3, MS Medeiros2, CRM Rieder2 and MH Hutz1 Levodopa is the most effective symptomatic therapy for Parkinson’s disease, but its chronic use could lead to chronic adverse outcomes, such as motor fluctuations, dyskinesia and visual hallucinations. HOMER1 is a protein with pivotal function in glutamate transmission, which has been related to the pathogenesis of these complications. This study investigates whether polymorphisms in the HOMER1 gene promoter region are associated with the occurrence of the chronic complications of levodopa therapy. A total of 205 patients with idiopathic Parkinson’s disease were investigated. Patients were genotyped for rs4704559, rs10942891 and rs4704560 by allelic discrimination with Taqman assays. The rs4704559 G allele was associated with a lower prevalence of dyskinesia (prevalence ratio (PR) ¼ 0.615, 95% confidence interval (CI) 0.426–0.887, P ¼ 0.009) and visual hallucinations (PR ¼ 0.515, 95% CI 0.295–0.899, P ¼ 0.020). Our data suggest that HOMER1 rs4704559 G allele has a protective role for the development of levodopa adverse effects. The Pharmacogenomics Journal (2014) 14, 289–294; doi:10.1038/tpj.2013.37; published online 15 October 2013 Keywords: dyskinesia; homer1; levodopa; Parkinson’s disease; pharmacogenetics; visual hallucinations. INTRODUCTION HOMER1 encodes a postsynaptic density protein highly expressed Idiopathic Parkinson’s disease (PD) affects 1–3% of people older in the brain. This protein has important roles in synaptic plasticity 9,10 than 65 years, and its core symptoms are slowness of movements, and glutamate signal transduction. This gene was mapped at rigidity and resting tremor.1 The complete pathological pathway chromosome 5, and it has two major products determined by underlying this condition remains unknown, but the mechanism alternative splicing. Homer1b/c is the long variant constitutively involved in the cardinal motor manifestations of disease results expressed and forms dimers that connect glutamate receptors from a progressive loss of dopaminergic cells in the midbrain, (mGluR1a and mGluR5) with signaling proteins (for example, Shank leading to a dopamine deficit in the striatum. Levodopa is a and IP3R), whereas Homer1a is the short variant of the gene dopamine precursor, and it is used as the major pharmacological transcript and is an immediate early gene product expressed under agent to restore this deficiency. Despite the important neuronal activation. Homer1a lacks the carboxy-terminal region, symptomatic effect provided by levodopa, its long-term use is which prevents dimer formation and counteracts the action of associated with adverse outcomes such as motor fluctuations, Homer1b/c. Previous studies with parkinsonism animal models dyskinesia and visual hallucinations, which could severely impair showed an overexpression of Homer1a after the administration of 11–13 daily life.2,3 dopaminergic agonists and a decreased expression after high- Motor fluctuation is a phenomenon characterized by a frequency deep brain stimulation of the subthalamic nucleus, a predictable (wearing-off) or an unpredictable (on-off) loss of similar kind of stimulation used in clinical practice to improve 14 levodopa effects, and dyskinesia consists of hyperkinetic involun- symptoms in PD patients. This evidence suggested a relationship tary movements triggered by the drug. Both phenomena affect between Homer1 and symptomatic therapies for PD. 40% of patients after 4–6 years of treatment.3,4 Visual halluci- The possibility of predicting complications of the chronic use of nations’ estimated prevalence is about 22–38% of PD patients levodopa in PD is an important goal toward a more personalized who use dopaminergic therapy.2 These complications are pheno- prescription. The aim of this study was to determine the typic features that vary between patients, and their risk factors are contribution of rs4704559, rs10942891 and rs4704560 polymorph- not completely understood. The theoretical framework to explain isms in the HOMER1 promoter region in the occurrence of chronic this differential individual response to the drug incorporates at complications of levodopa therapy, namely motor fluctuations, least two concepts: (1) disease-associated features, such as dyskinesia and visual hallucinations. severity of nigrostriatal denervation, and (2) pharmacological factors, given the non-physiological dopaminergic stimulation provided by levodopa.5–7 However, a growing body of evidence PATIENTS AND METHODS points to aberrant neuroplasticity, along with glutamatergic Patients hyperactivity, as a third concept in this model, especially for A total of 205 Brazilian PD patients were evaluated at the Movement dyskinesia.8 Disorder Clinics at ‘Hospital de Clı´nicas de Porto Alegre’, Brazil, from 2006 1Departamento de Gene´tica, Instituto de Biocieˆncias, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; 2Servic¸o de Neurologia, Hospital de Clı´nicas de Porto Alegre, Porto Alegre, Brazil and 3Departamento de Estatı´stica, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. Correspondence: Dr MH Hutz, Departamento de Gene´tica, Instituto de Biocieˆncias, Universidade Federal do Rio Grande do Sul, Caixa postal 15053, Porto Alegre, RS 91501-970, Brazil. E-mail: [email protected] Received 17 May 2013; revised 22 August 2013; accepted 23 August 2013; published online 15 October 2013 HOMER1 polymorphisms and levodopa side effects AF Schumacher-Schuh et al 290 to 2012. This sample has been fully described elsewhere.15,16 Briefly, using TaqMan assays according to the manufacturer’s recommended diagnosis of idiopathic PD was made in accordance with UK Parkinson protocols (Applied Biosystems, Foster City, CA, USA). Disease Society Brain Bank criteria17 and revised by one of us (CRMR), an experienced neurologist in movement disorders. The inclusion criteria Statistical analyses were the use of at least 200 mg of levodopa for 1 year or more with an initial good response to the drug. Patients with atypical manifestations or Allele frequencies were estimated by gene counting. Agreement of genotype frequencies to Hardy–Weinberg expectations was tested using a secondary parkinsonisms were excluded. The hospital Ethics Committee 2 23 approved the study, and all participants gave written informed consent. goodness-of-fit w test. The Haploview program V3.32 was used to estimate linkage disequilibrium (LD;D0) as a measure of pairwise LD and to create a graphical representation of LD structure.24 Haplotype frequencies and odds ratios were estimated using the default full model implemented Clinical evaluation in UNPHASED software (version 3.1.7), controlling for covariates. It tests the Patients and their caregivers underwent a structured interview for null hypothesis that there is no difference in OR between haplotypes by collecting clinical and demographic data. Information was also obtained using a likelihood-ratio test. P-values were estimated and adjusted for 1000 from an electronic database of medical records. A trained physician permutations. Individual P-values regarding the comparison between each applied the four parts of the Unified Parkinson’s Disease Rating Scale haplotype and the reference one was performed using the UNPHASED (UPDRS),18 the Hoehn and Yahr (HY) Scale19 and the Mini Mental State ‘compare with’ option. Bonferroni correction was used for multiple Examination.20 comparisons when it was the case. All other analyses were performed The principal outcomes investigated were motor fluctuations, dyskinesia using the SPSS version 18 software. Confounders were previously defined and visual hallucinations, and they were defined by the presence of at least by statistical or conceptual criteria, on the basis of literature review.4,5,7 one of two criteria. For motor fluctuation, the criteria were as follows: (1) a Statistical confounders were those associated with genetic markers and score of one or more in question 39 of the UPDRS and/or (2) intake of with the outcome at Pp0.1 in our sample. For categorical variables, levodopa five or more times a day. For dyskinesia, the criteria were as association was verified with w2 test, and for continuous data, with or follows: (1) Dyskinesia is a chronic adverse effect, and therefore it is not without normal distribution, Student’s t test or Wilcoxon–Mann–Whitney possible to determine the number of episodes; question 32 of the UPDRS was performed, respectively. Conceptual confounders for motor fluctua- evaluates how long during the day dyskinesia is present. A score of one tions were disease duration and severity of disease (assessed indirectly (1–25% of the day) or more in question 32 of the UPDRS and/or (2) any through HY Scale). For dyskinesia and visual hallucinations, age at onset, change in medical treatment due to dyskinesia (for example, adjustment in disease duration, HY Scale, use of dopamine agonist and levodopa dose dopaminergic therapy or use of amantadine due to dyskinesia). For visual corrected by the concomitant use of catechol-O-methyl transferase hallucinations, the criteria were as follows: (1) a score of two or more in the inhibitor were considered.25 Gender was also selected
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