Influence of Single Nucleotide Polymorphisms in COMT, MAO-A and BDNF Genes on Dyskinesias and Levodopa Use in Parkinson's Disease

被引：56

作者：

Cheshire, Perdita ^{[1
]}

Bertram, Kelly ^{[2
]}

Ling, Helen ^{[6
,7
]}

O'Sullivan, Sean S. ^{[7
,10
]}

Halliday, Glenda ^{[4
,5
]}

McLean, Catriona ^{[3
]}

Bras, Jose ^{[8
]}

Foltynie, Tom ^{[9
]}

Storey, Elsdon ^{[1
,2
]}

Williams, David R. ^{[1
,2
]}

机构：

[1] Monash Univ, Alfred Hosp, Dept Med Neurosci, Melbourne, Vic 3181, Australia

[2] Alfred Hosp, Dept Neurol, Melbourne, Vic 3004, Australia

[3] Alfred Hosp, Melbourne, Vic 3004, Australia

[4] Neurosci Res Australia, Sydney, NSW, Australia

[5] Univ New S Wales, Sydney, NSW, Australia

[6] UCL, Queen Sq Brain Bank Neurol Disorders, London, England

[7] UCL, Reta Lila Weston Inst, London, England

[8] UCL, Dept Mol Neurosci, London, England

[9] UCL, Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London, England

[10] Cork Univ Hosp, Neurosci Dept, Cork, Ireland

来源：

NEURODEGENERATIVE DISEASES | 2014年 / 13卷 / 01期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

Parkinson's disease; Levodopa-induced dyskinesias; Catechol-O-methyltransferase; Monoamine oxidase A; Brain-derived neurotrophic factor; FUNCTIONAL POLYMORPHISM; ASSOCIATION; DISSECTION; BRAIN;

D O I：

10.1159/000351097

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Background: Clinical heterogeneity in the development of levodopa-induced dyskinesias (LID) suggests endogenous factors play a significant role in determining their overall prevalence. Objective: We hypothesised that single nucleotide polymorphisms (SNPs) in specific genes may result in a clinical phenotype conducive to an increased risk of LID. Methods:We examined the influence of SNPs in the catechol-O-methyltransferase (COMT), monoamine oxidase A (MAO-A) and brain-derived neurotrophic factor (BDNF) genes on LID in a cohort of 285 pathologically confirmed Parkinson's disease patients, using data from their complete disease course. Results: Dyskinetic patients demonstrated younger age at disease onset (60.3 vs. 66.4 years, p < 0.0001), a longer disease duration (17.0 vs. 12.0 years, p < 0.0001) and a higher maximum daily levodopa equivalent dose (LED; 926.7 vs. 617.1 mg/day, p < 0.0001) than patients without dyskinesias. No individual SNP was found to influence prevalence or time to onset of dyskinesias, including after adjustment for known risk factors. We observed that patients carrying alleles conferring both high COMT activity and increased MAO-A mRNA expression received significantly higher maximum and mean daily LEDs than those with low enzyme activity/mRNA expression (max LED: 835 +/- 445 vs. 508 +/- 316 mg; p = 0.0056, mean LED: 601 +/- 335 vs. 398 +/- 260 mg; p = 0.025). Conclusions: Individual SNPs in BDNF, COMT and MAO-A genes did not influence prevalence or time to onset of dyskinesias in this cohort. The possibility that combined COMT and MAO-A genotype is a significant factor in determining an individual's lifetime levodopa exposure warrants further investigation. Copyright (C) 2013 S. Karger AG, Basel

引用

页码：24 / 28

页数：5

共 12 条

[1]

de Lau LM, 2011, MOVEMENT DISORD, V27, P132

[2] Levodopa-induced dyskinesias [J].

Fabbrini, Giovanni ;

Brotchie, Jonathan M. ;

Grandas, Francisco ;

Nomoto, Masahiro ;

Goetz, Christopher G. .

MOVEMENT DISORDERS, 2007, 22 (10) :1379-1389

[3]

Fahn S, 2004, NEW ENGL J MED, V351, P2498

[4] The BDNF Val66Met polymorphism has a gender specific influence on planning ability in Parkinson's disease [J].

Foltynie, T ;

Lewis, SGJ ;

Goldberg, TE ;

Blackwell, AD ;

Kolachana, BS ;

Weinberger, DR ;

Robbins, TW ;

Barker, RA .

JOURNAL OF NEUROLOGY, 2005, 252 (07) :833-838

[5] BDNF val66met influences time to onset of levodopa induced dyskinesia in Parkinson's disease [J].

Foltynie, T. ;

Cheeran, B. ;

Williams-Gray, C. H. ;

Edwards, M. J. ;

Schneider, S. A. ;

Weinberger, D. ;

Rothwell, J. C. ;

Barker, R. A. ;

Bhatia, K. P. .

JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 2009, 80 (02) :141-144

[6] Human catechol-O-methyltransferase pharmacogenetics: Description of a functional polymorphism and its potential application to neuropsychiatric disorders [J].

Lachman, HM ;

Papolos, DF ;

Saito, T ;

Yu, YM ;

Szumlanski, CL ;

Weinshilboum, RM .

PHARMACOGENETICS, 1996, 6 (03) :243-250

[7] Does levodopa accelerate the pathologic process in Parkinson disease brain? [J].

Parkkinen, L. ;

O'Sullivan, S. S. ;

Kuoppamaki, M. ;

Collins, C. ;

Kallis, C. ;

Holton, J. L. ;

Williams, D. R. ;

Revesz, T. ;

Lees, A. J. .

NEUROLOGY, 2011, 77 (15) :1420-1426

[8] Allelic mRNA expression of X-linked monoamine oxidase a (MAOA) in human brain:: dissection of epigenetic and genetic factors [J].

Pinsonneault, Julia K. ;

Papp, Audrey C. ;

Sadee, Wolfgang .

HUMAN MOLECULAR GENETICS, 2006, 15 (17) :2636-2649

[9] Dissection of the genetics of Parkinson's disease identifies an additional association 5′ of SNCA and multiple associated haplotypes at 17q21 [J].

Spencer, Chris C. A. ;

Plagnol, Vincent ;

Strange, Amy ;

Gardner, Michelle ;

Paisan-Ruiz, Coro ;

Band, Gavin ;

Barker, Roger A. ;

Bellenguez, Celine ;

Bhatia, Kailash ;

Blackburn, Hannah ;

Blackwell, Jennie M. ;

Bramon, Elvira ;

Brown, Martin A. ;

Brown, Matthew A. ;

Burn, David ;

Casas, Juan-Pablo ;

Chinnery, Patrick F. ;

Clarke, Carl E. ;

Corvin, Aiden ;

Craddock, Nicholas ;

Deloukas, Panos ;

Edkins, Sarah ;

Evans, Jonathan ;

Freeman, Colin ;

Gray, Emma ;

Hardy, John ;

Hudson, Gavin ;

Hunt, Sarah ;

Jankowski, Janusz ;

Langford, Cordelia ;

Lees, Andrew J. ;

Markus, Hugh S. ;

Mathew, Christopher G. ;

McCarthy, Mark I. ;

Morrison, Karen E. ;

Palmer, Colin N. A. ;

Pearson, Justin P. ;

Peltonen, Leena ;

Pirinen, Matti ;

Plomin, Robert ;

Potter, Simon ;

Rautanen, Anna ;

Sawcer, Stephen J. ;

Su, Zhan ;

Trembath, Richard C. ;

Viswanathan, Ananth C. ;

Williams, Nigel W. ;

Morris, Huw R. ;

Donnelly, Peter ;

Wood, Nicholas W. .

HUMAN MOLECULAR GENETICS, 2011, 20 (02) :345-353

[10] Systematic Review of Levodopa Dose Equivalency Reporting in Parkinson's Disease [J].

Tomlinson, Claire L. ;

Stowe, Rebecca ;

Patel, Smitaa ;

Rick, Caroline ;

Gray, Richard ;

Clarke, Carl E. .

MOVEMENT DISORDERS, 2010, 25 (15) :2649-2653

← 1 2 →