Post

gene-drug interaction may define subtypes

Haydeh Payami, PhD, Professor, Director Genomics Inst., NY State Dept of Health, Wadsworth Center
PD Subtypes
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MJFF Asks: What should the next funding program on PD Subtypes look like?
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Parsing of non-motor subtypes: inspired by Alberto Espay's post
MJFF Asks: What should the next funding program on PD Subtypes look like?
Michael T Rogan
12 Nov 2009 03:50 PM EST
Alberto Espay posted about how PD diagnostic categories can gloss over the phenotypic complexity of movement and therefore hide the possible presence of disease subtypes.  Is this also true ... 
Responses: 1

I think the answer is yes, and here is evidence. Part of this work was presented at the XVIII WFN World Congress on Parkinson's Disease and Related Disorders.

ABSTRACT

Authors: Taye Hamza; Stewart Factor; Eric Molho; Jennifer Montimurro; David Pratt; Michael Ernst; Donald Higgins; Haydeh Payami.


Objective: Up to 80% of Parkinson’s disease (PD) patients develop hallucinations and dementia. Pinpointing the causes of these complications has been hampered by the diversity of contributing variables and poorly understood correlations among not only the contributors but also the adverse outcomes themselves. We employed a comprehensive approach to test if psychiatric and cognitive decline in PD are induced by PD medication (l-dopa) and if there exists evidence for drug-gene interaction.


Methods: 638 PD patients were studied. Design was cross-sectional. Association of l-dopa with five adverse outcomes was tested for main-effect, gene-drug and exposure-drug interactions, while adjusting for clinical features, medications, genotype (SNCA, MAPT, CYP2D6, APOE) and exposures (smoking, coffee), and accounting for correlation among the outcomes.


Results: We detected significant dose-dependent association between l-dopa and increased risk of hallucinations (OR=15.3, P<0.001) and intellectual impairment (OR=4.1, P<0.05), as well as with dyskinesia which is well-established. Evidence for gene-drug interaction was significant. Presence of APOE-2 doubled the risk of dyskinesia (P=0.02) and its absence doubled the risk of l-dopa induced hallucinations to 30-fold (P=0.001).


Interpretation: Present study provides the first insights into gene-drug interactions in PD. Data suggest motor, cognitive and psychiatric outcomes in PD are influenced by interactive effects of l-dopa therapy and genotype. APOE-2 may mark a distinct PD entity that is prone to drug-induced motor complication but resistant to its psychiatric outcomes. If confirmed in longitudinal studies, these findings would facilitate deciphering disease heterogeneity and formulating strategies to reduce the burden of dyskinesia, psychosis and dementia in PD.

 

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