AUTHOR=Tirozzi Alfonsina , Modugno Nicola , Palomba Nicole Piera , Ferese Rosangela , Lombardi Alessia , Olivola Enrica , Gialluisi Alessandro , Esposito Teresa 

TITLE=Analysis of Genetic and Non-genetic Predictors of Levodopa Induced Dyskinesia in Parkinson’s Disease

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.640603

DOI=10.3389/fphar.2021.640603

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> Levodopa (<sc>L</sc>-Dopa), representing the therapeutic gold standard for the treatment of Parkinson disease (PD), is associated with side effects like <sc>L</sc>-Dopa induced dyskinesia (LID). Although several non-genetic and genetic factors have been investigated for association with LID risk, contrasting results were reported and its genetic basis remain largely unexplored.</p><p><bold>Methods:</bold> In an Italian PD cohort (N = 460), we first performed stepwise multivariable Cox Proportional Hazard regressions modeling LID risk as a function of gender, PD familiarity, clinical subtype, weight, age-at-onset (AAO) and years-of-disease (YOD), <sc>L</sc>-Dopa dosage, severity scores, and scales assessing motor (UPDRS-III), cognitive (MoCA), and non-motor symptoms (NMS). Then we enriched the resulting model testing two variants—rs356219 and D4S3481—increasing the expression of the <italic>SNCA</italic> gene, previously suggested as a potential mechanism of LID onset. To account for more complex (non-linear) relations of these variables with LID risk, we built a survival random forest (SRF) algorithm including all the covariates mentioned above.</p><p><bold>Results:</bold> Among tested variables (N = 460 case-complete, 211 LID events; total follow-up 31,361 person-months, median 61 months), disease duration showed significant association (<italic>p</italic> &lt; 0.005), with 6 (3–8)% decrease of LID risk per additional YOD. Other nominally significant associations were observed for gender—with women showing a 39 (5–82)% higher risk of LID—and AAO, with 2 (0.3–3)% decrease of risk for each year increase of PD onset. The SRF algorithm confirmed YOD as the most prominent feature influencing LID risk, with a variable importance of about 8% in the model. In genetic models, no statistically significant effects on incident LID risk was observed.</p><p><bold>Conclusions:</bold> This evidence supports a protective effect of late PD onset and gender (men) against LID risk and suggests a new independent protective factor, YOD. Moreover, it underlines the importance of personalized therapeutic protocols for PD patients in the future.</p>