Tirozzi Alfonsina, Modugno Nicola, Palomba Nicole Piera, Ferese Rosangela, Lombardi Alessia, Olivola Enrica, Gialluisi Alessandro, Esposito Teresa
IRCCS Neuromed, Pozzilli, Italy.
Institute of Genetics and Biophysics, CNR, Naples, Italy.
Front Pharmacol. 2021 Apr 29;12:640603. doi: 10.3389/fphar.2021.640603. eCollection 2021.
Levodopa (L-Dopa), representing the therapeutic gold standard for the treatment of Parkinson disease (PD), is associated with side effects like L-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. 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), L-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 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. 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 ( < 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. 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.
左旋多巴（L-Dopa）是治疗帕金森病（PD）的治疗金标准，但会引发如左旋多巴诱导的运动障碍（LID）等副作用。尽管已经对多种非遗传和遗传因素与LID风险的关联进行了研究，但报告结果相互矛盾，其遗传基础在很大程度上仍未得到探索。在一个意大利PD队列（N = 460）中，我们首先进行了逐步多变量Cox比例风险回归，将LID风险建模为性别、PD家族史、临床亚型、体重、发病年龄（AAO）、病程（YOD）、左旋多巴剂量、严重程度评分以及评估运动（UPDRS-III）、认知（MoCA）和非运动症状（NMS）的量表的函数。然后，我们通过测试两个增加基因表达的变体rs356219和D4S3481来丰富所得模型，该基因先前被认为是LID发病的潜在机制。为了考虑这些变量与LID风险之间更复杂的（非线性）关系，我们构建了一种生存随机森林（SRF）算法，其中包括上述所有协变量。在测试变量中（N = 460例完整病例，211例LID事件；总随访31361人月，中位数61个月），病程显示出显著关联（<0.005），每增加一年病程，LID风险降低6（3-8）%。在性别方面观察到其他名义上显著的关联——女性患LID的风险高39（5-82）%——以及AAO，PD发病每增加一年，风险降低2（0.3-3）%。SRF算法确认YOD是影响LID风险的最突出特征，在模型中的变量重要性约为8%。在遗传模型中，未观察到对新发LID风险有统计学显著影响。这一证据支持了PD发病较晚和男性性别对LID风险的保护作用，并提示了一个新的独立保护因素YOD。此外，它强调了未来针对PD患者制定个性化治疗方案的重要性。
