α-Synuclein genetic variants predict faster motor symptom progression in idiopathic Parkinson disease.
α-Synuclein genetic variants predict faster motor symptom progression in idiopathic Parkinson disease.
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DOI：
10.1371/journal.pone.0036199
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Bronstein J
中科院分区：
文献类型：
--
作者：
Ritz B;Rhodes SL;Bordelon Y;Bronstein J
目前，还没有报道帕金森病（PD）运动症状进展的遗传预测因子。在家族性PD中，疾病严重程度与较高的α-突触核蛋白（SNCA）表达水平相关，并且在尸检研究中，表达随SNCA遗传变异而变化。此外，SNCA是PD发生的众所周知的风险因素。我们从加州中部三个县的社区招募了帕金森病患者，以研究SNCA基因变异对特发性PD运动症状进展的影响。我们使用统一帕金森病评定量表（Unified Parkinson's Disease Rating Scale，简称CAFRS）对这组患者的运动症状变化进行了平均5.1年的反复评估。在363例基于人群的事件PD病例中，自基线评估诊断不到3年，242例成功重新联系，233例至少复查一次。在失访的受试者中，69%是由于死亡。调整协变量后，REP 1 263 bp启动子变异携带者运动功能更快下降的风险（通过运动神经功能缺损评分的年度增加来衡量）增加了4倍（OR 4.03，95%CI：1.57-10.4）。我们的数据还表明rs356165的G等位基因对风险增加有贡献（OR 1.66; 95%CI：0.96-2.88），当考虑两种遗传变异时，我们观察到跨类别的强烈趋势（趋势p = 0.002）。 我们基于人群的研究表明，SNCA变异是特发性PD运动功能下降更快的强预测因子。SNCA可能是一个很有前途的治疗靶点，并可能有助于确定从早期干预中获益最多的患者。这是第一项在纵向进展研究中将SNCA与运动症状下降联系起来的研究。
Currently, there are no reported genetic predictors of motor symptom progression in Parkinson’s disease (PD). In familial PD, disease severity is associated with higher α-synuclein (SNCA) expression levels, and in postmortem studies expression varies with SNCA genetic variants. Furthermore, SNCA is a well-known risk factor for PD occurrence. We recruited Parkinson’s patients from the communities of three central California counties to investigate the influence of SNCA genetic variants on motor symptom progression in idiopathic PD. We repeatedly assessed this cohort of patients over an average of 5.1 years for motor symptom changes employing the Unified Parkinson’s Disease Rating Scale (UPDRS). Of 363 population-based incident PD cases diagnosed less than 3 years from baseline assessment, 242 cases were successfully re-contacted and 233 were re-examined at least once. Of subjects lost to follow-up, 69% were due to death. Adjusting for covariates, risk of faster decline of motor function as measured by annual increase in motor UPDRS exam score was increased 4-fold in carriers of the REP1 263bp promoter variant (OR 4.03, 95%CI:1.57–10.4). Our data also suggest a contribution to increased risk by the G-allele for rs356165 (OR 1.66; 95%CI:0.96–2.88), and we observed a strong trend across categories when both genetic variants were considered (p for trend = 0.002). Our population-based study has demonstrated that SNCA variants are strong predictors of faster motor decline in idiopathic PD. SNCA may be a promising target for therapies and may help identify patients who will benefit most from early interventions. This is the first study to link SNCA to motor symptom decline in a longitudinal progression study.
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