Department of Neurology, Massachusetts General Hospital.
Harvard Medical School.
Ann Neurol. 2019 Apr;85(4):593-599. doi: 10.1002/ana.25436. Epub 2019 Mar 3.
LRRK2 mutations, the most common genetic cause of Parkinson disease (PD), display incomplete penetrance, indicating the importance of other genetic and environmental influences on disease pathogenesis in LRRK2 mutation carriers. The present study investigates whether urate, an antioxidant, Nrf2 activator, and inverse risk factor for idiopathic PD, is one such candidate biomarker of PD risk modulation in pathogenic LRRK2 mutation carriers.
Banked plasma samples or urate levels were obtained for 3 cohorts of age- and sex-matched subjects with and without a known LRRK2 mutation in PD and unaffected controls to conduct a pilot study of 192 subjects from the LRRK2 Cohort Consortium (LCC) and 2 validation studies of 380 additional subjects from the LCC and 922 subjects from the Parkinson's Progression Markers Initiative. Urate levels were compared by multiple regression between subjects with and without a PD diagnosis conditional on LRRK2 status, controlling for age and sex.
Nonmanifesting LRRK2 mutation carriers had significantly higher levels of urate than those who developed PD in each of the 3 independent cohorts. A meta-analysis demonstrated an adjusted mean difference of 0.62 mg/dL (p < 0.001), with similar results for separate assessments of women (p < 0.02) and men (p < 0.001). A 2 mg/dL increment in urate concentration decreased the odds of having PD by approximately 50% (odds ratio = 0.48, p = 0.004).
These findings identify and substantiate urate as a biomarker of resistance to PD among LRRK2 mutation carriers. Ann Neurol 2019;85:593-599.
LRRK2 突变是最常见的帕金森病（PD）遗传病因，其表现为不完全外显，表明其他遗传和环境因素对 LRRK2 突变携带者的疾病发病机制有重要影响。本研究旨在探讨尿酸（一种抗氧化剂、Nrf2 激活剂和特发性 PD 的反向风险因素）是否是致病性 LRRK2 突变携带者中 PD 风险调节的候选生物标志物之一。
本研究从 LRRK2 队列联盟（LCC）的 192 名受试者和 LCC 和帕金森进展标志物倡议（PPMI）的 922 名受试者的另外 380 名受试者中收集了已储存的血浆样本或尿酸水平，以开展针对 PD 患者和无病对照者中有无已知 LRRK2 突变的 3 个队列的试点研究。在控制 LRRK2 状态、年龄和性别条件下，采用多元回归比较 PD 诊断患者与无 PD 诊断患者的尿酸水平。
在 3 个独立队列中，非显性 LRRK2 突变携带者的尿酸水平明显高于发生 PD 的患者。Meta 分析显示，调整后的平均差异为 0.62mg/dL（p<0.001），女性（p<0.02）和男性（p<0.001）的单独评估也得到了类似的结果。尿酸浓度增加 2mg/dL，PD 的发病几率降低约 50%（优势比=0.48，p=0.004）。
这些发现确定并证实了尿酸是 LRRK2 突变携带者 PD 抗性的生物标志物。
