Multiple evidence has suggested the complex interplay between Parkinson’s disease (PD) and systemic inflammation marked by C-reactive protein (CRP) and interleukin 6 (IL-6). Nevertheless, the findings across studies have shown inconsistency, and the direction of the effect remains controversial. Here, we aimed to explore the link between CRP and IL-6 and the risk of PD. Based on data from the UK Biobank, we investigated the association between baseline CRP and IL-6 and the risk of incident PD with Cox proportional hazards regression analysis. We further performed extensive genetic analyses including genetic correlation, polygenic risk score (PRS), and pleiotropic enrichment based on summary statistics from previous genome-wide association studies. A higher level of CRP at baseline was associated with a lower risk of PD (HR = 0.85, 95 % CI: 0.79–0.90, P = 4.23E−07). The results remained consistent in the subgroup analyses stratified by sex, age and body mass index. From the genetic perspective, a significant negative genetic correlation was identified between CRP and PD risk (correlation: −0.14, P = 6.31E−05). Higher PRS of CRP was associated with a lower risk of PD (P = 0.015, beta = −0.04, SE = 0.017). Moreover, we observed significant pleiotropic enrichment for PD conditional on CRP, and identified 13 risk loci for PD, some of which are implicated in immune functionality and have been linked to PD, including , , , and . In contrast, no significant association was identified between IL and 6 and PD. Systemic inflammation at baseline measured by CRP level is associated with decreased future risk of PD. These discoveries contribute to a deeper comprehension of the role of inflammation in the risk of PD, and hold implications for the design of therapeutic interventions in clinical trials.

中文翻译：

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全身炎症和帕金森病的风险：前瞻性队列研究和遗传分析

多项证据表明帕金森病 (PD) 与以 C 反应蛋白 (CRP) 和白细胞介素 6 (IL-6) 为标志的全身炎症之间存在复杂的相互作用。然而，各项研究的结果显示出不一致，并且影响的方向仍然存在争议。在这里，我们旨在探讨 CRP 和 IL-6 与 PD 风险之间的联系。根据英国生物银行的数据，我们通过 Cox 比例风险回归分析研究了基线 CRP 和 IL-6 与 PD 事件风险之间的关联。我们进一步进行了广泛的遗传分析，包括遗传相关性、多基因风险评分（PRS）和基于先前全基因组关联研究的汇总统计数据的多效性富集。基线时较高的 CRP 水平与较低的 PD 风险相关（HR = 0.85，95% CI：0.79–0.90，P = 4.23E−07）。按性别、年龄和体重指数分层的亚组分析结果保持一致。从遗传角度来看，CRP 和 PD 风险之间存在显着的负遗传相关性（相关性：-0.14，P = 6.31E-05）。CRP 较高的 PRS 与较低的 PD 风险相关（P = 0.015，β = -0.04，SE = 0.017）。此外，我们观察到以 CRP 为条件的 PD 的显着多效性富集，并确定了 13 个 PD 风险位点，其中一些与免疫功能有关并与 PD 相关，包括 、 、 和 。相反，IL、6 和 PD 之间没有发现显着关联。通过 CRP 水平测量的基线全身炎症与未来 PD 风险降低相关。这些发现有助于更深入地理解炎症在帕金森病风险中的作用，并对临床试验中治疗干预措施的设计具有重要意义。