Zhu Xue, Huang Sijia, Kang Wenyan, Chen Peizhan, Liu Jun
Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Aging Neurosci. 2023 Feb 22;15:1123239. doi: 10.3389/fnagi.2023.1123239. eCollection 2023.
Observational studies demonstrated controversial effect of polyunsaturated fatty acids (PUFAs) on Parkinson's disease (PD) with limited causality evidence. Randomized control trials showed possible improvement in PD symptoms with PUFA supplement but had small study population and limited intervention time.
A two-sample Mendelian randomization was designed to evaluate the causal relevance between PUFAs and PD, using genetic variants of PUFAs as instrumental variables and PD data from the largest genome-wide association study as outcome. Inverse variance weighted (IVW) method was applied to obtain the primary outcome. Mendelian randomization Egger regression, weighted median and weighted mode methods were exploited to assist result analyses. Strict Mendelian randomization and multivariable Mendelian randomization (MVMR) were used to estimate direct effects of PUFAs on PD, eliminating pleiotropic effect. Debiased inverse variance weighted estimator was implemented when weak instrument bias was introduced into the analysis. A variety of sensitivity analyses were utilized to assess validity of the results.
Our study included 33,674 PD cases and 449,056 controls. Higher plasma level of arachidonic acid (AA) was associated with a 3% increase of PD risk per 1-standard deviation (SD) increase of AA (IVW; Odds ratio (OR)=1.03 [95% confidence interval (CI) 1.01-1.04], = 2.24E-04). After MVMR (IVW; OR=1.03 [95% CI 1.02-1.04], =6.15E-08) and deletion of pleiotropic single-nucleotide polymorphisms overlapping with other lipids (IVW; OR=1.03 [95% CI 1.01-1.05], =5.88E-04), result was still significant. Increased level of eicosapentaenoic acid (EPA) showed possible relevance with increased PD risk after adjustment of pleiotropy (MVMR; OR=1.05 [95% CI 1.01-1.08], =5.40E-03). Linoleic acid (LA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) and alpha-linolenic acid (ALA) were found not causally relevant to PD risk. Various sensitivity analyses verified the validity of our results. In conclusion, our findings from Mendelian randomization suggested that elevated levels of AA and possibly EPA might be linked to a higher risk of PD. No association between PD risk and LA, DHA, DPA, or ALA was found.
The odds ratio for plasma AA and PD risk was weak. It is important to approach our results with caution in clinical practice and to conduct additional studies on the relationship between PUFAs and PD risk.
观察性研究表明，多不饱和脂肪酸（PUFAs）对帕金森病（PD）的影响存在争议，因果关系证据有限。随机对照试验显示，补充PUFAs可能改善PD症状，但研究人群规模小且干预时间有限。
设计了一项两样本孟德尔随机化研究，以评估PUFAs与PD之间的因果相关性，使用PUFAs的基因变异作为工具变量，并将来自最大全基因组关联研究的PD数据作为结果。采用逆方差加权（IVW）方法获得主要结果。利用孟德尔随机化Egger回归、加权中位数和加权模式方法辅助结果分析。采用严格孟德尔随机化和多变量孟德尔随机化（MVMR）来估计PUFAs对PD的直接影响，消除多效性影响。当分析中引入弱工具偏差时，实施去偏逆方差加权估计器。进行了多种敏感性分析以评估结果的有效性。
我们的研究纳入了33674例PD病例和449056例对照。每增加1个标准差（SD）的花生四烯酸（AA），血浆中AA水平升高与PD风险增加3%相关（IVW；优势比（OR）=1.03 [95%置信区间（CI）1.01 - 1.04]，P = 2.24E - 04）。经过MVMR（IVW；OR = 1.03 [95% CI 1.02 - 1.04]，P = 6.15E - 08）以及删除与其他脂质重叠的多效性单核苷酸多态性后（IVW；OR = 1.03 [95% CI 1.01 - 1.05]，P = 5.88E - 04），结果仍然显著。在调整多效性后，二十碳五烯酸（EPA）水平升高显示出与PD风险增加可能存在相关性（MVMR；OR = 1.05 [95% CI 1.01 - 1.08]，P = 5.40E - 03）。发现亚油酸（LA）、二十二碳六烯酸（DHA）、二十二碳五烯酸（DPA）和α-亚麻酸（ALA）与PD风险无因果关系。各种敏感性分析验证了我们结果的有效性。总之，我们孟德尔随机化研究的结果表明，AA水平升高以及可能的EPA水平升高可能与更高的PD风险相关。未发现PD风险与LA、DHA、DPA或ALA之间存在关联。
血浆AA与PD风险的优势比很弱。在临床实践中谨慎对待我们的结果并对PUFAs与PD风险之间的关系进行更多研究很重要。
