Table_1_Associations between polyunsaturated fatty acid concentrations and Parkinson’s disease: A two-sample Mendelian randomization study.DOCX

IntroductionObservational 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.MethodsA 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.ResultsOur 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], P = 2.24E-04). After MVMR (IVW; OR=1.03 [95% CI 1.02-1.04], P =6.15E-08) and deletion of pleiotropic single-nucleotide polymorphisms overlapping with other lipids (IVW; OR=1.03 [95% CI 1.01-1.05], P =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], P =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.DiscussionThe 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.

引言 观察性研究揭示了多不饱和脂肪酸（PUFAs）对帕金森病（PD）的影响存在争议，因果关联证据有限。随机对照试验显示，PUFA补充剂可能改善PD症状，但研究样本量较小，干预时间有限。方法 设计了一种双样本孟德尔随机化分析，以评估PUFAs与PD之间的因果相关性，利用PUFAs的遗传变异作为工具变量，并以最大规模的全基因组关联研究中的PD数据作为结果。采用逆方差加权（IVW）方法获得主要结果。运用孟德尔随机化Egger回归、加权中位数和加权众数方法协助结果分析。采用严格的孟德尔随机化和多变量孟德尔随机化（MVMR）来估计PUFAs对PD的直接效应，消除多效性影响。当分析中引入弱工具变量偏差时，实施了去偏的逆方差加权估计器。通过多种敏感性分析评估结果的可靠性。结果 本研究纳入了33,674例PD病例和449,056例对照者。血浆中花生四烯酸（AA）水平每增加1个标准差（SD），PD风险增加3%，这一关联在IVW分析中显著（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）和多效性单核苷酸多态性删除（IVW；OR=1.03 [95% CI 1.01-1.05]，P=5.88E-04）后，结果依然显著。调整多效性后，二十碳五烯酸（EPA）水平升高可能与PD风险增加有关（MVMR；OR=1.05 [95% CI 1.01-1.08]，P=5.40E-03）。亚油酸（LA）、二十碳四烯酸（DHA）、二十二碳五烯酸（DPA）和α-亚麻酸（ALA）与PD风险无因果关联。各种敏感性分析验证了结果的可靠性。结论，基于孟德尔随机化的研究发现，AA水平升高可能以及EPA水平升高与PD风险增加有关。未发现PD风险与LA、DHA、DPA或ALA之间的关联。讨论 血浆中AA与PD风险的优势比较弱。在临床实践中，对待我们的结果需持谨慎态度，并需开展更多关于PUFAs与PD风险之间关系的研究。