Stochastic Epigenetic Mutations Influence Parkinson's Disease Risk, Progression, and Mortality.
Stochastic Epigenetic Mutations Influence Parkinson's Disease Risk, Progression, and Mortality.
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DOI：
10.3233/jpd-212834
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发表时间：
2022
影响因子：
5.2
通讯作者：
Ritz, Beate
中科院分区：
文献类型：
--
作者：
Chen, Gary K.;Yan, Qi;Paul, Kimberly C.;Kusters, Cynthia D. J.;Folle, Aline Duarte;Furlong, Melissa;Keener, Adrienne;Bronstein, Jeff;Horvath, Steve;Ritz, Beate
随机表观遗传突变 (SEM) 反映了与正常位点特异性甲基化模式的偏差。表观遗传突变负载 (EML) 捕获个体基因组中 SEM 的积累，并可能反映表观遗传维持系统在应对表观遗传挑战时的功能障碍。我们研究 EML 是否与 PD 风险和事件发生时间（即死亡和运动症状衰退）相关。我们采用逻辑回归和 Cox 比例风险回归来评估 EML 与多种结果之间的关联。我们的分析基于来自帕金森病、环境和基因 (PEG) 研究的 568 名帕金森病患者和 238 名对照者，这些患者的血液甲基化数据是可用的。我们发现所有基因（OR = 1.90；95% CI 1.52–2.37）和 PD 相关基因（OR = 1.87；95% CI 1.50–2.32）与 PD 发病和 EML 相关。 EML 还与运动 UPDRS 考试得分最低 35 分的时间（OR = 1.28；95% CI 1.06–1.56）和死亡时间（OR = 1.29，95% CI 1.11–1.49）相关。对 PD 相关基因的分析仅揭示了与 PD 风险相关的 5 个高 SEM 密度的基因内热点。我们的研究结果表明，帕金森病患者的甲基化失调总体上有所增加，特别是五个帕金森病相关基因的甲基化失调。 EML 还可能与 PD 患者的死亡时间和运动症状进展有关。
Stochastic epigenetic mutations (SEM) reflect a deviation from normal site-specific methylation patterns. Epigenetic mutation load (EML) captures the accumulation of SEMs across an individual’s genome and may reflect dysfunction of the epigenetic maintenance system in response to epigenetic challenges. We investigate whether EML is associated with PD risk and time to events (i.e., death and motor symptom decline). We employed logistic regression and Cox proportional hazards regression to assess the association between EML and several outcomes. Our analyses are based on 568 PD patients and 238 controls from the Parkinson’s disease, Environment and Genes (PEG) study, for whom blood-based methylation data was available. We found an association for PD onset and EML in all genes (OR = 1.90; 95% CI 1.52–2.37) and PD-related genes (OR = 1.87; 95% CI 1.50–2.32). EML was also associated with time to a minimum score of 35 points on the motor UPDRS exam (OR = 1.28; 95% CI 1.06–1.56) and time to death (OR = 1.29, 95% CI 1.11–1.49). An analysis of PD related genes only revealed five intragenic hotspots of high SEM density associated with PD risk. Our findings suggest an enrichment of methylation dysregulation in PD patients in general and specifically in five PD related genes. EML may also be associated with time to death and motor symptom progression in PD patients.