Stroke Unit, Department of Neurology Santa Creu i Sant Pau, Barcelona, Spain (C.G.-F., A.A.-S., R.M., L.P.-S., P.C.-R., R.D.-M., J.M.-F.).
Stroke Pharmacogenomics and Genetics, Biomedical Research Institute Sant Pau, Sant Pau Hospital, Barcelona, Spain (C.G.-F., E.M., N.C., J.C.-M., M.L., L.L.-C., J.M.M.-C., I.F.-C.).
Stroke. 2022 Jul;53(7):2320-2330. doi: 10.1161/STROKEAHA.121.037419. Epub 2022 Feb 25.
Stroke onset in women occurs later in life compared with men. The underlying mechanisms of these differences have not been established. Epigenetic clocks, based on DNA methylation (DNAm) profiles, are the most accurate biological age estimate. Epigenetic age acceleration (EAA) measures indicate whether an individual is biologically younger or older than expected. Our aim was to analyze whether sexual dichotomy at age of stroke onset is conditioned by EAA.
We used 2 DNAm datasets from whole blood samples of case-control genetic studies of ischemic stroke (IS), a discovery cohort of 374 IS patients (N women=163, N men=211), from GRECOS (Genotyping Recurrence Risk of Stroke) and SEDMAN (Dabigatran Study in the Early Phase of Stroke, New Neuroimaging Markers and Biomarkers) studies and a replication cohort of 981 IS patients (N women=411, N men=570) from BASICMAR register. We compared chronological age, 2 DNAm-based biomarkers of aging and intrinsic and extrinsic epigenetic age acceleration EAA (IEAA and extrinsic EAA, respectively), in IS as well as in individual IS etiologic subtypes. Horvath and Hannum epigenetic clocks were used to assess the aging rate. A proteomic study using the SOMAScan multiplex assay was performed on 26 samples analyzing 1305 proteins.
Women present lower Hannum-extrinsic EAA values, whereas men have higher Hannum-extrinsic EAA values (women=-0.64, men=1.24, =1.34×10); the same tendency was observed in the second cohort (women=-0.57, men=0.79, =0.02). These differences seemed to be specific to cardioembolic and undetermined stroke subtypes. Additionally, 42 blood protein levels were associated with Hannum-extrinsic EAA (<0.05), belonging to the immune effector process (=1.54×10) and platelet degranulation (<8.74×10) pathways.
This study shows that sex-specific underlying biological mechanisms associated with stroke onset could be due to differences in biological age acceleration between men and women.
与男性相比，女性中风发病年龄较晚。这些差异的潜在机制尚未确定。基于 DNA 甲基化 (DNAm) 谱的表观遗传时钟是最准确的生物年龄估算方法。表观遗传年龄加速 (EAA) 测量指标表明个体的生物年龄比预期的年轻还是年长。我们的目的是分析中风发病年龄的性别二分法是否与 EAA 有关。
我们使用了来自缺血性中风（IS）病例对照遗传研究的两个全血样本的 DNAm 数据集，一个包括 374 名 IS 患者的发现队列（女性=163 名，男性=211 名），来自 GRECOS（中风再发风险的基因分型研究）和 SEDMAN（达比加群在中风早期的研究、新的神经影像学标志物和生物标志物）研究，以及来自 BASICMAR 登记处的 981 名 IS 患者的复制队列（女性=411 名，男性=570 名）。我们比较了 IS 患者以及个体 IS 病因亚型中的实际年龄、两种基于 DNAm 的衰老生物标志物以及内在和外在表观遗传年龄加速 EAA（IEAA 和外在 EAA）。使用 Horvath 和 Hannum 表观遗传时钟来评估衰老速度。使用 SOMAScan 多重分析试剂盒对 26 个样本进行了蛋白质组学研究，分析了 1305 种蛋白质。
女性的 Hannum 外在 EAA 值较低，而男性的 Hannum 外在 EAA 值较高（女性=-0.64，男性=1.24，=1.34×10）；在第二个队列中也观察到了同样的趋势（女性=-0.57，男性=0.79，=0.02）。这些差异似乎是特定于心源性栓塞和未确定的中风亚型的。此外，有 42 种血液蛋白水平与 Hannum 外在 EAA 相关（<0.05），属于免疫效应过程（=1.54×10）和血小板脱颗粒（<8.74×10）途径。
本研究表明，与中风发病相关的性别特异性潜在生物学机制可能是由于男性和女性之间的生物年龄加速差异所致。
