From the Brown Foundation Institute of Molecular Medicine, McGovern Medical School (D.S., X.J., M.F.), and School of Public Health (B.Y., E.B., M.F.), The University of Texas Health Science Center at Houston; Institute for Stroke and Dementia Research (S.T., M.D.), Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany; Johns Hopkins University School of Medicine (R.F.G.), Baltimore, MD; The University of Mississippi Medical Center (T.H.M.), Jackson; German Center for Neurodegenerative Diseases (DZNE, Munich) (M.D.); and Munich Cluster for Systems Neurology (SyNergy) (S.T., M.D.), Germany.
Neurology. 2019 Apr 16;92(16):e1890-e1898. doi: 10.1212/WNL.0000000000007279. Epub 2019 Mar 13.
To identify promising blood-based biomarkers and novel etiologic pathways of disease risk, we applied an untargeted serum metabolomics profiling in a community-based prospective study of ischemic stroke (IS).
In 3,904 men and women from the Atherosclerosis Risk In Communities study, Cox proportional hazard models were used to estimate the association of incident IS with the standardized level of 245 fasting serum metabolites individually, adjusting for age, sex, race, field center, batch, diabetes, hypertension, current smoking status, body mass index, and estimated glomerular filtration rate. Validation of results was carried out in an independent sample of 114 IS cases and 112 healthy controls.
Serum levels of 2 long-chain dicarboxylic acids, tetradecanedioate and hexadecanedioate, were strongly correlated ( = 0.88) and were associated with incident IS after adjusting for covariates (hazard ratio [95% confidence interval (CI)] 1.11 [1.06-1.16] and 1.12 [1.07-1.17], respectively; < 0.0001). Analyses by IS subtypes suggested that these associations were specific to cardioembolic stroke (CES). Associations of tetradecanedioate and hexadecanedioate with IS were independently confirmed (odds ratio [95% CI] 1.76 [1.21; 2.56] and 1.60 [1.11; 2.32], respectively).
Two serum long-chain dicarboxylic acids, metabolic products of ω-oxidation of fatty acids, were associated with IS and CES independently of known risk factors. Pathways related to intracellular hexadecanedioate synthesis or those involved in its clearance from the circulation may mediate IS risk. These results highlight the potential of metabolomics to discover novel circulating biomarkers for stroke and to unravel novel pathways for IS and its subtypes.
为了确定有前途的血液生物标志物和疾病风险的新病因途径，我们在一项基于社区的缺血性中风（IS）前瞻性研究中应用了非靶向血清代谢组学分析。
在 Atherosclerosis Risk In Communities 研究的 3904 名男性和女性中，使用 Cox 比例风险模型来估计个体空腹血清 245 种代谢物的标准化水平与新发 IS 之间的关联，调整年龄、性别、种族、现场中心、批次、糖尿病、高血压、当前吸烟状态、体重指数和估计肾小球滤过率。在 114 例 IS 病例和 112 例健康对照的独立样本中进行了结果验证。
两种长链二羧酸，十四烷二酸和十六烷二酸的血清水平高度相关（ = 0.88），并在调整协变量后与新发 IS 相关（危险比 [95%置信区间（CI）] 1.11 [1.06-1.16] 和 1.12 [1.07-1.17]；<0.0001）。通过 IS 亚型分析表明，这些关联仅针对心源性栓塞性中风（CES）。十四烷二酸和十六烷二酸与 IS 的关联独立得到证实（比值比 [95%CI] 1.76 [1.21; 2.56] 和 1.60 [1.11; 2.32]）。
两种血清长链二羧酸，脂肪酸 ω-氧化的代谢产物，与 IS 和 CES 独立于已知的危险因素相关。与细胞内十六烷二酸合成相关的途径或其从循环中清除的途径可能介导 IS 风险。这些结果强调了代谢组学发现新型中风循环生物标志物和揭示 IS 及其亚型新途径的潜力。
