Data from: A prospective study of serum metabolites and risk of ischemic stroke

Objective: To identify promising blood-based biomarkers and novel
etiological pathways of disease risk, we applied an untargeted serum
metabolomics profiling in a community-based prospective study of ischemic
stroke (IS). Methods: In 3,904 men and women from the Atherosclerosis Risk
In Communities (ARIC) 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. Results: Serum levels of two long-chain dicarboxylic
acids, tetradecanedioate and hexadecanedioate, were strongly correlated
(r=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; p<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). Conclusion: 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.

研究目的：为识别具有应用前景的血液源性生物标志物及疾病风险的全新致病通路，我们在一项基于社区的缺血性脑卒中（ischemic stroke, IS）前瞻性研究中开展了非靶向血清代谢组学分析。
研究方法：纳入动脉粥样硬化风险社区（Atherosclerosis Risk In Communities, ARIC）队列的3904名男女受试者，采用Cox比例风险模型分别估算245种空腹血清代谢物的标准化水平与新发缺血性脑卒中事件的关联，并校正年龄、性别、种族、随访中心、检测批次、糖尿病、高血压、当前吸烟状态、体质量指数及估算肾小球滤过率等混杂因素。本研究在包含114例缺血性脑卒中病例与112名健康对照的独立样本中完成了结果验证。
研究结果：血清中两种长链二羧酸——十四烷二酸（tetradecanedioate）与十六烷二酸（hexadecanedioate）——的水平呈强相关性（r=0.88），在校正混杂因素后与新发缺血性脑卒中事件显著相关[风险比（95%置信区间（CI））分别为1.11[1.06~1.16]与1.12[1.07~1.17]，p<0.0001]。按缺血性脑卒中亚型进行的亚组分析显示，上述关联仅特异性见于心源性栓塞性脑卒中（cardioembolic stroke, CES）。在独立验证队列中，十四烷二酸与十六烷二酸与缺血性脑卒中的关联得到了独立验证[比值比（95% CI）分别为1.76[1.21~2.56]与1.60[1.11~2.32]]。
研究结论：本研究发现，两种血清长链二羧酸——脂肪酸ω氧化的代谢产物——十四烷二酸与十六烷二酸，与缺血性脑卒中及心源性栓塞性脑卒中的关联独立于已知的风险因素。细胞内十六烷二酸合成相关通路或其循环清除相关通路可能介导缺血性脑卒中的发病风险。上述结果凸显了代谢组学在挖掘脑卒中新型循环生物标志物及解析缺血性脑卒中及其亚型致病新通路方面的应用潜力。