核苷与 REGARDS 和 JHS 队列中缺血性中风事件的关系。
Nucleosides Associated With Incident Ischemic Stroke in the REGARDS and JHS Cohorts.
机构信息
From the Center for Genomic Medicine, Harvard Medical School (Z.A., W.T.K.), and Department of Neurology (Z.A., A.-L.G.G., W.T.K.), Massachusetts General Hospital, Boston; Departments of Epidemiology (A.P., N.C., R.M.I.) and Biostatistics (S.E.J., L.L.), School of Public Health, University of Alabama at Birmingham; Harvard Medical School (V.M.B.), Boston, MA; The Jackson Heart Study (Y.G., A.C.), University of Mississippi Medical Center, Jackson; Department of Medicine (R.E.G.), Beth Israel Deaconess Medical Center, Boston, MA; and Department of Medicine (M.C.), Larner College of Medicine at the University of Vermont, Burlington.
出版信息
Neurology. 2022 May 24;98(21):e2097-e2107. doi: 10.1212/WNL.0000000000200262. Epub 2022 Mar 9.
BACKGROUND AND OBJECTIVES
Both genetic and environmental factors contribute to stroke risk. We sought to identify novel metabolites associated with incident stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort and determine whether they reflected genetic or environmental variation.
METHODS
This was a stroke case-cohort observational study nested in REGARDS. Cases were defined as incident stroke and metabolomic profiles were compared to a randomly selected control cohort. In baseline plasma samples, 162 metabolites were measured using liquid chromatography-tandem mass spectrometry. Cox proportional hazards models were adjusted for age, sex, race, and age by race in the base model. Fully adjusted models included traditional stroke risk factors. Mediation analyses conducted for these stroke risk factors used the metabolite as mediator. Genome-wide associations with the leading candidate metabolites were calculated using array data. Replication analyses in the Jackson Heart Study (JHS) were conducted using random effects meta-analysis.
RESULTS
There were 2,043 participants who were followed over an average period of 7.1 years, including 1,075 stroke cases and 968 random controls. Nine metabolites were associated with stroke in the base model, 8 of which were measured and remained significant in meta-analysis with JHS. In the fully adjusted model in REGARDS, guanosine (hazard ratio [HR] 1.34, 95% CI 1.18-1.53; = 7.26 × 10) and pseudouridine (HR 1.28, 95% CI 1.13-1.45; = 1.03 × 10) were associated with incident ischemic stroke following Bonferroni adjustment. Guanosine also partially mediated the relationship between hypertension and stroke (17.6%) and pseudouridine did not mediate any risk factor. Genome-wide association analysis identified loci rs34631560 and rs34631560 associated with pseudouridine, but these did not explain the association of pseudouridine with stroke.
DISCUSSION
Guanosine and pseudouridine are nucleosides associated with incident ischemic stroke independently of other risk factors. Genetic and mediation analyses suggest that environmental exposures rather than genetic variation link nucleoside levels to stroke risk.
CLASSIFICATION OF EVIDENCE
This study provides Class II evidence that guanosine and pseudouridine are associated with incident stroke.
背景与目的
遗传和环境因素均会增加中风风险。我们试图在 Reasons for Geographic and Racial Differences in Stroke（REGARDS）队列中确定与中风发病相关的新型代谢物，并确定它们是否反映了遗传或环境变异。
方法
这是一项在 REGARDS 中嵌套的中风病例-队列观察性研究。病例定义为中风发病，代谢组学谱与随机选择的对照队列进行比较。在基线血浆样本中，使用液相色谱-串联质谱法测量了 162 种代谢物。在基本模型中，使用 Cox 比例风险模型调整年龄、性别、种族和年龄种族。完全调整的模型包括传统的中风危险因素。使用代谢物作为中介物对这些中风危险因素进行中介分析。使用阵列数据计算与主要候选代谢物相关的全基因组关联。在 Jackson Heart Study（JHS）中进行了复制分析，使用随机效应荟萃分析。
结果
共有 2043 名参与者平均随访 7.1 年，包括 1075 例中风病例和 968 例随机对照。在基本模型中，有 9 种代谢物与中风相关，其中 8 种在与 JHS 的荟萃分析中进行了测量且仍有意义。在 REGARDS 中的完全调整模型中，鸟苷（危险比[HR]1.34，95%置信区间[CI]1.18-1.53； = 7.26×10）和假尿嘧啶（HR 1.28，95%CI 1.13-1.45； = 1.03×10）与经 Bonferroni 校正后的缺血性中风发病相关。鸟苷还部分介导了高血压与中风之间的关系（17.6%），而假尿嘧啶则没有介导任何危险因素。全基因组关联分析确定了与假尿嘧啶相关的 rs34631560 和 rs34631560 位点，但这些位点并不能解释假尿嘧啶与中风的关联。
讨论
鸟苷和假尿嘧啶是与独立于其他危险因素的缺血性中风发病相关的核苷。遗传和中介分析表明，环境暴露而不是遗传变异将核苷水平与中风风险联系起来。
分类证据
本研究提供了 II 级证据，表明鸟苷和假尿嘧啶与中风发病相关。
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