Background Long noncoding RNA (lncRNA) and mRNA profiles in leukocytes have shown potential as biomarkers for acute ischemic stroke (AIS). This study aimed to identify altered lncRNA and target mRNA profiles in peripheral blood leukocytes as biomarkers and to assess the diagnostic value and association with AIS prognosis. Methods and Results Differentially expressed lncRNAs (DElncRNAs) and differentially expressed target mRNAs (DEmRNAs) were screened by RNA sequencing in the discovery set, which consisted of 10 patients with AIS and 20 controls. Validation sets consisted of a multicenter (311 AIS versus 303 controls) and a nested case–control study (351 AIS versus 352 controls). The discriminative value of DElncRNAs and DEmRNAs added to the traditional risk factors was estimated with the area under the curve. NAMPT‐AS , FARP1‐AS1 , FTH1 , and NAMPT were identified in the multicenter case–control study ( P &lt;0.05). LncRNA NAMPT‐AS was associated with cis‐target mRNA NAMPT and trans‐target mRNA FTH1 in all validation sets ( P &lt;0.001). Similarly, AIS cases exhibited upregulated lncRNA FARP‐AS1 and FTH1 expression ( P &lt;0.001) in the nested case–control study ( P &lt;0.001). Furthermore, lncRNA FARP1‐AS1 expression was upregulated in AIS patients at discharge with an unfavorable outcome ( P &lt;0.001). Positive correlations were found between NAMPT expression level and NIHSS scores of AIS patients ( P &lt;0.05). Adding 2 lncRNAs and 2 target mRNAs to the traditional risk factor model improved area under the curve by 22.8% and 5.2% in the multicenter and the nested case–control studies, respectively. Conclusions lncRNA NAMPT‐AS and FARP1‐AS1 have potential as diagnostic biomarkers for AIS and exhibit good performance when combined with target mRNA NAMPT and FTH1 .

Multicenter Validation of lncRNA and Target mRNA Diagnostic and Prognostic Biomarkers of Acute Ischemic Stroke From Peripheral Blood Leukocytes