Stroke ·12 Nov 2026 ·Added 12 Nov 2026

Proteomics and Risk of Incident Ischemic Stroke: Meta-Analysis of the ARIC Study and CHS.

Wendy Wang, Yinxiang Wu, Rizwan Kalani, Ting Ye, Traci M Bartz, Michael J Zhang, James S Pankow, Kamakshi Lakshminarayan, Alvaro Alonso, Pamela L Lutsey, Christie M Ballantyne, Kunihiro Matsushita, Michelle C Johansen, Rebecca F Gottesman, Josef Coresh, Wei Pan, Keenan A Walker, Susan R Heckbert, Bruce M Psaty, Colleen M Sitlani, Jennifer A Brody, Nancy Finkel, Valborg Gudmundsdottir, Vilmundur Gudnason … James S Floyd (27 authors)

DOI ↗

Abstract

BACKGROUND: Ischemic stroke preventive therapies have been slow to emerge due to a limited understanding of the underlying molecular mechanisms. We aimed to discover new protein risk factors that are potential etiologic factors and may be candidates for therapeutic intervention. METHODS: We included ARIC study (Atherosclerosis Risk in Communities) and CHS (Cardiovascular Health Study) participants without prevalent stroke at the time of proteomic profiling (1990-1992 in ARIC and 1992-1993 in CHS). Relative concentrations of proteins in blood were assessed with aptamers (n=4954). Ischemic stroke events were adjudicated through 2019 in ARIC and 2015 in CHS. Study-specific Cox regression adjusting for ischemic stroke risk factors was used to estimate associations between proteins and incident ischemic stroke. Study-specific estimates were combined using fixed-effects meta-analysis. Replication was conducted in 2 independent cohorts (AGES-Reykjavik, UK Biobank). Proteins with a false discovery rate q value <0.05 were considered replicated. Mendelian randomization analyses assessed for potential causal associations between proteins and ischemic stroke. RESULTS: Median follow-up was 25 and 12 years in ARIC and CHS. 1397 out of 14 139 (10%) participants experienced an ischemic stroke. 44 proteins were significantly associated with ischemic stroke risk (P<1.0×10-5), of which 26 are novel. In 2 independent cohorts, 37 (84%) associations were directionally concordant, and 26 (59%) met criteria for replication. Mendelian randomization analyses suggested MMP12 (matrix metallopeptidase-12) and CNTN1 (contactin-1) may be causally related to ischemic stroke risk. In multivariable Mendelian randomization analyses, higher MMP12 levels had a direct protective effect on ischemic stroke risk, while CNTN1 had a direct harmful effect. CONCLUSIONS: This proteomic and genomic investigation of ischemic stroke identified novel risk biomarkers and 2 potential etiologic CNTN1 factors that are regulated in response to atherosclerosis and obesity. If future studies confirm our findings, these results may have implications for the development of new preventive therapies.