Causal Effects of YKL‐40 on Ischemic Stroke and Its Subtypes: A 2‐Sample Mendelian Randomization Study

BACKGROUND: Chitinase‐3 like protein 1 (CHI3L1, YKL‐40) was reported to be implicated in the development of ischemic stroke, but whether the association between them was causal remained unclear. We conducted a 2‐sample Mendelian randomization study to explore the associations of genetically determined plasma YKL‐40 with ischemic stroke and its subtypes (large artery stroke, small vessel stroke, and cardioembolic stroke). METHODS AND RESULTS: Based on genome‐wide association study data of 3394 European‐descent individuals, we selected 13 single‐nucleotide polymorphisms associated with plasma YKL‐40 as genetic instruments. Summary data about ischemic stroke and its subtypes were obtained from the Multiancestry Genome‐wide Association Study of Stroke Consortium, involving 34 217 ischemic stroke cases and 406 111 controls of European ancestry. We used the inverse‐variance weighted method followed by a series of sensitivity analyses to assess the causal associations of plasma YKL‐40 with ischemic stroke and its subtypes. The primary analysis showed that genetically determined high YKL‐40 levels were associated with increased risks of large artery stroke (odds ratio [OR], 1.08 [95% CI, 1.04–1.12]; P=1.73×10(−4)) and small vessel stroke (OR, 1.05 [95% CI, 1.01–1.09]; P=7.96×10(−3)) but not with ischemic stroke or cardioembolic stroke. Sensitivity analyses further confirmed these associations, and Mendelian randomization‐Egger indicated no evidence of genetic pleiotropy. In addition, supplementary analysis based on the summary data from the Olink proximity extension assay cardiovascular I (Olink CVD‐I) panel showed that high YKL‐40 levels were positively associated with the risks of large artery stroke (OR, 1.15 [95% CI, 1.08–1.22]; P=4.16×10(−6)) but not with small vessel stroke. CONCLUSIONS: Genetically determined high plasma YKL‐40 levels were causal associated with increased risks of large artery stroke.