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.