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BACKGROUND: Arteriolosclerotic cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia, yet no disease-modifying therapies exist. Anti-inflammatory strategies targeting IL-6 (interleukin-6) signaling have shown efficacy in preventing atherosclerotic cardiovascular disease, but their potential in arteriolosclerotic cSVD remains unexplored. We investigated whether genetically downregulated IL-6 signaling is associated with clinical, imaging, and pathological manifestations of arteriolosclerotic cSVD.METHODS: We applied 2-sample Mendelian randomization using (1) 26 genetic variants near (interleukin-6 receptor) associated with circulating C-reactive protein levels and (2) rs2228145, a well-characterized missense variant, as proxies of IL-6 signaling downregulation. Outcomes included clinical (small vessel stroke, magnetic resonance imaging-defined lacunar stroke, nonlobar intracerebral hemorrhage, vascular dementia), imaging (white matter hyperintensity volume, extensive basal ganglia perivascular space, nonlobar/mixed cerebral microbleeds), and pathological (arteriolosclerosis burden in autopsy) traits of cSVD, as well as atherosclerosis traits (ultrasound-defined carotid plaque, large artery stroke) as positive controls. We used inverse-variance weighting and the Wald ratio estimator for primary analyses. Mendelian randomization-Egger regression, weighted median, and weighted mode estimators were used as sensitivity analyses.RESULTS: Genetically downregulated IL-6 signaling (30% decrement in C-reactive protein via 26 variants) was not associated with small vessel stroke (odds ratio [OR], 1.02 [95% CI, 0.95-1.10]), magnetic resonance imaging-confirmed lacunar stroke (OR, 0.95, [95% CI, 0.81-1.11]), nonlobar intracerebral hemorrhage (OR, 1.04 [95% CI, 0.72-1.50]), or vascular dementia (OR, 1.09 [95% CI, 0.95-1.25]). Similarly, we found no significant association with cSVD imaging biomarkers or pathology-defined arteriolosclerosis. As expected, genetically downregulated IL-6 signaling was associated with lower odds of large artery stroke (OR, 0.79 [95% CI, 0.74-0.84]) and carotid plaque (OR, 0.88 [95% CI, 0.83-0.94]). Results were consistent across sensitivity analyses and when using the rs2228145 missense variant to proxy IL-6 signaling downregulation.CONCLUSIONS: Unlike atherosclerotic traits, genetically proxied IL-6 signaling downregulation is not associated with clinical, imaging, or pathological manifestations of arteriolosclerotic cSVD. These genetic findings suggest that targeting IL-6 signaling is unlikely to yield effects on cSVD prevention comparable with those expected for atherosclerotic disease.