Genetic downregulation of interleukin-6 signaling and arteriolosclerotic cerebral small vessel disease: a drug target Mendelian randomization analysis

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ABSTRACT 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 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 two-sample Mendelian randomization (MR) using (i) 26 genetic variants near IL6R associated with circulating C-reactive protein (CRP) levels and (ii) rs2228145, a well- characterized IL6R missense variant, as proxies of IL-6 signaling downregulation. Outcomes included clinical (small-vessel stroke, MRI-defined lacunar stroke, non-lobar intracerebral hemorrhage [ICH], vascular dementia), imaging (white matter hyperintensity volume, extensive basal ganglia perivascular space, non-lobar/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. MR-Egger regression, weighted median, and weighted mode estimators were used as sensitivity analyses. Results Genetically downregulated IL-6 signaling (30%-decrement in CRP via 26 IL6R variants) was not associated with small-vessel stroke (OR: 1.02, 95%CI: 0.95–1.10), MRI-confirmed lacunar stroke (OR: 0.95, [0.81–1.11]), non-lobar ICH (OR: 1.04, [0.72–1.50]), or vascular dementia (OR: 1.09, [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, [0.74-0.84]) and carotid plaque (OR: 0.88, [0.83–0.94]). Results were consistent across sensitivity analyses and when using the rs2228145 missense variant to proxy IL-6 signaling downregulation. Conclusion Genetically proxied IL-6 signaling downregulation is not associated with clinical, imaging or pathological manifestations of arteriolosclerotic cSVD. Therefore, genetic data suggest that targeting IL-6 signaling is unlikely to prevent cSVD manifestations.

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