Phenotypic and genetic effect of carotid intima-media thickness on the risk of stroke.

While carotid intima-media thickness (cIMT) as a noninvasive surrogate measure of atherosclerosis is widely considered a risk factor for stroke, the intrinsic link underlying cIMT and stroke has not been fully understood. We aimed to evaluate the clinical value of cIMT in stroke through the investigation of phenotypic and genetic relationships between cIMT and stroke. We evaluated phenotypic associations using observational data from UK Biobank (N = 21,526). We then investigated genetic relationships leveraging genomic data conducted in predominantly European ancestry for cIMT (N = 45,185) and any stroke (AS, N _case /N _control =40,585/406,111). Observational analyses suggested an increased hazard of stroke per one standard deviation increase in cIMT (cIMT _max -AS: hazard ratio (HR) = 1.39, 95%CI = 1.09-1.79; cIMT _mean -AS: HR = 1.39, 95%CI = 1.09-1.78; cIMT _min -AS: HR = 1.32, 95%CI = 1.04-1.68). A positive global genetic correlation was observed (cIMT _max -AS: [Formula: see text]=0.23, P=9.44 × 10 ^-5 ; cIMT _mean -AS: [Formula: see text]=0.21, P=3.00 × 10 ^-4 ; cIMT _min -AS: [Formula: see text]=0.16, P=6.30 × 10 ^-3 ). This was further substantiated by five shared independent loci and 15 shared expression-trait associations. Mendelian randomization analyses suggested no causal effect of cIMT on stroke (cIMT _max -AS: odds ratio (OR)=1.12, 95%CI=0.97-1.28; cIMT _mean -AS: OR=1.09, 95%CI=0.93-1.26; cIMT _min -AS: OR=1.03, 95%CI = 0.90-1.17). A putative association was observed for genetically predicted stroke on cIMT (AS-cIMT _max : beta=0.07, 95%CI = 0.01-0.13; AS-cIMT _mean : beta=0.08, 95%CI = 0.01-0.15; AS-cIMT _min : beta = 0.08, 95%CI = 0.01-0.16) in the reverse direction MR, which attenuated to non-significant in sensitivity analysis. Our work does not find evidence supporting causal associations between cIMT and stroke. The pronounced cIMT-stroke association is intrinsic, and mostly attributed to shared genetic components. The clinical value of cIMT as a surrogate marker for stroke risk in the general population is likely limited.
(© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)