<i>RNF213</i> p.Arg4810Lys (c.14429G&amp;gt;A) is associated with extracranial arterial stenosis

<i>Ring finger protein 213</i> (<i>RNF213</i>) p.Arg4810Lys (c.14429G > A) is associated with intracranial artery stenosis; however, its association with extracranial artery stenosis remains unknown. We aimed to elucidate the clinical significance and association of <i>RNF213</i> p.Arg4810Lys with stroke subtypes, extracranial artery stenosis, and maximum intima-media thickness. A cohort of 600 patients with stroke prospectively collected over 1 year was assessed for the presence of <i>RNF213</i> p.Arg4810Lys. A total of 1202 patients served as controls. The association of <i>RNF213</i> p.Arg4810Lys with various stroke subtypes was studied. In sub-analyses, the association of <i>RNF213</i> p.Arg4810Lys with intracranial artery stenosis/extracranial artery stenosis and maximum intima-media thickness were assessed. <i>RNF213</i> p.Arg4810Lys was more common in patients with stroke (3.3%) than in those without stroke (1.1%). <i>RNF213</i> p.Arg4810Lys was significantly associated with stroke. Among various stroke subtypes, large-artery atherosclerosis, both due to intracranial artery stenosis and extracranial artery stenosis, was most significantly associated with <i>RNF213</i> p.Arg4810Lys. In the sub-analysis, intracranial artery stenosis-only, extracranial artery stenosis-only, and concurrent intracranial artery stenosis and extracranial artery stenosis groups were significantly associated with <i>RNF213</i> p.Arg4810Lys, regardless of stroke type (adjusted odds ratio, 3.72; 95% confidence interval, 1.30-10.60; <i>P</i> <i>=</i> 0.014, adjusted odds ratio, 7.04; 95% confidence interval, 1.51-32.77; <i>P=</i> 0.013, adjusted odds ratio, 11.68; 95% confidence interval, 4.25-32.07; <i>P</i> 0.001, respectively). <i>RNF213</i> p.Arg4810Lys was associated with increased maximum intima-media thickness, measured using carotid artery ultrasonography (multiple regression analysis β = 0.165; <i>P</i> = 0.004). These results were replicated in an independent validation cohort. In conclusion, <i>RNF213</i> p.Arg4810Lys increases the risk of stroke. In addition to intracranial artery stenosis, <i>RNF213</i> p.Arg4810Lys is associated with extracranial artery stenosis and maximum intima-media thickness. Evaluating <i>RNF213</i> p.Arg4810Lys may help predict the incidence and type of stroke.