RNF213 p.Arg4810Lys (c.14429G>A) is associated with extracranial arterial stenosis

Abstract

Ring finger protein 213 (RNF213) 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 RNF213 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 RNF213 p.Arg4810Lys. A total of 1202 patients served as controls. The association of RNF213 p.Arg4810Lys with various stroke subtypes was studied. In sub-analyses, the association of RNF213 p.Arg4810Lys with intracranial artery stenosis/extracranial artery stenosis and maximum intima-media thickness were assessed. RNF213 p.Arg4810Lys was more common in patients with stroke (3.3%) than in those without stroke (1.1%). RNF213 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 RNF213 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 RNF213 p.Arg4810Lys, regardless of stroke type (adjusted odds ratio, 3.72; 95% confidence interval, 1.30-10.60; P = 0.014, adjusted odds ratio, 7.04; 95% confidence interval, 1.51-32.77; P= 0.013, adjusted odds ratio, 11.68; 95% confidence interval, 4.25-32.07; P 0.001, respectively). RNF213 p.Arg4810Lys was associated with increased maximum intima-media thickness, measured using carotid artery ultrasonography (multiple regression analysis β = 0.165; P = 0.004). These results were replicated in an independent validation cohort. In conclusion, RNF213 p.Arg4810Lys increases the risk of stroke. In addition to intracranial artery stenosis, RNF213 p.Arg4810Lys is associated with extracranial artery stenosis and maximum intima-media thickness. Evaluating RNF213 p.Arg4810Lys may help predict the incidence and type of stroke.

Keywords: RNF213 p.Arg4810Lys (c.14429G>A); intracranial and extracranial artery stenosis; maximum intima-media thickness; stroke.

graphical abstract

Figure 1

Flowchart of the Kyorin cohort showing the association of the RNF213 p.Arg4810Lys variant with ICAS/ECAS and max-IMT. ECAS, extracranial artery stenosis; ICAS, intracranial artery stenosis; max-IMT, maximum intima-media thickness.

Figure 2

Max-IMT of carotid artery by RNF213 p.Arg4810Lys genotypes in the Kyorin cohort. Box plot shows the significantly increased max-IMT of the carotid artery in the RNF213 p.Arg4810Lys variant group (N = 14) compared to the wild-type group (N = 388). Statistical analysis was performed using the Mann–Whitney U test, with *P < 0.05 indicating significance. Max-IMT, maximum intima-media thickness.