Independent Association of RNF213 p.R4810K With Extracranial Carotid Artery Disease Beyond Intracranial Atherosclerosis.

Abstract

Background: The RNF213 p.R4810K variant, a susceptibility variant for moyamoya disease, has also been linked to intracranial atherosclerotic disease (ICAD). However, its association with extracranial carotid artery disease (ECAD), particularly whether this association is independent of concomitant ICAD and whether it differs by stenosis severity, remains unclear.

Methods: We conducted a multicenter registry-based observational study of patients with acute ischemic stroke (AIS) or transient ischemic attack enrolled in the Fukuoka Stroke Registry. Patients were genotyped for RNF213 p.R4810K and classified as noncarriers (G/G) or variant carriers (G/A or A/A). ECAD was defined as ≥50% stenosis or occlusion of the extracranial carotid arteries. Multivariable logistic regression was used to assess the association between RNF213 p.R4810K and ECAD after adjusting for vascular risk factors and ICAD, and stratified analyses were performed by ICAD status. ECAD severity was modeled ordinally (none, moderate, severe, and occlusion) using a partial proportional-odds model.

Results: Of 15 569 registry patients with AIS or transient ischemic attack, 13 994 were included in the present analysis after exclusions (mean age, 73±12 years; 59.5% men). The RNF213 p.R4810K variant was identified in 359 patients (2.6%). ECAD was present in 2181 patients (15.6%), including 78 variant carriers. Variant carriers had significantly higher odds of ECAD after adjustment for vascular risk factors and ICAD (odds ratio, 1.69 [95% CI, 1.29-2.22]). This association was consistent irrespective of ICAD status (P_{heterogeneity}=0.32). In severity analyses, the association strengthened stepwise with increasing ECAD severity; the largest effect estimate was for occlusion (odds ratio, 4.55 [95% CI, 2.81-7.38]).

Conclusions: The RNF213 p.R4810K variant was associated with ECAD independent of concomitant ICAD and showed a graded association with ECAD severity. Extracranial disease expression may involve modifiers distinct from those driving ICAD.