Amplified Risk of Intracranial Artery Stenosis/Occlusion Associated With RNF213 p.R4810K in Familial Hypercholesterolemia

Kotaro Noda; Yorito Hattori; Mika Hori; Yuriko Nakaoku; Akito Tanaka; Takeshi Yoshimoto; Kunihiro Nishimura; Takanori Yokota; Mariko Harada-Shiba; Masafumi Ihara

doi:10.1016/j.jacasi.2023.03.011

Amplified Risk of Intracranial Artery Stenosis/Occlusion Associated With RNF213 p.R4810K in Familial Hypercholesterolemia

JACC Asia. 2023 Jun 13;3(4):625-633. doi: 10.1016/j.jacasi.2023.03.011. eCollection 2023 Aug.

Authors

Affiliations

¹ Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan.
² Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
³ Department of Endocrinology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
⁴ Department of Preventive Medicine and Epidemiology, National Cerebral and Cardiovascular Center, Suita, Japan.
⁵ Cardiovascular Center, Osaka Medical and Pharmaceutical University, Takatsuki, Japan.

Abstract

Background: The RNF213 p.R4810K variant is associated with moyamoya disease in East Asian individuals and increases the risk of developing intracranial major artery stenosis/occlusion (ICASO) that affects anterior circulation. Meanwhile, 0.5% to 2.5% of asymptomatic East Asian individuals also carry this variant. As such, additional factors are likely required to develop ICASO in variant carriers. Familial hypercholesterolemia (FH) is a common genetic disorder in Japan that has a significant associated risk of developing premature coronary atherosclerosis; however, the relationship between ICASO and FH remains unknown.

Objectives: This study aimed to determine if FH facilitates RNF213 p.R4810K carriers to develop ICASO.

Methods: We enrolled patients with FH who had undergone brain magnetic resonance angiography at our hospital from May 2005 to March 2020. The RNF213 p.R4810K variant, and LDLR and PCSK9 mutations were genotyped. ICASO lesions in the brain magnetic resonance angiogram were analyzed.

Results: Six RNF213 p.R4810K variant carriers were identified among 167 patients with FH (LDLR, n = 104; PCSK9, n = 22). Five of the carriers (83.3%) exhibited ICASO in the anterior circulation; a significant difference in ICASO frequency was observed between the variant carriers and noncarriers (P = 0.025). The median number of stenotic or occluded arteries in the anterior circulation was also significantly larger in the variant carriers (3 vs 1, P = 0.01); however, did not differ between patients with FH with LDLR and PCSK9 mutations.

Conclusions: Patients with FH exhibit increased prevalence and severity of ICASO associated with RNF213 p.R4810K. Gene mutations for FH may confer an increased risk of ICASO in RNF213 p.R4810K carriers.

Keywords: RNF213 p.R4810K; familial hypercholesterolemia; genetic interaction; genetic mutation; intracranial artery stenosis/occlusion.