Abstract TMP78: Relationship Of RNF213 p.R4810k Variant And Familial Hypercholesterolemia To Intracranial Major Arterial Stenosis/occlusion

Abstract

Introduction: The ring finger protein 213 gene ( RNF213 ) p.R4810K variant is a susceptibility gene for Moyamoya disease in East Asians. Besides, the variant is also strong genetic risk factor for ischemic stroke due to intracranial major arterial stenosis/occlusion (ICASO) responsible for anterior circulation, and 2–3% of East Asians also harbor the variant as asymptomatic carriers. Therefore, it is suggested that several additional factors should be required to develop ICASO in the patients with the variant. Familial hypercholesterolemia (FH) is the most common genetic disorder in Japan, caused by LDLR , PCSK9 , and/or APOB gene mutations. FH is a great risk factor for coronary atherosclerosis, but the relationship between FH and ICASO is still unknown. We aimed to investigate whether RNF213 p.R4810K affects the prevalence of ICASO in FH patients. Methods: We enrolled the patients who were diagnosed as FH and underwent brain MRI at our hospital from May 2005 to June 2021. We examined RNF213 p. R4810K variant, and LDLR and PCSK9 gene mutations, and analyzed the existence of ICASO in the brain MRA. Results: A hundred and sixty-seven patients with FH ( LDLR , n=104; PCSK9 , n=22) underwent MRI. The average age at MRI testing was 61, and 46.1% were male. Six patients harbored RNF213 p. R4810K (3.59%) without past history of stroke. ICASO in anterior circulation was observed in 5 with the variant (85%), and there was a significant difference in the existence of ICASO between the patients with the variant and those without it (OR 9.12, 95% CI 1.38-18.7, p=0.027). The number of arteries with stenotic lesions in anterior circulation was significantly larger in the patients with the variant than those without the variant (3.33 vs. 0.68:p=0.01). LDLR and/or PCSK9 gene mutations similarly induced ICASO in the FH patients. Discussion: Our study revealed that RNF213 p. R4810K was associated with ICASO in the patients with FH. The incidence of ICASO in normal volunteers has been reported to be around 10%, suggesting that FH may raise the occurrence of ICASO associated with RNF213 p.R4810K. The combination of gene mutations responsible for FH and RNF213 p. R4810K variant would confer the greater risk of ICASO in anterior circulation.