The ring finger protein 213 gene (RNF213) encodes a 590 kDa protein that is thought to be involved in angiogenesis. This gene was first recognized as a vasculopathy-susceptibility locus through genome-wide association studies undertaken in a Japanese population, demonstrating that heterozygotes for RNF213 p.Arg4810Lys (c.14429G>A, rs112735431) had a greatly increased risk of moyamoya disease. The association of RNF213 p.Arg4810Lys as a susceptibility variant of moyamoya disease was reproduced in Korean and Chinese individuals and, later, in Caucasians. Variants of the RNF213 gene have been linked to a number of vascular diseases such as moyamoya disease, intracranial major artery stenosis, pulmonary arterial hypertension, and peripheral pulmonary artery stenosis, and have also been associated with co-occurrent diseases and vascular disease in different organs. Based on the findings that we have reported to date, our paper proposes a new concept of “RNF213-associated vascular disease” to unify these conditions with the aim of capturing patients with multiple diseases but with a common genetic background. This concept will be highly desirable for clarifying all of the diseases in the RNF213-associated vascular disease category by means of global epidemiological investigations because of the possibility of such diseases appearing asymptomatically in some patients.
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