Dataset Information

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

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.

SUBMITTER: Noda K

PROVIDER: S-EPMC10442882 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Publications

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

Noda Kotaro K Hattori Yorito Y Hori Mika M Nakaoku Yuriko Y Tanaka Akito A Yoshimoto Takeshi T Nishimura Kunihiro K Yokota Takanori T Harada-Shiba Mariko M Ihara Masafumi M

JACC. Asia 20230613 4

<h4>Background</h4>The <i>RNF213</i> 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 s ...[more]

PMID: 37614551

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Project description:BACKGROUND:The p.R4810K and other rare variants of ring finger protein 213 gene (RNF213) were illustrated as susceptibility variants for moyamoya (MMD) and non-moyamoya intracranial artery stenosis/occlusion disease (ICASO) recently. However, the effect sizes of p.R4810K were in great discrepancy even in studies of the same ethnic population and firm conclusions of other rare variants have been elusive given the small sample sizes and lack of replication. Thus, we performed this study to quantitatively evaluate whether or to what extent the rare variants of RNF213 contribute to MMD and ICASO in different populations. METHODS:A systematic search of PubMed, EMBASE, ISI web of science, CNKI, and WANFANG DATA was conducted up to 5 September 2017. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random- or fixed-effect models based on the between-study heterogeneity. The subgroup analyses were performed by the ethnicity and family history. Sensitivity and publication bias analysis were performed to test the robustness of associations. All the statistical analyses were conduct using STATA 12.0. RESULTS:Twenty studies including 2353 MMD cases and 5488 controls and 11 studies including 1778 ICASO cases and 3140 controls were included in this study. Pooled ORs indicated that RNF213 p.R4810K significantly increased MMD and ICASO risk in East Asians with great effect sizes of discrepancy (dominant model: odds ratios 184.04, 109.77, and 31.53 and 10.07, 28.52, and 5.59 for MMD and ICASO, respectively, in Japan, Korea, and China). It significantly increased familial MMD risk in Japan, Korea, and China with 5 ~ 36 times larger effect sizes than that for sporadic ones in each country (dominant model ORs 1802.44, 512.42, 1109.02 and 134.35, 99.82, and 30.52, respectively, for familial and sporadic cases). The effect sizes of RNF213 p.R4810K to sporadic MMD were 3 ~ 4 times larger in Japan and Korea than those in China. RNF213 p.R4810K also increased the ICASO risk in Japan and Korea with 2 ~ 4 times larger effect sizes than that in China (dominant model ORs 10.71, 28.52, and 5.59, respectively). Another two rare variants- p.E4950D and p.A5021V significantly increased MMD risk in Chinese population (dominant model ORs 9.06 and 5.01, respectively). Various other rare variants in RNF213 were identified in Japanese, Chinese, European, and Hispanic American populations without association evidence available yet. CONCLUSIONS:This meta-analysis shows the critical roles of RNF213 p.R4810K in MMD especially familial MMD and ICASO in Japan, Korea, and China. Except for RNF213 p.R4810K, MMD seems to have more complex determiners in China. Distinct genetic background exists and other environmental or genetic factor(s) may contribute to MMD. Studies focused on delineating the ethnicity-specific factors and pathological role of RNF213 variants in MMD and ICASO are needed.