Poor outcomes in carriers of the RNF213 variant (p.Arg4810Lys) with pulmonary arterial hypertension
Poor outcomes in carriers of the RNF213 variant (p.Arg4810Lys) with pulmonary arterial hypertension
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DOI：
10.1016/j.healun.2019.08.022
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发表时间：
2020-02-01
影响因子：
8.9
通讯作者：
Fukuda, Keiichi
中科院分区：
文献类型：
--
作者：
Hiraide, Takahiro;Kataoka, Masaharu;Fukuda, Keiichi
背景技术背景：环指蛋白213基因（RNF 213; NM_001256071.2）中的c.14429G>A（p.Arg4810Lys，rs 112735431）变异体最近被鉴定为肺动脉高压（PAH）的危险等位基因。PAH可以作为RNF 213相关血管疾病的新成员，包括烟雾病和周围性肺动脉狭窄。我们的目的是确定PAH患者的临床特征和结果与此variant.METHODS：全外显子组测序进行了139特发性（或可能遗传性）PAH patients.RESULTS：RNF 213 p.Arg4810Lys变异被确定为杂合状态的11例（7.9%）。与携带骨形态发生蛋白受体2型（BMPR 2）突变的患者（n = 36）相比，携带RNF 213 p.Arg4810Lys变异的患者在联合治疗后血流动力学的时程变化明显较差（平均肺动脉压变化的比较，p = 0.007）。RNF 213 p.Arg4810Lys变异携带者的死亡或肺移植无事件率显著低于BMPR 2突变携带者（自引入前列腺素I-2输注以来的5年无事件率分别为0%和93%; p < 0.001）。携带RNF 213 p.Arg4810Lys变异的特发性PAH患者即使在最近也与不良临床结局相关。对于正在发生PAH的RNF 213 p.Arg4810Lys变异携带者，可能需要早期考虑肺移植。RNF 213 p.Arg4810Lys变异体以及已知的致病基因（如BMPR 2）的记录可以为治疗策略提供临床相关信息，从而为PAH的治疗提供个性化方法。(C)2019年国际心肺移植学会。All rights reserved.
BACKGROUND: A variant of c.14429G>A (p.Arg4810Lys, rs112735431) in the ring finger protein 213 gene (RNF213; NM_001256071.2) has been recently identified as a risk allele for pulmonary arterial hypertension (PAH). PAH can be added as a new member of RNF213-associated vascular diseases, which include Moyamoya disease and peripheral pulmonary stenosis. Our aim was to identify the clinical features and outcomes of PAH patients with this variant.METHODS: Whole-exome sequencing was performed in 139 idiopathic (or possibly heritable) PAH patients.RESULTS: The RNF213 p.Arg4810Lys variant was identified in a heterozygous state in 11 patients (7.9%). Time-course changes in hemodynamics after combination therapy in the patients with the RNF213 p.Arg4810Lys variant were significantly poorer compared with those carrying the bone morphogenic protein receptor type 2 (BMPR2) mutation (n = 36) (comparison of changes in mean pulmonary arterial pressure, p = 0.007). The event-free rate of death or lung transplantation was significantly poorer in RNF213 p.Arg4810Lys variant carriers than in BMPR2 mutation carriers (5-year event-free rate since the introduction of prostaglandin I-2 infusion, 0% vs 93%, respectively; p < 0.001).CONCLUSIONS: Idiopathic PAH patients with the RNF213 p.Arg4810Lys variant are associated with poor clinical outcomes even in recent times. Earlier consideration of lung transplantation might be required for RNF213 p.Arg4810Lys variant carriers who are developing PAH. Documentation of the RNF213 p.Arg4810Lys variant, as well as already known pathogenic genes, such as BMPR2, can provide clinically relevant information for therapeutic strategies, leading to a personalized approach for the treatment of PAH. (C) 2019 International Society for Heart and Lung Transplantation. All rights reserved.