Poor outcomes in carriers of the RNF213 variant (p.Arg4810Lys) with pulmonary arterial hypertension

Takahiro Hiraide, Masaharu Kataoka, Hisato Suzuki, Yuki Aimi, Tomohiro Chiba, Sarasa Isobe, Yoshinori Katsumata, Shinichi Goto, Kohsuke Kanekura, Yoshitake Yamada, Hidenori Moriyama, Hiroki Kitakata, Jin Endo, Shinsuke Yuasa, Yasumichi Arai, Nobuyoshi Hirose, Toru Satoh, Yoji Hakamata, Motoaki Sano, Shinobu GamouKenjiro Kosaki, Keiichi Fukuda

Research output: Contribution to journalArticle

Abstract

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 I2 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.

Original languageEnglish
JournalJournal of Heart and Lung Transplantation
DOIs
Publication statusAccepted/In press - 2019 Jan 1

Fingerprint

Pulmonary Hypertension
Lung Transplantation
Bone and Bones
Proteins
Exome
Moyamoya Disease
Mutation
Pulmonary Valve Stenosis
Epoprostenol
Vascular Diseases
Documentation
Fingers
Arterial Pressure
Therapeutics
Hemodynamics
Alleles
Lung
Mortality
Genes
Familial Primary Pulmonary Hypertension

Keywords

  • BMPRs
  • pulmonary arterial hypertension
  • RNF213
  • variant
  • whole-exome sequencing

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

Cite this

Poor outcomes in carriers of the RNF213 variant (p.Arg4810Lys) with pulmonary arterial hypertension. / Hiraide, Takahiro; Kataoka, Masaharu; Suzuki, Hisato; Aimi, Yuki; Chiba, Tomohiro; Isobe, Sarasa; Katsumata, Yoshinori; Goto, Shinichi; Kanekura, Kohsuke; Yamada, Yoshitake; Moriyama, Hidenori; Kitakata, Hiroki; Endo, Jin; Yuasa, Shinsuke; Arai, Yasumichi; Hirose, Nobuyoshi; Satoh, Toru; Hakamata, Yoji; Sano, Motoaki; Gamou, Shinobu; Kosaki, Kenjiro; Fukuda, Keiichi.

In: Journal of Heart and Lung Transplantation, 01.01.2019.

Research output: Contribution to journalArticle

Hiraide, T, Kataoka, M, Suzuki, H, Aimi, Y, Chiba, T, Isobe, S, Katsumata, Y, Goto, S, Kanekura, K, Yamada, Y, Moriyama, H, Kitakata, H, Endo, J, Yuasa, S, Arai, Y, Hirose, N, Satoh, T, Hakamata, Y, Sano, M, Gamou, S, Kosaki, K & Fukuda, K 2019, 'Poor outcomes in carriers of the RNF213 variant (p.Arg4810Lys) with pulmonary arterial hypertension', Journal of Heart and Lung Transplantation. https://doi.org/10.1016/j.healun.2019.08.022
Hiraide, Takahiro ; Kataoka, Masaharu ; Suzuki, Hisato ; Aimi, Yuki ; Chiba, Tomohiro ; Isobe, Sarasa ; Katsumata, Yoshinori ; Goto, Shinichi ; Kanekura, Kohsuke ; Yamada, Yoshitake ; Moriyama, Hidenori ; Kitakata, Hiroki ; Endo, Jin ; Yuasa, Shinsuke ; Arai, Yasumichi ; Hirose, Nobuyoshi ; Satoh, Toru ; Hakamata, Yoji ; Sano, Motoaki ; Gamou, Shinobu ; Kosaki, Kenjiro ; Fukuda, Keiichi. / Poor outcomes in carriers of the RNF213 variant (p.Arg4810Lys) with pulmonary arterial hypertension. In: Journal of Heart and Lung Transplantation. 2019.
@article{002b4290647147c9a16b10a965a99432,
title = "Poor outcomes in carriers of the RNF213 variant (p.Arg4810Lys) with pulmonary arterial hypertension",
abstract = "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 I2 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.",
keywords = "BMPRs, pulmonary arterial hypertension, RNF213, variant, whole-exome sequencing",
author = "Takahiro Hiraide and Masaharu Kataoka and Hisato Suzuki and Yuki Aimi and Tomohiro Chiba and Sarasa Isobe and Yoshinori Katsumata and Shinichi Goto and Kohsuke Kanekura and Yoshitake Yamada and Hidenori Moriyama and Hiroki Kitakata and Jin Endo and Shinsuke Yuasa and Yasumichi Arai and Nobuyoshi Hirose and Toru Satoh and Yoji Hakamata and Motoaki Sano and Shinobu Gamou and Kenjiro Kosaki and Keiichi Fukuda",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.healun.2019.08.022",
language = "English",
journal = "Journal of Heart and Lung Transplantation",
issn = "1053-2498",
publisher = "Elsevier USA",

}

TY - JOUR

T1 - Poor outcomes in carriers of the RNF213 variant (p.Arg4810Lys) with pulmonary arterial hypertension

AU - Hiraide, Takahiro

AU - Kataoka, Masaharu

AU - Suzuki, Hisato

AU - Aimi, Yuki

AU - Chiba, Tomohiro

AU - Isobe, Sarasa

AU - Katsumata, Yoshinori

AU - Goto, Shinichi

AU - Kanekura, Kohsuke

AU - Yamada, Yoshitake

AU - Moriyama, Hidenori

AU - Kitakata, Hiroki

AU - Endo, Jin

AU - Yuasa, Shinsuke

AU - Arai, Yasumichi

AU - Hirose, Nobuyoshi

AU - Satoh, Toru

AU - Hakamata, Yoji

AU - Sano, Motoaki

AU - Gamou, Shinobu

AU - Kosaki, Kenjiro

AU - Fukuda, Keiichi

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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 I2 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.

AB - 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 I2 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.

KW - BMPRs

KW - pulmonary arterial hypertension

KW - RNF213

KW - variant

KW - whole-exome sequencing

UR - http://www.scopus.com/inward/record.url?scp=85072253503&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072253503&partnerID=8YFLogxK

U2 - 10.1016/j.healun.2019.08.022

DO - 10.1016/j.healun.2019.08.022

M3 - Article

AN - SCOPUS:85072253503

JO - Journal of Heart and Lung Transplantation

JF - Journal of Heart and Lung Transplantation

SN - 1053-2498

ER -