Genomic Comparison With Supercentenarians Identifies RNF213 as a Risk Gene for Pulmonary Arterial Hypertension
2018; Wolters Kluwer; Volume: 11; Issue: 12 Linguagem: Inglês
10.1161/circgen.118.002317
ISSN2574-8300
AutoresHisato Suzuki, Masaharu Kataoka, Takahiro Hiraide, Yuki Aimi, Yoshitake Yamada, Yoshinori Katsumata, Tomohiro Chiba, Kohsuke Kanekura, Sarasa Isobe, Yasunori Sato, Toru Satoh, Shinobu Gamou, Keiichi Fukuda, Kenjiro Kosaki,
Tópico(s)Vascular Anomalies and Treatments
ResumoHomeCirculation: Genomic and Precision MedicineVol. 11, No. 12Genomic Comparison With Supercentenarians Identifies RNF213 as a Risk Gene for Pulmonary Arterial Hypertension Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBGenomic Comparison With Supercentenarians Identifies RNF213 as a Risk Gene for Pulmonary Arterial Hypertension Hisato Suzuki, MD, Masaharu Kataoka, MD, Takahiro Hiraide, MD, Yuki Aimi, MHS, Yoshitake Yamada, MD, Yoshinori Katsumata, MD, Tomohiro Chiba, MD, Kohsuke Kanekura, MD, Sarasa Isobe, MD, Yasunori Sato, PhD, Toru Satoh, MD, Shinobu Gamou, PhD, Keiichi Fukuda, MD and Kenjiro Kosaki, MD Hisato SuzukiHisato Suzuki Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan (H.S., K. Kosaki) , Masaharu KataokaMasaharu Kataoka Masaharu Kataoka, MD, Department of Cardiology, Keio University School of Medicine, Shinanomachi 35, Shinjuku-ku, Tokyo, 160–8582 Japan. Email E-mail Address: [email protected] Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (M.K., T.H., Y.K., S.I., S.G., K.F.) , Takahiro HiraideTakahiro Hiraide Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (M.K., T.H., Y.K., S.I., S.G., K.F.) , Yuki AimiYuki Aimi Division of Cardiology, Second Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan (Y.A., T.S.) , Yoshitake YamadaYoshitake Yamada Department of Diagnostic Radiology, Keio University School of Medicine, Tokyo, Japan (Y.Y.) , Yoshinori KatsumataYoshinori Katsumata Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (M.K., T.H., Y.K., S.I., S.G., K.F.) , Tomohiro ChibaTomohiro Chiba Department of Pathology, Kyorin University School of Medicine, Tokyo, Japan (T.C.) , Kohsuke KanekuraKohsuke Kanekura Department of Molecular Pathology, Tokyo Medical University, Japan (K. Kanekura). , Sarasa IsobeSarasa Isobe Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (M.K., T.H., Y.K., S.I., S.G., K.F.) , Yasunori SatoYasunori Sato Department of Preventive Medicine and Public Health, Biostatistics Unit at Clinical and Translational Research Center, Keio University School of Medicine, Tokyo, Japan (Y.S.) , Toru SatohToru Satoh Division of Cardiology, Second Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan (Y.A., T.S.) , Shinobu GamouShinobu Gamou Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (M.K., T.H., Y.K., S.I., S.G., K.F.) , Keiichi FukudaKeiichi Fukuda Department of Cardiology, Keio University School of Medicine, Tokyo, Japan (M.K., T.H., Y.K., S.I., S.G., K.F.) and Kenjiro KosakiKenjiro Kosaki Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan (H.S., K. Kosaki) Originally published11 Dec 2018https://doi.org/10.1161/CIRCGEN.118.002317Circulation: Genomic and Precision Medicine. 2018;11:e002317Pulmonary arterial hypertension (PAH) is characterized by a strong genetic component. About 30% of patients with idiopathic or heritable PAH are considered to have monogenic disorders: most of these patients have heterozygous BMPR2 mutations.1 The causative genes, if any, in the remaining 70% of patients have yet to be clarified. In some rare diseases, relatively common pathogenic variants, together with monogenic mutations, can play significant roles. We hypothesized that such potentially disease-causing variants, if associated with PAH, would be absent among an extremely long-lived healthy cohort because the lifespans of patients with PAH are limited. Accordingly, we looked for candidate variants that were enriched among patients with PAH but absent among supercentenarians who had lived for >110 years.The data, analytical methods, and study materials will not be made available to other researchers for the purposes of reproducing the results or replicating the procedure. We performed a standard whole-exome analysis in 2 cohorts: (1) 76 Japanese patients with idiopathic PAH who had tested negative for BMPR2 and other known pathogenic gene mutations, and (2) 79 Japanese supercentenarians, none of whom had past histories of any significant health problems. The study was approved by an institutional review committee, and the subjects gave informed consent. Patients with idiopathic PAH (19 males, 57 females) were diagnosed according to the Japanese Circulation Society guideline, and their age and mean pulmonary arterial pressure at diagnosis were 35.8±16.7 (mean±SD) years old and 49.6±15.5 mm Hg, respectively. Sequencing was performed using a HiSeq 2500 platform (Illumina, San Diego, CA) and SureSelectXT Human All Exon Kit (Agilent Technologies, Santa Clara, CA) for hybridization capture. The software Filtus, which implements a statistical modeling framework, allowed the detection of genes with distinctive variant distributions between the 2 cohorts using exome datasets under the assumption that mutations occur within a gene in a random manner with a probability proportional to the relative gene length.2We identified 2 genes with rare variants (ie, minor allele frequency A [p.Arg4810Lys, rs112735431]) was identified in a heterozygous state in 7 (9.2%) of the 76 PAH patients and represents a well-known risk factor for Moyamoya disease, a vascular disorder of the brain.3 The allele frequency for this variant is 0.7681% in the 3515 normal Japanese population according to Integrative Japanese Genome Variation Database (The genome cohort study of Tohoku Medical Megabank Organization), indicating a variant frequency ratio for idiopathic PAH relative to that in the normal population of 6.0. None of the 7 PAH patients with the RNF213 p.Arg4810Lys variant had any cerebral brain defects suggestive of Moyamoya disease as determined using cranial computed tomography angiography. Intriguingly, one of the 7 PAH patients with the heterozygous RNF213 p.Arg4810Lys variant in the present study had a daughter with the same variant in a heterozygous state who had been diagnosed as having Moyamoya disease but did not have PAH (Figure). TMEM8A has no previously known association with vascular defects, although the possibility that it could be a novel finding of relevance to PAH cannot be ruled out.Download figureDownload PowerPointFigure. A family with the RNF213 p.Arg4810Lys variant in which the mother exhibited pulmonary arterial hypertension (PAH) and the daughter exhibited Moyamoya disease.A, A pedigree of this rare family with the RNF213 p.Arg4810Lys variant. The asterisks indicate people from whom DNA samples were obtained from peripheral blood samples for whole-exome sequencing analysis. B, Echocardiography of the mother demonstrated severe PAH and right heart overload. C, Cerebral angiography of the daughter demonstrated Moyamoya disease.Through a genomic comparison of a PAH cohort and supercentenarians, we identified the ATPase family protein RNF213 p.Arg4810Lys variant as a strong risk allele for PAH in Japanese individuals. These 2 genetic findings warrant replication in independent cohorts. This p.Arg4810Lys allele is well known to have a causal relationship with, Moyamoya disease, a cerebral vascular disease, and an in vitro analysis of this substitution has been shown to have a relatively low angiogenic activity.3 Recent human studies, including our own, indicate that the RNF213 p.Arg4810Lys variant also confers a risk for extracranial vascular diseases including peripheral pulmonary stenosis.4 The current study adds PAH as a new member of RNF213-associated diseases. Our results agree with those of an animal experimental study showing that mice with the RNF213 p.Arg4810Lys variant developed pulmonary hypertension after exposure to hypoxic stimuli.5 The factor that influences the anatomic location of the vascular defects, that is, the brain or the lung, remains to be elucidated.AcknowledgmentsWe thank Ms. Tomomi Hirayama and Ms. Yasuko Ogawa for their technical assistance and Ms. Hiromi Momota for data analysis in this study.DisclosuresNone.FootnotesMasaharu Kataoka, MD, Department of Cardiology, Keio University School of Medicine, Shinanomachi 35, Shinjuku-ku, Tokyo, 160–8582 Japan. Email m.[email protected]jpReferences1. Gamou S, et al. Genetics in pulmonary arterial hypertension in a large homogeneous Japanese population.Clin Genet. 2018; 94:70–80. doi: 10.1111/cge.13154CrossrefMedlineGoogle Scholar2. Zhi D, et al. Statistical guidance for experimental design and data analysis of mutation detection in rare monogenic M endelian diseases by exome sequencing.PLoS One. 2012; 7:e31358. doi: 10.1371/journal.pone.0031358CrossrefMedlineGoogle Scholar3. Koizumi A, et al. A new horizon of moyamoya disease and associated health risks explored through RNF213.Environ Health Prev Med. 2016; 21:55–70. doi: 10.1007/s12199-015-0498-7CrossrefMedlineGoogle Scholar4. Fukushima H, et al. Homozygosity for moyamoya disease risk allele leads to moyamoya disease with extracranial systemic and pulmonary vasculopathy.Am J Med Genet A. 2016; 170:2453–2456. doi: 10.1002/ajmg.a.37829CrossrefMedlineGoogle Scholar5. Kobayashi H, et al. Rare variants in RNF213, a susceptibility gene for moyamoya disease, are found in patients with pulmonary hypertension and aggravate hypoxia-induced pulmonary hypertension in mice.Pulm Circ. 2018; 8:2045894018778155. doi: 10.1177/2045894018778155CrossrefGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Goto K, Minatsuki S, Fujita K, Takeda N, Hatano M and Komuro I (2022) Two Siblings With Peripheral Pulmonary Arterial Stenosis, Chest, 10.1016/j.chest.2021.08.058, 161:2, (e75-e80), Online publication date: 1-Feb-2022. Miyawaki S and Saito N (2021) RNF213 Variant as a Biomarker of Cerebrovascular Disease Moyamoya Disease: Current Knowledge and Future Perspectives, 10.1007/978-981-33-6404-2_6, (73-83), . Momoi M, Hiraide T, Shinya Y, Momota H, Fukui S, Kawakami M, Itabashi Y, Fukuda K and Kataoka M (2021) Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension, Therapeutic Advances in Respiratory Disease, 10.1177/1753466621995048, 15, (175346662199504), Online publication date: 1-Jan-2021. Nagai A (2021) Updates in Basic Research on Molecular Genetic Background of Pulmonary Hypertension肺高血圧症における基礎研究の最近の話題:分子遺伝学的背景を中心に, Pediatric Cardiology and Cardiac Surgery, 10.9794/jspccs.37.2, 37:1, (2-9), Online publication date: 1-Apr-2021. 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 and Fukuda K (2020) Poor outcomes in carriers of the RNF213 variant (p.Arg4810Lys) with pulmonary arterial hypertension, The Journal of Heart and Lung Transplantation, 10.1016/j.healun.2019.08.022, 39:2, (103-112), Online publication date: 1-Feb-2020. Miyawaki S and Saito N (2020) Genetic Factor for Intracranial Artery Stenosis頭蓋内血管狭窄病変の遺伝的要因, Japanese Journal of Neurosurgery, 10.7887/jcns.29.680, 29:10, (680-689), . Hongo H, Miyawaki S, Imai H, Shimizu M, Yagi S, Mitsui J, Ishiura H, Yoshimura J, Doi K, Qu W, Teranishi Y, Okano A, Ono H, Nakatomi H, Shimizu T, Morishita S, Tsuji S and Saito N (2020) Comprehensive investigation of RNF213 nonsynonymous variants associated with intracranial artery stenosis, Scientific Reports, 10.1038/s41598-020-68888-1, 10:1, Online publication date: 1-Dec-2020. Hiraide T, Suzuki H, Momoi M, Shinya Y, Fukuda K, Kosaki K and Kataoka M (2022) RNF213-Associated Vascular Disease: A Concept Unifying Various Vasculopathies, Life, 10.3390/life12040555, 12:4, (555) Luo Y, Cao Z, Wu S and Sun X (2022) Ring Finger Protein 213 in Moyamoya Disease With Pulmonary Arterial Hypertension: A Mini-Review, Frontiers in Neurology, 10.3389/fneur.2022.843927, 13 Dofuku S, Sonehara K, Miyawaki S, Sakaue S, Imai H, Shimizu M, Hongo H, Shinya Y, Ohara K, Teranishi Y, Okano A, Ono H, Nakatomi H, Teraoka A, Yamamoto K, Maeda Y, Nii T, Kishikawa T, Suzuki K, Hirata J, Takahashi M, Matsuda K, Kumanogoh A, Matsuda F, Okada Y and Saito N (2022) Genome-Wide Association Study of Intracranial Artery Stenosis Followed by Phenome-Wide Association Study, Translational Stroke Research, 10.1007/s12975-022-01049-w December 2018Vol 11, Issue 12 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.118.002317PMID: 30562119 Originally publishedDecember 11, 2018 KeywordsHypertensionBone Morphogenetic Protein ReceptorsType II Genetic Association StudiesPulmonary Artery Whole Exome SequencingPulmonary Moyamoya Disease RING Finger Domains StenosisPDF download Advertisement SubjectsGeneticsPulmonary HypertensionVascular Disease
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