Genetics in pulmonary arterial hypertension in a large homogeneous Japanese population

Gamou, Shinobu; Kataoka, Masaharu; Aimi, Yuki; Chiba, Tomohiro; Momose, Yuichi; Isobe, Satoshi; Hirayama, Tomomi; Yoshino, Hideaki; Fukuda, Keiichi; Satoh, Tohru

doi:10.1111/cge.13154

Cited by 15 publications

(9 citation statements)

References 58 publications

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“…Then, the full text of each of the remaining 42 articles was retrieved for further review to determine whether they met the predetermined criteria. Finally, 17 papers were identified and included in the present study [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24].…”

Section: Resultsmentioning

confidence: 99%

Gender differences in pulmonary arterial hypertension patients with BMPR2 mutation: a meta-analysis

Zhu

Zhang

et al. 2020

Respir Res

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Objective: To investigate the differences in the proportions of BMPR2 mutations in familial hereditary pulmonary arterial hypertension (HPAH) and idiopathic pulmonary arterial hypertension (IPAH) between males and females and the relationship between BMPR2 mutation and PAH severity. Methods: A computer was used to search the electronic Cochrane Library, PubMed/MEDLINE, and EMBASE databases for clinical trials containing information on the relationship between PAH prognosis and BMPR2 mutations through March 2019. After obtaining the data, a meta-analysis was performed using Review Manager Version 5.3 and Stata. Results: A meta-analysis was performed on 17 clinical trials (2198 total patients: 644 male, 1554 female). The results showed that among patients with HPAH and IPAH, the BMPR2 mutation rate is higher in male than in female patients [male group (224/644, 34.78%), female group (457/1554, 29.41%), OR = 1.30, 95% CI: 1.06~1.60, P = 0.01, I 2 = 10%]. Furthermore, haemodynamic and functional parameters were more severe in IPAH and HPAH patients with BMPR2 mutations than in those without, and those with BMPR2 mutation were diagnosed at a younger age. The risk of death or transplantation was higher in PAH patients with BMPR2 mutations than in those without (OR = 2.51, 95% CI: 1.29~3.57, P = 0.003, I 2 = 24%). Furthermore, the difference was significant only in male patients (OR = 5.58, 95% CI: 2.16~14.39, P = 0.0004, I 2 = 0%) and not in female patients (OR = 1.41, 95% CI: 0.75~2.67, P = 0.29, I 2 = 0%). Conclusion: Among patients with HPAH and IPAH, men are more likely to have BMPR2 mutations, which may predict more severe PAH indications and prognosis.

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Section: Resultsmentioning

confidence: 99%

Gender differences in pulmonary arterial hypertension patients with BMPR2 mutation: a meta-analysis

Zhu

Zhang

et al. 2020

Respir Res

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“…9 Whole-exome sequencing and direct sequencing by polymerase chain reaction were performed to identify BMPR2 mutations and the RNF213 p.Arg4810Lys variant. Details are described in our previous report 10 and in the Supplement Materials available online at www.jhltonline.org.…”

Section: Whole-exome Sequencing and Direct Sequencingmentioning

confidence: 99%

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

Hiraide

Kataoka

Suzuki

et al. 2020

The Journal of Heart and Lung Transplantation

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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).

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“…Among the 8 patients with BMPR2 gene variants, 3 had frameshifts, 2 had non-sense, 2 had missense variants and 1 had BMPR2 exon 8-9 deletions ( Table 1 and Supplementary Figure 1 ). Among the 8 BPMPR2 variants, 4 variant genetic types were previously reported in the literature ( 4 , 5 , 41 – 45 ). We identified three novel BMPR2 gene variants (c.1512 deletion, c.479 duplicate, c.1165 G>A) in the current study and one patient with exon 8-9 deletions ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

Whole Exome Sequencing of Patients With Heritable and Idiopathic Pulmonary Arterial Hypertension in Central Taiwan

Liang

Chang

Chen

et al. 2022

Front. Cardiovasc. Med.

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BackgroundGenetic variants could be identified in subjects with idiopathic and heritable pulmonary arterial hypertension (PAH). The 6th World Symposium on Pulmonary Hypertension (WSPH) provided a list of genes with evidence of association with PAH. However, reports using whole exome sequencing (WES) from southeastern Asian PAH cohorts were scarce.MethodsSubjects with idiopathic and heritable PAH (N = 45) from two medical centers in central Taiwan were screened for PAH related gene variants. The genomic DNA was prepared from peripheral blood lymphocytes. We performed WES for all patients enrolled in this study. All identified gene variants were validated by polymerase-chain reaction and Sanger sequencing. The clinical and hemodynamic data were compared between bone morphogenetic protein receptor type-2 (BMPR2) gene variants carriers vs. non-carriers.ResultsEight patients (8/45 = 17.8%) was identified carrying BMPR2 gene variants and 8 patients (8/45 = 17.8%) had other WSPH-listed PAH-related gene variants (1 with ACVRL1, 1 with ENG, 1 with SMAD9, 1 with SMAD1, 1 with ATP13A3 and 3 with AQP1). In addition, a total of 14 non-WSPH-listed PAH-related genetic variant sites (ABCC8, NOTCH1, NOTCH2, NOTCH3, JAG1, BMP10, GGCX, FBLN2, ABCA3 and PTGIS) were found in this PAH cohort. Subjects carrying BMPR2 gene variant (N = 8) were younger at diagnosis of PAH (30 ± 11 vs 49 ± 13 years, p = 0.001) than the non-carrier group (N = 37). BMPR2 variant carriers had a trend toward having higher mean pulmonary arterial pressure (PAP) (61 ± 19 vs. 51 ± 13 mmHg, p = 0.076) than the non-carriers upon initial diagnosis. Pulmonary vascular resistance, right atrial pressure, cardiac output, as well as functional class were similar between BMPR2 variant carriers and non-carriers at initial diagnosis.ConclusionsWe identified 17.8% of patients with BMPR2 gene variants and 17.8% subjects with other 6th WSPH-listed PAH-related gene variants in a Taiwanese idiopathic and heritable PAH cohort. PAH patients carrying BMPR2 variants presented at a younger age with a trend toward having higher mean PAP at initial diagnosis.

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Genetics in pulmonary arterial hypertension in a large homogeneous Japanese population

Cited by 15 publications

References 58 publications

Gender differences in pulmonary arterial hypertension patients with BMPR2 mutation: a meta-analysis

Gender differences in pulmonary arterial hypertension patients with BMPR2 mutation: a meta-analysis

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

Whole Exome Sequencing of Patients With Heritable and Idiopathic Pulmonary Arterial Hypertension in Central Taiwan

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