Novel identification and functional analysis of the causative genes in pulmonary arterial hypertension

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K15782
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Laboratory medicine
• Research Institution: Kyorin University
• Principal Investigator: Momose Yuichi 杏林大学, 医学部, 助教 (60795798)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 肺動脈性肺高血圧症 / 全エクソーム解析 / 発症原因遺伝子 / 発症感受性遺伝子

Outline of Final Research Achievements

We performed all exome sequencing including 140 Japanese PAH patients and their healthy families, and found that 4 patients and 1 unaffected family had SOX17 mutations as a novel causative gene mutation of pulmonary arterial hypertension (PAH). These patients were poorly responsive to multidrug therapy of pulmonary vasodilators, and autopsy revealed severe PAH with Heath-Edwards 5 degrees. In addition, the relationship with congenital heart disease and SOX17 mutation was also suggested. In addition, the RNF213 gene mutation, R4910K, was found in a high frequency in about 10% of patients with idiopathic PAH, confirming that these patients are consistent with a refractory and poor prognosis population. These results are evaluated as outcomes leading to personalized medicine specialized in Japanese PAH patients.

Free Research Field

循環器病学

Academic Significance and Societal Importance of the Research Achievements

難病循環器疾患PAHにおいて、ゲノム情報と臨床情報とを丁寧に解析することによって、治療反応性や予後と相関する重要な知見を得ることが出来た。欧米を中心として、患者サンプルを収集したドライビッグデータは既に存在しており、数々のエビデンスも報告されている。しかしながら、海外からのエビデンスをそのまま日本人患者へ応用することはリスクを伴う。異質性(heterogeneity)が高い海外の解析結果に比べ、統一プロトコールで収集した均質性の高い(homogeneous)日本人患者の臨床検体から得られた本研究での知見は、日本人患者の病態に最適化した個別精密化医療の実現にとって非常に重要な基盤になると考える。