Elucidation of the effect of variants in the PCSK9 gene and molecular type on lifestyle-related diseases and its regulatory mechanism

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08681
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: Hori Mika 国立研究開発法人国立循環器病研究センター, 研究所, 室長 (60598043)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 家族性高コレステロール血症 / 冠動脈疾患 / 糖尿病 / PCSK9 / LDLR / バリアント / 遺伝子解析

Outline of Final Research Achievements

The variants in the PCSK9 gene detected in Japan were annotated in familial hypercholesterolemia (FH) according to ACMG guideline. The E32K variant in the PCSK9 gene can cause FH, but the V4I variant alone does not contribute to the pathophysiology of FH. The V4I・E32K variants in the PCSK9 gene showed no difference in the levels of intracellular expression and secretion of PCSK9, intracellular and membrane expression of LDLR and LDL uptake compared to wild type of PCSK9 using cultured cells. In addition, the prevalence of diabetes mellitus was lower in patients with variants in the LDLR and PCSK9 genes than in patients without variants in the LDLR and PCSK9 genes. Patients with FH with variants in the LDLR gene and V4I/E32K variant in the PCSK9 gene had poor prognosis compared to patients with a variant in the LDLR or PCSK9 gene.

Free Research Field

脂質代謝、動脈硬化、分子生物学

Academic Significance and Societal Importance of the Research Achievements

本邦のFH 遺伝子解析ではPCSK9 遺伝子V4I・E32Kバリアントが高頻度に検出される。これらのバリアントの意義付けはFH 遺伝子解析結果の解釈に役立つ。また、PCSK9遺伝子 V4I/E32KバリアントにLDLR 遺伝子バリアントの重なるFH患者は予後不良であることから、FH 遺伝子解析により冠動脈疾患高リスク患者を早期に発見し、早期診断・早期の治療開始が重要である。