2018 Fiscal Year Final Research Report

Discovery and mechanistic analysis of a novel molecule associated with high-density lipoprotein metabolism using whole exome sequencing

Research Project

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Project/Area Number	15K09118
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Cardiovascular medicine
Research Institution	Kanazawa University
Principal Investigator	Kawashiri Masaaki 金沢大学, 医学系, 准教授 (90345637)
Co-Investigator(Kenkyū-buntansha)	野原淳金沢大学, 保健管理センター, 助教 (50313648) 多田隼人金沢大学, 附属病院, 助教 (90623653)
Project Period (FY)	2015-04-01 – 2019-03-31
Keywords	高比重リポ蛋白 / 動脈硬化 / 全エクソームシーケンス
Outline of Final Research Achievements	The causal genes of 2 cases with extreme hypo-HDL-cholesterolemia (2mg/dL, 6mg/dL) and single case with extreme hyper-HDL-cholesterolemia (170mg/dL) were analyzed by whole exome sequencing. The causes of both of hypo-HDL-cholesterolemia were compound heterozygosity of ABCA1 gene (c.6230C>A/c.6137G>A and c.2842G>A/c.1130C>T). The potential causal gene of the extreme hyper-HDL-cholesterolemia supposed to be "molecule X". The gene was introduced into HEK293 cells. The cholesterol efflux capacity of "molecule X" was not different from that of controls, which suggested the hyper-HDL-cholesterolemia of this index case was not due to increased cholesterol efflux capacity.
Free Research Field	循環器内科
Academic Significance and Societal Importance of the Research Achievements	HDLコレステロールは俗に善玉コレステロールと呼ばれ、動脈硬化抑制的と考えられている。著明な低HDLコレステロール血症と高HDLコレステロール血症の原因遺伝子を、全エクソームシーケンス法という新しい手法を用いて検討した。前者は既報のABCA1遺伝子異常であることが比較的短期間で判明し、特に潜性遺伝性疾患の遺伝子解析に有益な手法と考えられる。高HDLコレステロール血症の原因遺伝子は新規の分子であることが想定された。そのメカニズムは、コレステロール引き抜き能亢進によらない可能性が示唆された。