An integrated genomic and transcriptomic analysis to reveals susceptibility genes for Cronh's disease in Japanese populations

Research Project

Project/Area Number	18K07929
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 53010:Gastroenterology-related
Research Institution	Tohoku University
Principal Investigator	Kinouchi Yoshitaka 東北大学, 高度教養教育・学生支援機構, 教授 (20250780)
Co-Investigator(Kenkyū-buntansha)	角田洋一東北大学, 大学病院, 助教 (50509205)
Project Period (FY)	2018-04-01 – 2021-03-31
Project Status	Completed (Fiscal Year 2020)
Budget Amount *help	¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000) Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000) Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000) Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords	炎症性腸疾患 / クローン病 / 潰瘍性大腸炎 / eQTL / 疾患感受性遺伝子
Outline of Final Research Achievements	eQTL for the efector memory T cells (TEM) located in the lamina propria mononuclear cells (LPMCs), which play an important role in Crohn’s disease (CD), are not yet available. We conducted RNA sequencing and eQTL analyses of TEM cells located in the LPMCs from IBD patients (n=20). Genome-wide association study (GWAS) was performed using genotyping data of 713 Japanese CD patients and 2,063 controls. We compared the results of GWAS and eQTL of TEM, and also performed a transcriptome-wide association study using eQTL from Genotype Tissue Expression project. By eQTL analyses of TEM, correlations of possible candidates were confrmed in 22,632 pairs and 2,463 genes. Among these candidates, 19 SNPs which showed signifcant correlation with tenascin-XA (TNXA) expression were signifcantly associated with CD in GWAS. By TWAS, TNFSF15(FDR=1.35e-13) in whole blood in lymphocytes was signifcantly associated with CD.
Academic Significance and Societal Importance of the Research Achievements	炎症性腸疾患に200以上のゲノム領域に疾患感受性があることが確認されているが、相関する多型と疾患発症のメカニズムが未解明のままである。近年、eQTL 解析が数多く行われ、これを活用すれば相関を示す遺伝子多型が、どの遺伝子の発現にどの程度影響しているか予測することが可能となった。本研究ではクローン病の病態に関連があると考えられる腸管粘膜固有層単核球のCD4陽性Effector Memory T細胞を採取し、eQTL解析を行い、さらに既存のeQTLデータも活用し、日本人クローン病発症にかかわる疾患感受性遺伝子の同定を行った。その結果、炎症性腸疾患の発病メカニズムを解明する有用な知見を報告した。