A Genome-wide Association Study Identifying RAP1A as a Novel Susceptibility Gene for Crohn's Disease in Japanese Individuals. (29th November 2018)

• Record Type: Journal Article
• Authors: Kakuta, Yoichi; Kawai, Yosuke; Naito, Takeo; Hirano, Atsushi; Umeno, Junji; Fuyuno, Yuta; Liu, Zhenqiu; Li, Dalin; Nakano, Takeru; Izumiyama, Yasuhiro; Ichikawa, Ryo; Okamoto, Daisuke; Nagai, Hiroshi; Matsumoto, Shin; Yamamoto, Katsutoshi; Yokoyama, Naonobu; Chiba, Hirofumi; Shimoyama, Yusuke; Onodera, Motoyuki; Moroi, Rintaro; Kuroha, Masatake; Kanazawa, Yoshitake; Kimura, Tomoya; Shiga, Hisashi; Endo, Katsuya; Negoro, Kenichi; Yasuda, Jun; Esaki, Motohiro; Tokunaga, Katsushi; Nakamura, Minoru; Matsumoto, Takayuki; McGovern, Dermot P B; Nagasaki, Masao; Kinouchi, Yoshitaka; Shimosegawa, Tooru; Masamune, Atsushi;
• Is Part Of: Journal of Crohn's and colitis. Volume 13:Number 5(2019)
• Page Start: 648
• Page End: 658
• Publication Date: 2018-11-29
• Subjects: RAP1A -- Crohn's disease -- susceptibility gene; Inflammatory bowel diseases -- Periodicals; 616.344005
• DOI: 10.1093/ecco-jcc/jjy197
• Languages: English
• ISSNs: 1873-9946

Abstract

Abstract: Background and Aims: Genome-wide association studies [GWASs] of European populations have identified numerous susceptibility loci for Crohn's disease [CD]. Susceptibility genes differ by ethnicity, however, so GWASs specific for Asian populations are required. This study aimed to clarify the Japanese-specific genetic background for CD by a GWAS using the Japonica array [JPA] and subsequent imputation with the 1KJPN reference panel. Methods: Two independent Japanese case/control sets (Tohoku region [379 CD patients, 1621 controls] and Kyushu region [334 CD patients, 462 controls]) were included. GWASs were performed separately for each population, followed by a meta-analysis. Two additional replication sets [254 + 516 CD patients and 287 + 565 controls] were analysed for top hit single nucleotide polymorphisms [SNPs] from novel genomic regions. Results: Genotype data of 4 335 144 SNPs from 713 Japanese CD patients and 2083 controls were analysed. SNPs located in TNFSF15 (rs78898421, Pmeta = 2.59 × 10 −26, odds ratio [OR] = 2.10), HLA-DQB1 [rs184950714, p meta = 3.56 × 10 −19, OR = 2.05], ZNF365, and 4p14 loci were significantly associated with CD in Japanese individuals. Replication analyses were performed for four novel candidate loci [ p <1 × 10 −6 ], and rs488200 located upstream of RAP1A was significantly associated with CD [ p combined = 4.36 × 10 −8, OR = 1.31]. Transcriptome analysis of CD4+ effector memory T cells from lamina propria mononuclear cells of CD patients revealed a significant association of rs488200 with RAP1A expression. Conclusions: RAP1A is a novel susceptibility locus for CD in the Japanese population.