Background Genome-wide association studies and meta-analyses have revealed the genetic background of ulcerative colitis (UC) by identifying common variants. However, these variants do not fully explain the disease variance in UC. To identify novel variants, we performed deep resequencing of UC-associated genes in Korean UC patients and subsequently investigated the functional roles of identified susceptibility genes. Methods We performed targeted deep resequencing of 108 genes in 24 Korean UC patients and then performed association analysis with data from 126 healthy controls. We validated these variants using 2-stage replication studies including 793 UC patients and 783 controls. We performed in silico and pathway analyses and functional analyses. Results The combined analysis including 2 replication studies identified 6 novel susceptibility loci and reconfirmed 10 previously reported loci. Among the novel single nucleotide variants (SNVs), rs10035653 in C5orf55 (P = 2.08 × 10 -3 ; OR = 1.50), rs41417449 in BTNL2 (P = 1.27 × 10 -2 ; OR = 1.32), rs3117099 in HCG23 (P = 9.98 × 10 -6 ; OR = 1.40), rs7192 in HLA-DRA (P = 6.95 × 10 -9 ; OR = 1.57), and rs3744246 in ORMDL3 (P = 2.21 × 10 -2 ; OR = 1.21) were identified as causal variants, whereas rs713669 in IL17REL (P = 2.69 × 10 -2 ; OR = 0.84) as a protective variant for UC. When correcting multiple testing, 3 novel SNVs (rs41417449 in BTNL2, rs3744246 in ORMDL3, and rs713669 in IL17REL) and 4 previously reported SNVs did not reach a statistical significance. Functional study suggested that SNVs of BTNL2 and C5orf55 exacerbated the inflammatory response both in vitro and in vivo. Conclusions This study identified 3 novel susceptibility loci and validated 6 previously reported SNVs for UC through deep resequencing in Koreans and revealed the functional roles of BTNL2 and C5orf55.
Bibliographical noteFunding Information:
Received for publications July 17, 2017; Editorial Decision February 27, 2018. *Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea; †Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea; ‡Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea; §Department of Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea. Conflict of Interest: The authors disclose no conflicts of interest. 1These authors contributed equally to this work as the first authors. Supported by: This work was supported by grants from the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning [grant numbers NRF-2011-0025131, NRF-2014R1A1A1008096, NRF-2017R1A1A1A05001011] and by the Brain Korea 21 Project for Medical Science, Yonsei University. Author Contributions: Chang Mo Moon and Seung Won Kim: study concept and design, acquisition of data, analysis and interpretation of data, and drafting of the manuscript; Jae Hee Cheon: study concept and design, analysis and interpretation of data, drafting, and critical revision of the manuscript; Jae Bum Ahn, Hyun Woo Ma, and Xiumei Che: acquisition of data and analysis and interpretation of data: Tae Il Kimand Won Ho Kim: acquisition of data and critical revision of the manuscript. Address correspondence to: Jae Hee Cheon, MD, PhD, Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, 50–1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea. E-mail: GENIUSHEE@yuhs.ac. © 2018 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: firstname.lastname@example.org.
All Science Journal Classification (ASJC) codes
- Immunology and Allergy