제1저자 문창모(내과학교실) 김승원(내과학교실, BK21 졸업)
Inflamm Bowel Dis. 2018 May 4. doi: 10.1093/ibd/izy122. [Epub ahead of print]
Deep Resequencing of Ulcerative Colitis-Associated Genes Identifies Novel Variants in Candidate Genes in the Korean Population.
Moon CM1, Kim SW1,2,3, Ahn JB4, Ma HW1, Che X1,3, Kim TI1, Kim WH1, Cheon JH1,2,3.
1Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea.2Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.3Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.4Department of Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
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.
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.
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.
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.