Deep Resequencing of Ulcerative Colitis-Associated Genes Identifies Novel Variants in Candidate Genes in the Korean Population

Chang Mo Moon, Seung Won Kim, Jae Bum Ahn, Hyun Woo Ma, Xiumei Che, Tae Il Kim, Won Ho Kim, JaeHee Cheon

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)1706-1717
Number of pages12
JournalInflammatory Bowel Diseases
Volume24
Issue number9
DOIs
Publication statusPublished - 2018 Aug 16

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Ulcerative Colitis
Nucleotides
Population
Genes
HLA-DR alpha-Chains
Genome-Wide Association Study
Computer Simulation
Meta-Analysis

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Gastroenterology

Cite this

Moon, Chang Mo ; Kim, Seung Won ; Ahn, Jae Bum ; Ma, Hyun Woo ; Che, Xiumei ; Kim, Tae Il ; Kim, Won Ho ; Cheon, JaeHee. / Deep Resequencing of Ulcerative Colitis-Associated Genes Identifies Novel Variants in Candidate Genes in the Korean Population. In: Inflammatory Bowel Diseases. 2018 ; Vol. 24, No. 9. pp. 1706-1717.
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title = "Deep Resequencing of Ulcerative Colitis-Associated Genes Identifies Novel Variants in Candidate Genes in the Korean Population",
abstract = "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.",
author = "Moon, {Chang Mo} and Kim, {Seung Won} and Ahn, {Jae Bum} and Ma, {Hyun Woo} and Xiumei Che and Kim, {Tae Il} and Kim, {Won Ho} and JaeHee Cheon",
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Deep Resequencing of Ulcerative Colitis-Associated Genes Identifies Novel Variants in Candidate Genes in the Korean Population. / Moon, Chang Mo; Kim, Seung Won; Ahn, Jae Bum; Ma, Hyun Woo; Che, Xiumei; Kim, Tae Il; Kim, Won Ho; Cheon, JaeHee.

In: Inflammatory Bowel Diseases, Vol. 24, No. 9, 16.08.2018, p. 1706-1717.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Deep Resequencing of Ulcerative Colitis-Associated Genes Identifies Novel Variants in Candidate Genes in the Korean Population

AU - Moon, Chang Mo

AU - Kim, Seung Won

AU - Ahn, Jae Bum

AU - Ma, Hyun Woo

AU - Che, Xiumei

AU - Kim, Tae Il

AU - Kim, Won Ho

AU - Cheon, JaeHee

PY - 2018/8/16

Y1 - 2018/8/16

N2 - 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.

AB - 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.

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