Exome sequencing for disease gene discovery in rheumatoid arthritis

2012 Fiscal Year Final Research Report

• Project/Area Number: 22510213
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Medical genome science
• Research Institution: Tokai University
• Principal Investigator: MITSUNAGA Shigeki 東海大学, 医学部, 教授 (20510051)
• Co-Investigator(Kenkyū-buntansha): INOKO Hidetoshi 東海大学, 医学部, 教授 (10101932) ; INOUE Ituro 東海大学, 医学部, 教授 (00192500) ; SHIINA Takashi 東海大学, 医学部, 准教授 (00317744)
• Project Period (FY): 2010 – 2012
• Keywords: 疾患関連遺伝子 / 稀少変異 / 関節リウマチ

Research Abstract

The butyrophilin-like protein 2 gene (BTNL2) within the class III region of the Major Histocompatability Complex (MHC) genomic region was identified as a rheumatoid arthritis (RA) susceptibility gene by exome sequencing (19 RA cases) with stepwise filtering analysis and then validated by Sanger sequencing and association analysis using 432 cases and 432 controls. Logistic regression of the Sanger-sequenced single nucleotide variants (SNVs) in an association study of 432 cases and 432 controls showed that twelve non-synonymous SNPs in BTNL2 were significantly associated with RA. The lowest p values were obtained from 3 SNPs, rs41521946, rs28362677, and rs28362678, which were in absolute linkage disequilibrium: p = 4.55E-09, OR = 1.88, 95% CI = 1.52 - 2.33. The BTNL2 locates on chromosome 6 between HLA-DRB1 and NOTCH4 and is 170 kb apart from these two genes. Although DRB1 and NOTCH4 were reported to be RA-susceptible, the 3 BTNL2 SNPs retained significant association with RA when evaluated by the logistic regression with the adjustment for RA-susceptible HLA-DRB1 alleles in Japanese or rs2071282-T in NOTCH4: p = 0.0156 and p = 0.00368, respectively. These results suggest that the 3 non-synonymous SNPs in BTNL2 confer RA-risk independently from HLA-DRB1 and NOTCH4

Research Products

• [Journal Article] Detection of Ancestry Informative HLA Alleles Confirms the Admixed Origins of Japanese Population (2013)
  • Author(s): Nakaoka H, Mitsunaga S, Hosomichi K, Shyh-Yuh L,Sawamoto T, Fujiwara T, Tsutsui N, Suematsu K, Shinagawa A, Inoko H, Inoue I.
  • Journal Title: PLoS One Volume: 8(4) Pages: e60793
  • Peer Reviewed
• [Journal Article] Improved loop-mediated isothermal amplification for HLA-DRB1 genotyping using RecA and a restriction enzyme for enhanced amplification specificity. (2013)
  • Author(s): Mitsunaga S, Shimizu S, Okudaira Y, Oka A, Tanaka M, Kimura M, Kulski JK, Inoue I, Inoko H.
  • Journal Title: Immunogenetics
  • Peer Reviewed
• [Journal Article] Exome sequencing identifies novel rheumatoid arthritis-susceptible variants in the BTNL2 (2013)
  • Author(s): Mitsunaga S, Hosomichi K, Okudaira Y, Nakaoka H, Kunii N, Suzuki Y, Kuwana M, Sato S, Kaneko Y, Homma Y, Kashiwase K, Azuma F, Kulski JK, Inoue I, Inoko H.
  • Journal Title: J Hum Gene Volume: 58(4) Pages: 210-5
  • Peer Reviewed
• [Journal Article] Super high resolution for single molecule-sequence-based typing of classical HLA loci at the 8-digit level using next generation sequencers. (2012)
  • Author(s): Shiina T, Suzuki S, Ozaki Y, Taira H, Kikkawa E, Shigenari A, Oka A, Umemura T, Joshita S, Takahashi O, Hayashi Y, Paumen M, Katsuyama Y, Mitsunaga S, Ota M, Kulski JK, Inoko H.
  • Journal Title: Tissue Antigens Volume: 80(4) Pages: 305-16
  • Peer Reviewed
• [Journal Article] Associations between six classical HLA loci and rheumatoid arthritis: a comprehensive analysis. (2012)
  • Author(s): Mitsunaga S, Suzuki Y, Kuwana M, Sato S, Kaneko Y, Homma Y, Narita A, Kashiwase K, Okudaira Y, Inoue I, Kulski JK, Inoko H
  • Journal Title: Tissue Antigens Volume: 80(1) Pages: 16-25
  • Peer Reviewed
• [Journal Article] A systems genetics approach provides a bridge from discovered genetic variants to biological pathways in rheumatoid arthritis. (2011)
  • Author(s): Nakaoka H, Cui T, Tajima A, Oka A, Mitsunaga S, Kashiwase K, Homma Y, Sato S, Suzuki Y, Inoko H, Inoue I.
  • Journal Title: PLoS One Volume: 6(9) Pages: e25389
  • Peer Reviewed
• [Journal Article] Exact break point of a 50 kb deletion 8 kb centromeric of the HLA-A locus with HLA-A*24:02: the same deletion observed in other A*24 alleles and A*23:01 allele (2011)
  • Author(s): Mitsunaga S, Okudaira Y, Kunii N, Cui T, Hosomichi K, Oka A, Suzuki Y, Homma Y, Sato S, Inoue I, Inoko H
  • Journal Title: Immunogenetics Volume: 63(8) Pages: 467-74
  • Peer Reviewed
• [Journal Article] Particular human leukocyte antigen alleles are associated with biochemical traits in the Japanese population (2011)
  • Author(s): Mitsunaga S, Homma Y, Narita A, Kashiwase K, Okudaira Y, Shiina Y, Inoue I, Inoko H.
  • Journal Title: Hum Immuno Volume: 72(7) Pages: 566-70
  • Peer Reviewed
• [Presentation] Integrative analysis of whole-gene co-expression network and exome sequence data to characterize pathways relevant to rheumatoid arthritis. (2012)
  • Author(s): Hirofumi Nakaoka, Shigeki Mitsunaga, Hidetoshi Inoko, Ituro Inoue:
  • Organizer: 62nd Annual Meeting of the American Society of Human Genetics
  • Place of Presentation: San Francisco, CA
  • Year and Date: 20121106-10
• [Presentation] 関節リウマチとHLA 6座との関連解析 (2012)
  • Author(s): 奥平裕子、光永滋樹、鈴木康夫、桑名正隆、佐藤慎二、金子祐子、本間康彦、成田暁、柏瀬貢一、井ノ上逸朗、猪子英俊
  • Organizer: 第21回日本組織適合性学会大会
  • Place of Presentation: 東京 明治大学駿河台キャンパス
  • Year and Date: 20120915-17
• [Presentation] エクソーム解析による関節リウマチ感受性遺伝子の探索 (2011)
  • Author(s): 奥平裕子、光永滋樹、國井七絵、細道一善、田中政之、林英樹、河田寿子、鈴木康夫、佐藤慎二、本間康彦、井ノ上逸朗、猪子英俊
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜 パシフィコ横浜
  • Year and Date: 20111213-16
• [Presentation] 関節リウマチにおけるシステムズ・ジェネティクス・アプローチ~感受性遺伝子座から生物学的経路の推定 (2011)
  • Author(s): 中岡 博史, 崔 泰林, 田嶋 敦, 光永滋樹, 猪子 英俊, 井ノ上 逸朗
  • Organizer: 日本人類遺伝学会第56回大会
  • Place of Presentation: 千葉 幕張メッセ
  • Year and Date: 20111109-12
• [Presentation] 関節リウマチ感受性遺伝子における希少多型・変異の探索 (2010)
  • Author(s): 國井七絵、光永滋樹、細道一善、奥平裕子、鈴木康夫、本間康彦、井ノ上逸朗、猪子英俊
  • Organizer: 第33回日本分子生物学会年会・ 第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸 ポートアイランド
  • Year and Date: 20101207-10
• [Presentation] A systematic approach to constructing genomic risk prediction model of common disease and assessing its clinical validity: A case study of rheumatoid arthritis (2010)
  • Author(s): 中岡 博史, 崔 泰林, 田嶋 敦, 光永滋樹, 井ノ上 逸朗
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会 合同大会
  • Place of Presentation: 神戸 ポートアイランド
  • Year and Date: 20101207-10
• [Presentation] A*24:02を有するHLA-A遺伝子近傍の欠失領域の解析 (2010)
  • Author(s): 奥平裕子、光永滋樹、崔 泰林、河田寿子、細道一善、山口香織、岡 晃、井ノ上逸朗、猪子英俊
  • Organizer: 第19回日本組織適合性学会大会
  • Place of Presentation: 東京 東京大学本郷キャンパス
  • Year and Date: 20100917-19
• [Presentation] 関節リウマチの病型とHLAとの関連解析 (2010)
  • Author(s): 國井七絵、 光永滋樹、奥平裕子、成田暁、鈴木康夫、本間康彦、桑名正隆、柏瀬貢一、井ノ上逸朗、猪子英俊
  • Organizer: 第19回日本組織適合性学会大会
  • Place of Presentation: 東京東京大学本郷キャンパス
  • Year and Date: 20100917-19
• [Presentation] HLA-DRB1*14:54 の分布 (2010)
  • Author(s): 勝山喜彦、太田雅穂、吉川枝里、光永滋樹、益尾清恵、猪子英俊
  • Organizer: 第19回日本組織適合性学会大会
  • Place of Presentation: 東京 東京大学本郷キャンパス
  • Year and Date: 20100917-19