自己免疫性膵炎関連遺伝子の全ゲノム関連解析

2011 Fiscal Year Research-status Report

• Project/Area Number: 23591012
• Research Institution: Shinshu University
• Principal Investigator: 川 茂幸 信州大学, 総合健康安全センター, 教授 (10177628)
• Co-Investigator(Kenkyū-buntansha): 太田 正穂 信州大学, 医学部, 准教授 (50115333)
• Project Period (FY): 2011-04-28 – 2014-03-31
• Keywords: 自己免疫性膵炎 / GWAS / IgG4

Research Abstract

自己免疫性疾患(AIP)は遺伝的要因と環境要因が背景に存在する多因子疾患である。本疾患の病態に関連する遺伝的要因解明の目的で、Affimetrix社製SNPチップ、GeneChip Human Mapping 500k Array Setを用いて自己免疫性膵炎115検体の全ゲノム網羅的な相関解析（genome-wide association study: GWAS）を行った。コントロールのタイピングデータは健常人315例分をもちいた。本検討、解析１はAIP とコントロールとの相関を、解析２ではAIP におけるIgG4高値群とコントロールとの相関を評価した。P値が0.0001未満を示すSNPを抽出したところ、解析1で38SNP、解析２で37SNP、で強い相関を認め、それらに共通するSNPとして17SNPを認めた。これらの関連遺伝子から機能的に興味深い3種類の遺伝子CLNK、PAX５、FCER2に注目した。CLNKは、T細胞およびB細胞抗原レセプターの下流で免疫シグナルを調節し、IgEレセプターを介したMAST細胞の脱顆粒反応や,サイトカイン刺激に伴う多様なシグナル伝達に関与している。PAX5は、CD19遺伝子プロモーター、B細胞に特異的なtyrosine kinase遺伝子BLK、heavy chain locusの調節領域に結合するBSAPをコードしている。CD23とも呼ばれるFCER2は、低親和性IgE受容体として、主に成熟B細胞、単球、濾胞樹状細胞に発現し、B細胞の活性化とIgEの下方制御に関与しており、細胞接着、抗原提示、B・T細胞の増殖と分化、アポトーシスからの救済、細胞毒性物質の放出、IgE産生の調節にも関与している。これら3種類の遺伝子内のSNPで確認試験を行ったところ、CLNKとPAX5では相関を示したが、FCER２では有意な相関を認めなかった。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

Affimetrix社製SNPチップ、GeneChip Human Mapping 500k Array Setを用いて自己免疫性膵炎115検体の全ゲノム網羅的な相関解析（genome-wide association study: GWAS）を行い、候補遺伝子を3種類同定した。これらの臨床的意義については検索が進んでいないので、検討が必要である。また、検体数が未だ充分ではなく、集積する必要がある。

Strategy for Future Research Activity

今回明らかになった、自己免疫性膵炎の病態に関連していると考えられる候補遺伝子の臨床的意義について検討を進める。また、GWASを推し進め、さらに涙腺・唾液腺炎に関連した遺伝子の検索を行う。涙腺・唾液腺炎合併例と非合併例の間で、有意な相関を認めるSNPsを検索し、関連する遺伝子を見つけ出す。GWASの検討には充分な症例数をそろえることが望まれるが、臨床検体のさらなる集積に努める。

Expenditure Plans for the Next FY Research Funding

当初計画で見込んだよりも安価に研究が完了したため、次年度使用額が生じた。自己免疫性膵炎の病態に関連した候補遺伝子、涙腺・唾液腺炎の病態に関連する候補遺伝子を見つけ出し、遺伝子内SNPsで確認試験を推し進める。各候補遺伝子について臨床的意義の検討を行う。

Research Products

• [Journal Article] The Utility of Serum IgG4 Concentrations as a Biomarker. (2012)
  • Author(s): Kawa S, Ito T, Watanabe T, Maruyama M, Hamano H, Maruyama M, Muraki T, Arakura N.
  • Journal Title: International Journal of Rheumatology Volume: on line Pages: on line
  • DOI: 10.1155/2012/198314
  • Peer Reviewed
• [Journal Article] Risk factors for pancreatic stone formation in autoimmune pancreatitis over a long-term course. (2012)
  • Author(s): Maruyama M, Arakura N, Ozaki Y, Watanabe T, Ito T, Yoneda S, Maruyama M, Muraki T, Hamano H, Matsumoto A, Kawa S.
  • Journal Title: J Gastroenterol. Volume: 47 Pages: in press
  • Peer Reviewed
• [Journal Article] Type 1 autoimmune pancreatitis. (2012)
  • Author(s): Zen Y, Bogdanos DP, Kawa S.
  • Journal Title: Orphanet Journal of Rare Diseases Volume: 6 Pages: in press
  • Peer Reviewed
• [Journal Article] Characteristic magnetic resonance features of focal autoimmune pancreatitis useful for differentiation from pancreatic cancer. (2012)
  • Author(s): Sugiyama Y, Fujinaga Y, Kadoya M, Ueda K, Kurozumi M, Hamano H, Kawa S.
  • Journal Title: Jpn J Radiol. Volume: 30 Pages: in press
  • Peer Reviewed
• [Journal Article] Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD) (2012)
  • Author(s): Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, Matsui S, Yoshino T, Nakamura S, Kawa S, et al.
  • Journal Title: Mod Rheumatol Volume: 22 Pages: 21-30
  • Peer Reviewed
• [Journal Article] International Consensus Diagnostic Criteria for Autoimmune Pancreatitis: Guidelines of the International Association of Pancreatology. (2011)
  • Author(s): Shimosegawa T, Chari ST, Frulloni L, Kamisawa T, Kawa S, Mino-Kenudson M, Kim MH, Klöppel G, Lerch MM, Löhr M, Notohara K, Okazaki K, Schneider A, Zhang L.
  • Journal Title: Pancreas Volume: 40 Pages: 352-358
  • Peer Reviewed
• [Journal Article] History of Autoimmune Pancreatitis and Mikulicz’s Disease. (2011)
  • Author(s): Kawa S, Sugai S.
  • Journal Title: Current Immunology Reviews Volume: 7 Pages: 137-143
• [Journal Article] Autoimmune Pancreatitis and Diagnostic Criteria. (2011)
  • Author(s): Kawa S, Fujinaga Y, Ota M, Hamano H, Bahram S.
  • Journal Title: Current Immunology Reviews Volume: 7 Pages: 144-161
  • Peer Reviewed
• [Journal Article] Radiologic Findings of IgG4-Related Disease. (2011)
  • Author(s): Fujinaga Y, Kadoya M, Hamano H, Kawa S, Momose M, Kawakami S, Watanabe T, Sugiyama Y , Uehara T.
  • Journal Title: Current Immunology Reviews Volume: 7 Pages: 186-203
  • Peer Reviewed
• [Journal Article] Infraorbital nerve swelling associated with autoimmune pancreatitis. (2011)
  • Author(s): Watanabe T, Fujinaga Y, Kawakami S, Hatta T, Hamano H, Kawa S, Kadoya M.
  • Journal Title: Jpn J Radiol. Volume: 29 Pages: 194-201
  • Peer Reviewed
• [Journal Article] IgG4-related pleural disease diagnosed by a re-evaluation of chronic bilateral pleuritis in a patient who experienced occasional acute left bacterial pleuritis. (2011)
  • Author(s): Yamamoto H, Suzuki T, Yasuo M, Kobayashi O, Tsushima K, Ito M, Urushihata K, Yamazaki Y, Hanaoka M, Koizumi T, Uehara T, Kawakami S, Hamano H, Kawa S, Kubo K.
  • Journal Title: Intern Med Volume: 50 Pages: 893-7
  • Peer Reviewed
• [Journal Article] Elevated IgG4 levels in patients demonstrating sarcoidosis-like radiologic findings. (2011)
  • Author(s): Tsushima K, Yokoyama T, Kawa S, Hamano H, Tanabe T, Koizumi T, Honda T, Kawakami S, Kubo K.
  • Journal Title: Medicine (Baltimore) Volume: 90 Pages: 194-200
  • Peer Reviewed
• [Journal Article] A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. (2011)
  • Author(s): Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, Matsui S, Sumida T, Mimori T, Tanaka Y, Tsubota K, Yoshino T, Kawa S, et.al.
  • Journal Title: Mod Rheumatol. Volume: 22 Pages: 1-14
  • Peer Reviewed
• [Journal Article] Polymorphism in the KCNA3 gene is associated with susceptibility to autoimmune pancreatitis in the Japanese population. (2011)
  • Author(s): Ota M, Ito T, Umemura T, Katsuyama Y, Yoshizawa K, Hamano H, Kawa S.
  • Journal Title: Dis Markers. Volume: 31 Pages: 223-9
  • Peer Reviewed
• [Presentation] IgG4関連硬化性胆管炎診断におけるIgG4値の多施設検討 (2011)
  • Author(s): 村木崇、浜野英明、 川 茂幸
  • Organizer: 第46回日本胆道学会学術集会
  • Place of Presentation: 宮崎
  • Year and Date: 2011. 9.17
• [Presentation] IgG4関連疾患における甲状腺機能低下症の検討 (2011)
  • Author(s): 渡邊貴之、伊藤哲也，川 茂幸
  • Organizer: 第53回日本消化器病学会大会
  • Place of Presentation: 福岡
  • Year and Date: 2011.9.17
• [Presentation] Clinical Features of IgG4 Negative Autoimmune Pancreaｔitis. (2011)
  • Author(s): Ito T, Maruyama M, Watanabe T, Maruyama M, Yoneda S, Kodama R, Ozaki Y, Muraki T, Hamano H, Arakura N, Kawa S
  • Organizer: 4th AOPA & KPBA
  • Place of Presentation: Jeju, Korea.
  • Year and Date: 2011. September 3rd
• [Presentation] Thyroiditis: an IgG4-related disease. (2011)
  • Author(s): Watanabe T, Maruyama M, Ito T, Fujinaga Y, Maruyama M, Yoneda S, Ozaki Y, Muraki T, Hamano H, Arakura N, Kawa S.
  • Organizer: 4th AOPA & KPBA
  • Place of Presentation: Jeju, Korea.
  • Year and Date: 2011. September 3rd
• [Presentation] Mechanism of Pancreatic Stone Formation in Patients with Autoimmune Pancreatitis. (2011)
  • Author(s): Maruyama M, Ozaki Y, Arakura N, Watanabe T, Ito T, Yoneda S, Maruyama M, Muraki T, Hamano H, Kawa S.
  • Organizer: 4th AOPA & KPBA
  • Place of Presentation: Jeju, Korea.
  • Year and Date: 2011. September 3rd
• [Presentation] How frequently does AIP relapse and how can it be prevented? Japanese experience. (2011)
  • Author(s): Kawa S. Ito T, Maruyama M, Watanabe T, Ozaki Y, Maruyama M, Yoneda K, Kodama R, Muraki T, Hamano H, Arakura N.
  • Organizer: 4th AOPA & KPBA
  • Place of Presentation: Jeju, Korea
  • Year and Date: 2011. September 2nd
• [Presentation] The utility of serum IgG4 concentrations as a biomarker. (2011)
  • Author(s): Kawa S
  • Organizer: The First International Conference On IgG4-Related Disease (IgG4-RD)
  • Place of Presentation: Boston, Massachusetts, USA
  • Year and Date: 2011. October 6th
• [Presentation] Approach for Pathogenesis Humoral Immunity. 1) IgG4. (2011)
  • Author(s): Kawa S
  • Organizer: Pancreas Research Forum (IPRF) 2011
  • Place of Presentation: OSAKA Japan
  • Year and Date: 2011. November 26th
• [Presentation] Frequency and Prevention of Autoimmune Pancreatitis Relapse in a Japanese Population. (2011)
  • Author(s): Ito T, Maruyama M, Watanabe T, Maruyama M, Yoneda S, Kodama R, Ozaki Y, Muraki T, Hamano H, Arakura N, Kawa S,
  • Organizer: Pancreas Research Forum (IPRF) 2011
  • Place of Presentation: OSAKA Japan
  • Year and Date: 2011. November 26th
• [Presentation] The Mechanism of Lower Bile Duct Stricture seen in IgG4-related Sclerosing Cholangitis. (2011)
  • Author(s): Watanabe T, Maruyama M, Ito T, Fujinaga Y, Maruyama M, Yoneda S, Ozaki Y, Muraki T, Hamano H, Arakura N, Kawa S.
  • Organizer: Pancreas Research Forum (IPRF) 2011
  • Place of Presentation: OSAKA Japan
  • Year and Date: 2011. November 26th
• [Presentation] IgG4-related disease: a new disease group explaining Morbus Ormond, pancreatitis and SSA- or SSB-netative sialoadenitis.- Clinical Science Session, Too much immunoglobulin-diseases relvant for the rhyumatologis. (2011)
  • Author(s): Kawa S
  • Organizer: EULAR2011
  • Place of Presentation: London
  • Year and Date: 2011. May 25th
• [Presentation] 自己免疫性膵炎の免疫遺伝学的解析 (2011)
  • Author(s): 伊藤哲也、渡邊貴之、丸山真弘、米田傑、丸山雅史、児玉亮、尾崎弥生、村木崇、浜野英明、新倉則和、川茂幸
  • Organizer: 第42回日本膵臓学会大会
  • Place of Presentation: 弘前
  • Year and Date: 2011. 7.30
• [Presentation] Clinical Characteristics of Cases with Autoimmune Pancreatitis Showing Steroid Non-responsive Ductal Narrowing (2011)
  • Author(s): Maruyama M, Kawa S
  • Organizer: Pancreas Research Forum (IPRF) 2011
  • Place of Presentation: OSAKA Japan
  • Year and Date: 2011-11-26
• [Presentation] 自己免疫性膵炎患者における抗H.pylori IgG値とIgG4値の検討 (2011)
  • Author(s): 伊藤哲也、川茂幸
  • Organizer: 第97回消化器病学会総会
  • Place of Presentation: 東京
  • Year and Date: 2011-05-15
• [Book] IgG4関連疾患アトラス (2012)
  • Author(s): 川 茂幸、渡邊貴之、丸山真弘、伊藤哲也、丸山雅史、尾崎弥生、村木 崇、浜野英明、新倉則和
  • Total Pages: 199
  • Publisher: 歴史：膵臓
• [Book] Annual Review 消化器2011 (2011)
  • Author(s): 川 茂幸
  • Total Pages: 362
  • Publisher: 自己免疫性膵炎とIgG4関連疾患