Rigorous analysis of epigenetic factors associating with the clinical course of diseases using discordant monozygotic twin pairs

• Project/Area Number: 16H03261
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied health science
• Research Institution: Osaka University
• Principal Investigator: WATANABE Mikio 大阪大学, 医学系研究科, 教授 (50294088)
• Co-Investigator(Kenkyū-buntansha): 竹中 要一 関西大学, 総合情報学部, 教授 (00324830)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2017: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2016: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: エピゲノム / 双生児 / 臨床検査 / 自己抗体 / 自己免疫疾患 / 甲状腺 / 環境因子 / 遺伝因子 / 甲状腺疾患 / 生活習慣病 / DNAメチル化 / 一卵性双生児 / 遺伝子型 / エピジェネティクス / 性差

Outline of Final Research Achievements

We targeted epigenomic factors as environmental factors involved in the disease or its clinical condition, and rigorously analyzed identical twins, whose genetic background are the same but showing discordant phenotype. Focusing on autoimmune diseases among various diseases, we searched for monozygotic twins discordant for the positivity of autoantibodies and found 19 pairs of monozygotic twins discordant for the positivity of anti-thyroglobulin antibodies.
We found no significant differences in DNA methylation levels, representative of epigenomic changes, between twins using all 19 discordant pairs, but significant differences in methylation levels were found when we only analyzed discordant pairs with specific genetic backgrounds.

Academic Significance and Societal Importance of the Research Achievements

エピゲノム変化のような環境因子を解析するには、一般集団ではなく一卵性双生児ペアを対象とするのが重要であるが、その中でも、環境因子に感受性のある遺伝的背景をもっている個体でのみ、環境因子が表現型に影響すると考えられる。
本研究成果では、遺伝子多型により環境因子に感受性をもつ一卵性双生児ペア、すなわち特定の表現型が不一致なペアに特異的な遺伝的背景を見出し、その遺伝的な背景をもつ個体で環境因子が表現型に関与する機序をはじめて解明した。遺伝因子と環境因子のクロストークを解析する上で必須の研究手法を用いたはじめての双生児研究であり、ゲノム・エピゲノム情報とヒトの表現型の関連を解明する手法の先鞭といえる。

Research Products

• [Int'l Joint Research] ヘルシンキ大学(フィンランド)
• [Int'l Joint Research] ヘルシンキ大学(フィンランド)
• [Journal Article] Genotype-based epigenetic differences in monozygotic twins discordant for positive anti-thyroglobulin autoantibodies. (2018)
  • Author(s): Watanabe, M., Takenaka, Y., Honda, C., Osaka Twin Research Group, Iwatani, Y.
  • Journal Title: Thyroid Volume: 28 Pages: 110-123
  • Peer Reviewed
• [Journal Article] Methylation levels of the TNFA gene are different between Graves’ and Hashimoto’s diseases and influenced by the TNFA polymorphism (2018)
  • Author(s): Morita Emi、Watanabe Mikio、Inoue Naoya、Hashimoto Hidemi、Haga Emi、Hidaka Yoh、Iwatani Yoshinori
  • Journal Title: Autoimmunity Volume: 印刷中 Issue: 3 Pages: 118-125
  • DOI: 10.1080/08916934.2018.1448078
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Association of current and former smoking with body mass index: A study of smoking discordant twin pairs from 21 twin cohorts (2018)
  • Author(s): Piirtola Maarit、Jelenkovic Aline、Latvala Antti、Sund Reijo、Honda Chika、Inui Fujio、Watanabe Mikio、et al., Silventoinen Karri
  • Journal Title: PLOS ONE Volume: 13 Issue: 7 Pages: e0200140-e0200140
  • DOI: 10.1371/journal.pone.0200140
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Polymorphisms and expression of genes encoding Argonautes 1 and 2 in autoimmune thyroid diseases (2018)
  • Author(s): Tokiyoshi Ena、Watanabe Mikio、Inoue Naoya、Hidaka Yoh、Iwatani Yoshinori
  • Journal Title: Autoimmunity Volume: 51 Issue: 1 Pages: 35-42
  • DOI: 10.1080/08916934.2017.1416468
  • Peer Reviewed
• [Journal Article] Genotype-Based Epigenetic Differences in Monozygotic Twins Discordant for Positive Antithyroglobulin Autoantibodies (2018)
  • Author(s): Watanabe Mikio、Takenaka Yoichi、Honda Chika、Osaka Twin Research Group、Iwatani Yoshinori
  • Journal Title: Thyroid Volume: 28 Issue: 1 Pages: 110-123
  • DOI: 10.1089/thy.2017.0273
  • Peer Reviewed
• [Journal Article] Functional polymorphisms of the type 1 and type 2 iodothyronine deiodinase genes in autoimmune thyroid diseases (2018)
  • Author(s): Inoue, N., Watanabe, M., Katsumata, Y., Ishido, N., Hidaka, Y., Iwatani, Y.
  • Journal Title: Immunol Invest Volume: 47 Issue: 5 Pages: 534-542
  • DOI: 10.1080/08820139.2018.1458861
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Polymorphisms in Th17-related genes and the pathogenesis of autoimmune thyroid disease (2018)
  • Author(s): Kunisato T, Watanabe M, Inoue N, Okada A, Nanba T, Kobayashi W, Inoue Y, Katsumata Y, Omori N, Nobuhara T, Takemura K, Hidaka Y, Iwatani Y
  • Journal Title: Autoimmunity Volume: 51 Issue: 7 Pages: 360-369
  • DOI: 10.1080/08916934.2018.1534963
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] TSHR gene polymorphisms in the enhancer regions are most strongly associated with the development of Graves’ disease, especially intractable disease, and with that of Hashimoto’s disease. (2017)
  • Author(s): Fujii, A., Inoue, N., Watanabe, M., Kawakami, C., Hidaka, Y., Hayashizaki, Y. and Iwatani, Y.
  • Journal Title: Thyroid Volume: 27 Issue: 1 Pages: 111-119
  • DOI: 10.1089/thy.2016.0345
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Intraindividual variation of microRNA expression levels in plasma and peripheral blood mononuclear cells and the associations of these levels with the pathogenesis of autoimmune thyroid diseases. (2017)
  • Author(s): Otsu, H., Watanabe, M., Inoue, N., Masutani, R., Iwatani, Y.
  • Journal Title: Clin Chem Lab Med Volume: 55 Issue: 5 Pages: 626-635
  • DOI: 10.1515/cclm-2016-0449
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Within-pair differences of DNA methylation levels between monozygotic twins are different between male and female pairs. (2016)
  • Author(s): Watanabe, M., Honda, C., The Osaka Twin Research Group, Iwatani, Y.
  • Journal Title: BMC Medical Genomics Volume: 9 Issue: 1 Pages: 55-63
  • DOI: 10.1186/s12920-016-0217-2
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] DICER and DROSHA gene expression and polymorphisms in autoimmune thyroid diseases (2016)
  • Author(s): Saeki, M., Watanabe, M., Inoue, N., Tokiyoshi, E. Takuse, Y., Arakawa, Y. Hidaka, Y., Iwatani, Y.
  • Journal Title: Autoimmunity, Volume: 9 Issue: 8 Pages: 514-522
  • DOI: 10.1080/08916934.2016.1230846
  • Peer Reviewed
• [Journal Article] Increases of microRNA let-7e in peripheral blood mononuclear cells in Hashimoto’s disease (2016)
  • Author(s): Kagawa, T., Watanabe, M., Inoue, N., Otsu, H., Saeki, M., Katsumata, Y., Takuse, Y., Iwatani, Y.
  • Journal Title: Endocrine Journal Volume: 63 Issue: 4 Pages: 375-380
  • DOI: 10.1507/endocrj.EJ15-0577
  • NAID: 130005146453
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed
• [Journal Article] Genetic and environmental influences on adult human height across birth cohorts from 1886 to 1994 (2016)
  • Author(s): Jelenkovic A, Hur YM, Sund R, Yokoyama Y, Siribaddana SH, Hotopf M, Sumathipala A, Rijsdijk F, Tan Q, Zhang D, Pang Z, Aaltonen S, Heikkilä K, Öncel SY, Aliev F, Rebato E, Tarnoki AD, Tarnoki DL, Christensen K, Skytthe A, Kyvik KO, Silberg JL, Eaves LJ, Maes HH, Cutler TL, Hopper JL, et al.
  • Journal Title: Elife Volume: 5 Pages: 1-14
  • DOI: 10.7554/elife.20320
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Genotype-based epigenetic factors in identical twins discordant for positive TgAb (2018)
  • Author(s): Watanabe, M., Takenaka, Y., Honda, C., Osaka Twin Research Group, Iwatani, Y.
  • Organizer: AACC Annual Meeting & Clinical Lab Expo 2018
  • Int'l Joint Research
• [Presentation] Genetic contributions to individuality of natural audio-visual experiences. the 1st international symposium (2018)
  • Author(s): Toyoda, S., Nishida, S., Honda, C., Watanabe, M., Osaka Twin Research Group, Nishimoto, S.
  • Organizer: the 1st international symposium “Towards Understanding INDIVIDUALITY”
  • Int'l Joint Research
• [Presentation] TgAb出現が一致しない一卵性双生児ペアを対象とした、自己抗体出現に関するエピゲノム要因の解析 (2018)
  • Author(s): 渡邉幹夫、竹中要一、本多智佳、大阪ツインリサーチグループ、岩谷良則
  • Organizer: 第61回日本甲状腺学会学術集会
• [Presentation] 臨床検査へのゲノム・エピゲノム情報の応用 (2018)
  • Author(s): 渡邉幹夫
  • Organizer: 第58回日本臨床化学会年次学術集会
  • Invited
• [Presentation] 自己免疫性甲状腺疾患の発症・病態予後とIL6プロモータ―領域のCpGのメチル化率との関連 (2018)
  • Author(s): 平井那知、渡邉幹夫、井上直哉、日高洋、岩谷良則
  • Organizer: 第58回日本臨床化学会年次学術集会
• [Presentation] Genotype-based epigenetic factors in identical twins discordant for positive TgAb (2018)
  • Author(s): Watanabe, M., Takenaka, Y., Honda, C., Osaka Twin Research Group, Iwatani, Y.
  • Organizer: AACC Annual Meeting & Clinical Lab Expo 2018, Chicago, Jul 31st, 2018
  • Int'l Joint Research
• [Presentation] TgAb出現が一致しない一卵性双生児ペアを対象とした、自己抗体出現に関するエピゲノム要因の解析 (2018)
  • Author(s): 渡邉幹夫、竹中要一、本多智佳、大阪ツインリサーチグループ、岩谷良則、
  • Organizer: 第61回日本甲状腺学会学術集会（川越）、2018.11.23
• [Presentation] 受賞講演「臨床検査へのゲノム・エピゲノム情報の応用」 (2018)
  • Author(s): 渡邉幹夫
  • Organizer: 第58回日本臨床化学会年次学術集会（名古屋）、2018.8.25
  • Invited
• [Presentation] 自己免疫性甲状腺疾患の発症・病態予後とIL6プロモータ―領域のCpGのメチル化率との関連 (2018)
  • Author(s): 平井那知、渡邉幹夫、井上直哉、日高洋、岩谷良則
  • Organizer: 第58回日本臨床化学会年次学術集会（名古屋）、2018.8.25-26
• [Presentation] Genotype specific for monozygotic twins discordant for anti-thyrogrobulin autoantibody (TgAb) positivity. (2017)
  • Author(s): Watanabe, M., Takenaka, Y., Honda, C., Osaka Twin Research Group, Iwatani, Y.
  • Organizer: The 16th Congress of the International Society for Twin Studies (ISTS), Madrid, Nov. 16-18, 2017
  • Int'l Joint Research
• [Presentation] Sex-related Individual Differences in DNA Methylation in Monozygotic Twin Pairs. (2016)
  • Author(s): Watanabe, M., Honda, C., Osaka Twin Research Group, Iwatani, Y
  • Organizer: Behavior genetics Association 46th Annual Meeting
  • Int'l Joint Research
• [Presentation] 一卵性双生児におけるDNAメチル化ペア内差の男女間比較 (2016)
  • Author(s): 渡邉幹夫、本多智佳、大阪ツインリサーチグループ、岩谷良則
  • Organizer: 第10回日本エピジェネティクス研究会年会
• [Book] DNA and Histone Methylation as Cancer Targets（分担執筆） (2017)
  • Author(s): Suetake, I., Watanabe, M., Takeshita, K., Takahashi, S., Carlton, P.
  • Total Pages: 622
  • Publisher: Humana Press
  • ISBN: 3319597841