The search and prospective follow-up study of genetic predisposition and environmental factors of ectopic fat accumulation

• Project/Area Number: 25461343
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Osaka University (2015); Kyoto University (2013-2014)
• Principal Investigator: Hotta Kikuko 大阪大学, 医学部附属病院, 講師 (30360639)
• Co-Investigator(Kenkyū-buntansha): KITAMOAO Takuya 京都大学, 大学院医学研究科, 特定技術職員 (10456882) ; KITAMOAO Aya 京都大学, 大学院医学研究科, 教務補佐 (30381627)
• Co-Investigator(Renkei-kenkyūsha): YONEDA Masato 横浜市立大学, 大学病院, 助教 (10423831) ; HYOGO Hideyuki 広島大学, 学内共同利用施設等, 助教 (40397930)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 非アルコール性脂肪肝疾患 / 内臓脂肪蓄積 / 次世代シークエンサー / エピゲノム / 遺伝子多型 / メタボリックシンドローム / RNAシークエンス / メチル化DNA / メチル化 / PNPLA3 / ターゲット・リシークエンス

Outline of Final Research Achievements

Genome-wide association study (GWAS) was performed and revealed that SNP rs738409 in the PNPLA3 plays a key role in the development of non-alcoholic fatty liver disease (NAFLD). We performed targeted next-generation sequence analysis and fine mapping of the linkage disequilibrium block containing PNPLA3 rs738409 and found that polymorphisms in the encoding the SAMM50 and PARVB are associated with the development and progression of NAFLD as well. We performed targeted-bisulfite sequencing and found that hypomethylation of CpG26 and hypermethylation of CpG99 may contribute to the severity of fibrosis in NAFLD. The levels of CpG99 methylation and PNPLA3 mRNA were affected by the rs738409 genotype.

Research Products

• [Journal Article] <i>CDH13</i> Polymorphisms are Associated with Adiponectin Levels and Metabolic Syndrome Traits Independently of Visceral Fat Mass (2016)
  • Author(s): Kitamoto A, Kitamoto T, Nakamura T, Matsuo T, Nakata Y, Hyogo H, Ochi H, Kamohara S, Miyatake N, Kotani K, Mineo I, Wada J, Ogawa Y, Yoneda M, Nakajima A, Funahashi T, Miyazaki S, Tokunaga K, Masuzaki H, Ueno T, Chayama K, Hamaguchi K, Yamada K, Hanafusa T, Oikawa S, Sakata T, Tanaka K, Matsuzawa Y, Hotta K.
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 23 Issue: 3 Pages: 309-319
  • DOI: 10.5551/jat.31567
  • NAID: 130005131888
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Influence of the rs738409 polymorphism in patatin-like phospholipase 3 on the treatment efficacy of non-alcoholic fatty liver disease with type 2 diabetes mellitus. (2016)
  • Author(s): Kan H, Hyogo H, Ochi H, Hotta K, Fukuhara T, Kobayashi T, Naeshiro N, Honda Y, Kawaoka T, Tsuge M, Hiramatsu A, Imamura M, Kawakami Y, Aikata H, Chayama K
  • Journal Title: Hepatol Res Volume: 46 Issue: 3 Pages: 146-153
  • DOI: 10.1111/hepr.12552
  • Peer Reviewed
• [Journal Article] The characteristics of non-obese NAFLD: Effect of genetic and environmental factors. (2016)
  • Author(s): Honda Y, Yoneda M, Kessoku T, Ogawa Y, Tomeno W, Imajo K, Mawatari H, Fujita K, Hyogo H, Ueno T, Chayama K, Saito S, Nakajima A, Hotta K
  • Journal Title: Hepatol Res Volume: - Issue: 10 Pages: 636-636
  • DOI: 10.1111/hepr.12648
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] <i>ADIPOQ</i> polymorphisms are associated with insulin resistance in Japanese women (2015)
  • Author(s): KitamotoA, KitamotoT, SoR, MatsuoT, NakataY, HyogoH, OchiH, NakamuraT, KamoharaS, MiyatakeN, KotaniK, MineoI, WadaJ, OgawaY, YonedaM, NakajimaA, FunahashiT, MiyazakiS, TokunagaK, MasuzakiH, UenoT, ChayamaK, HamaguchiK, YamadaK, HanafusaT, OikawaS, SakataT, TanakaK, MatsuzawaY, HottaK.
  • Journal Title: Endocrine Journal Volume: 62 Issue: 6 Pages: 513-521
  • DOI: 10.1507/endocrj.EJ14-0574
  • NAID: 130005085774
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Targeted-bisulfite sequence analysis of the methylation of CpG islands in genes encoding PNPLA3, SAMM50, and PARVB of patients with nonalcoholic fatty liver disease. (2015)
  • Author(s): Kitamoto T, Kitamoto A, Ogawa Y, Honda Y, Imajo K, Saito S, Yoneda M, Nakamura T, Nakajima A, Hotta K.
  • Journal Title: J Hepatol Volume: 印刷中 Issue: 2 Pages: 494-502
  • DOI: 10.1016/j.jhep.2015.02.049
  • NAID: 120005690144
  • Peer Reviewed
• [Journal Article] Association of polymorphisms in GCKR and TRIB1 with nonalcoholic fatty liver disease and metabolic syndrome traits (2014)
  • Author(s): Kitamoto A, Kitamoto T, Nakamura T, Ogawa Y, Yoneda M, Hyogo H, Ochi H, Mizusawa S, Ueno T, Nakao K, Sekine A, Chayama K, Nakajima A, Hotta K
  • Journal Title: Endocrine Journal Volume: 8
  • NAID: 130004677938
  • Peer Reviewed
• [Journal Article] Targeted next-generation sequencing and fine linkage disequilibrium mapping reveals association of PNPLA3 and PARVB with the severity of nonalcoholic fatty liver disease (2014)
  • Author(s): Kitamoto T, Kitamoto A, Yoneda M, Hyogo H, Ochi H, Mizusawa S, Ueno T, Nakao K, Sekine A, Chayama K, Nakajima A, Hotta K
  • Journal Title: Journal of Human Genetics Volume: 6 Issue: 5 Pages: 241-6
  • DOI: 10.1038/jhg.2014.17
  • NAID: 120005477223
  • Peer Reviewed
• [Presentation] 非アルコール性脂肪肝疾患（NAFLD）のエピゲノム解析 (2015)
  • Author(s): 堀田紀久子、北本卓也、北本綾、小川祐二、中島淳
  • Organizer: 日本人類遺伝学会第60回大会
  • Place of Presentation: 東京都新宿区
  • Year and Date: 2015-10-14
• [Presentation] 非アルコール性脂肪肝疾患のエピゲノム解析 (2015)
  • Author(s): 堀田紀久子、小川祐二、本多靖、米田正人、中島淳
  • Organizer: 第36回日本肥満学会
  • Place of Presentation: 愛知県名古屋市
  • Year and Date: 2015-10-02
• [Presentation] 非アルコール性脂肪肝疾患（NAFLD）のエピゲノム解析 (2015)
  • Author(s): 堀田紀久子、北本卓也、北本綾、小川裕二、米田正人、中島 淳
  • Organizer: 第2回肝臓と糖尿病・代謝研究会
  • Place of Presentation: 山口県下関市
  • Year and Date: 2015-05-23
• [Presentation] 非アルコール性脂肪肝疾患感受性領域の次世代シークエンサーによるターゲットリシークエンス (2014)
  • Author(s): 堀田紀久子,北本卓也,北本綾,兵庫秀幸,越智秀典,上野隆登,茶山一彰,米田正人,小川裕二,中島淳
  • Organizer: 日本人類遺伝学会第59回大会
  • Place of Presentation: 東京都江戸川区
  • Year and Date: 2014-11-19 – 2014-11-22
• [Presentation] GCKR、TRIB1の遺伝子多型とメタボリックシンドローム及び非アルコール性脂肪肝疾患との関連 (2014)
  • Author(s): 堀田紀久子,北本綾,北本卓也,小川裕二,米田正人, 上野隆登,兵庫秀幸,越智秀典,茶山一彰,中島淳
  • Organizer: 第35回日本肥満学会
  • Place of Presentation: 宮崎県宮崎市
  • Year and Date: 2014-10-24 – 2014-10-25
• [Presentation] Targeted next-generation sequencing and fine linkage disequilibrium mapping reveals association of PNPLA3 and PARVB with the severity of nonalcoholic fatty liver disease (2014)
  • Author(s): Hotta K, Kitamoto T, Kitamoto A, Yoneda M, Hyogo H, Ochi H, Ueno T, Chayama K, Nakajima A
  • Organizer: th Metabolic Syndrome, Type 2 Diabetes and Atherosclerosis Congress
  • Place of Presentation: 京都府京都市
  • Year and Date: 2014-09-12 – 2014-09-14
• [Presentation] 非アルコール性脂肪肝炎感受性領域の次世代シークエンサーによるターゲットリシークエンス (2014)
  • Author(s): 堀田紀久子,北本綾,北本卓也,小川裕二,米田正人, 上野隆登,兵庫秀幸,越智秀典,茶山一彰,中島淳
  • Organizer: 第57回日本糖尿病学会
  • Place of Presentation: 大阪府大阪市
  • Year and Date: 2014-05-22 – 2014-05-24
• [Presentation] シンポジウム4：肥満症の成因と疫学～成因のコントロールによる効果的な予防～肥満症の遺伝素因 (2013)
  • Author(s): 堀田紀久子
  • Organizer: 第34回日本肥満学会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
• [Presentation] 非アルコール性脂肪肝炎のゲノムワイド関連解析 (2013)
  • Author(s): 堀田紀久子、中尾一和
  • Organizer: 第34回日本肥満学会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
• [Presentation] 特別シンポジウム4：糖尿病関連遺伝子研究の進化 肥満及び肥満症関連遺伝子 (2013)
  • Author(s): 堀田紀久子
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: ホテル日航熊本（熊本県熊本市）
• [Presentation] ウエスト：ヒップ比及びBMI感受性遺伝子多型の内臓脂肪および皮下脂肪面積に及ぼす効果 (2013)
  • Author(s): 堀田紀久子、松尾知明、中田由夫、兵庫秀幸、越智秀典、蒲原聖可、小谷一晃、伊藤直人、嶺尾郁夫、和田淳、米田正人、中島淳、船橋徹、宮崎滋、徳永勝人、益崎裕章、茶山一彰、上野隆登、浜口和之、山田研太郎、花房俊昭、及川眞一、坂田利家、田中喜代次、松澤佑次、中尾一和
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: ホテル日航熊本（熊本県熊本市）