Molecular Epidemiological and pathological studies on the association between lipoprotein(a) and malignant neoplasms

• Project/Area Number: 17K08718
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Sawabe Motoji 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (30196331)
• Co-Investigator(Kenkyū-buntansha): 池田 仁子 国立研究開発法人国立国際医療研究センター, その他部局等, 上級研究員 (20415508) ; 三重野 牧子 自治医科大学, 医学部, 准教授 (60464707) ; 副島 友莉恵 東京医科歯科大学, 大学院医歯学総合研究科, 助教 (60596964) ; 山崎 茉莉亜 地方独立行政法人東京都健康長寿医療センター(東京都健康長寿医療センター研究所), 東京都健康長寿医療センター研究所, 研究員 (60776516) ; 田中 紀子 地方独立行政法人東京都健康長寿医療センター(東京都健康長寿医療センター研究所), 東京都健康長寿医療センター研究所, 専門副部長 (10376460)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: リポタンパク / 悪性腫瘍 / アポリポプロテイン(a) / 遺伝子関連解析 / 分子疫学研究 / リポタンパク質 / リポプロテイン(a) / 病理学 / 疫学 / ゲノム / 癌 / 脂質

Outline of Final Research Achievements

Hyperliproteinemia (a) is a strong cardiovascular risk factor. We have already reported significant associations between hypolipoproteinemia (a) and malignant neoplasms. LPA, a gene coding apolipoprotein (a), has a large repeated structures called Kringle, and LPA genotypes determine over 90% of the plasma Lp(a) level. We hypothesized the genetic variations of LPA might be associated with malignant neoplasms, and performed the genetic association study using the data of JPHC cohort. The subjects comprised of 9,926 cases and we analyzed the incidence of all and site-specific malignant neoplasms. We used 103 SNPs located in LPA and surrounding area. The number of incidence of malignant neoplasms and all-cause-death was 1,093 and 1,090 cases, respectively. We could identify weak associations between several SNPs and the incidence of all cancer and some site-specific cancers.

Academic Significance and Societal Importance of the Research Achievements

心血管危険因子である高Lp(a)血症に対して最近LPAアンチセンス薬が開発され、心血管イベントの減少が検討されている。我々はJMSコホートを用いて低Lp(a)血症と悪性腫瘍の関連を世界で初めて報告した。その後Lp(a)と悪性腫瘍の関連についていくつか報告がされているが結果は一定していない。Lp(a)値がLPA遺伝子変異と強く関連することから本研究を行い、いくつかのSNPで悪性腫瘍罹患との間に弱い関連が得られた。アンチセンス薬によりLp(a)値が低下すると心血管イベントが減少するが悪性腫瘍が増加する可能性もある。今後も低Lp(a)血症と悪性腫瘍の関連について検討していく必要がある。

Research Products

• [Journal Article] Analysis of urinary sphingolipids using liquid chromatography-tandem mass spectrometry in diabetic nephropathy. (2020)
  • Author(s): Morita Y, Kurano M, Sakai E, Nishikawa T, Nishikawa M, Sawabe M, Aoki J, Yatomi Y.
  • Journal Title: J Diabetes Investig Volume: 11 Issue: 2 Pages: 441-449
  • DOI: 10.1111/jdi.13154
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of Lysophospholipid Measurement in Cerebrospinal Fluid Samples using Liquid Chromatography-Tandem Mass Spectrometry. (2019)
  • Author(s): Morita Y, Kurano M, Sakai E, Nishikawa M, Sawabe M, Aoki J, Yatomi Y.
  • Journal Title: Lipids. Volume: 54 Issue: 8 Pages: 487-500
  • DOI: 10.1002/lipd.12175
  • Peer Reviewed / Open Access
• [Journal Article] Age-associated proteomic alterations in human aortic media (2019)
  • Author(s): Miura Y., Tsumoto H., Iwamoto M., Yamaguchi Y., Ko P., Soejima Y., Yoshida S., Toda T., Arai T., Hamamatsu A., Endo T., Sawabe M.
  • Journal Title: Geriatr Gerontol Int Volume: 19 Issue: 10 Pages: 1054-1062
  • DOI: 10.1111/ggi.13757
  • Peer Reviewed / Open Access
• [Journal Article] MRTF-A regulates proliferation and survival properties of pro-atherogenic macrophages (2019)
  • Author(s): An J, Naruse K T, Hinohara K, Soejima Y, Sawabe M, Nakagawa Y, Kuwahara K, Kimura A.
  • Journal Title: Journal of Molecular and cellular cardiology Volume: 133 Pages: 26-35
  • DOI: 10.1016/j.yjmcc.2019.05.015
  • NAID: 130007811832
  • Peer Reviewed / Open Access
• [Journal Article] The stem cell-specific intermediate filament nestin missense variation p.A1199P is associated with pancreatic cancer (2019)
  • Author(s): Matsuda Yoko、Tanaka Masashi、Sawabe Motoji、Mori Seijiro、Muramatsu Masaaki、Naka Mieno Makiko、Ishiwata Toshiyuki、Arai Tomio
  • Journal Title: Oncology Letters Volume: 17 Pages: 4647-54
  • DOI: 10.3892/ol.2019.10106
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] P-Selectin Glycoprotein Ligand-1 (PSGL-1) Expressing CD4 T Cells Contribute Plaque Instability in Acute Coronary Syndrome (2018)
  • Author(s): Kitamura Kazutaka、Sato Kayoko、Sawabe Motoji、Yoshida Masayuki、Hagiwara Nobuhisa
  • Journal Title: Circulation Journal Volume: 82 Issue: 8 Pages: 2128-2135
  • DOI: 10.1253/circj.CJ-17-1270
  • NAID: 130007418858
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2018-07-25
  • Peer Reviewed / Open Access
• [Journal Article] Identification of novel hyper- or hypomethylated CpG sites and genes associated with atherosclerotic plaque using an epigenome-wide association study (2018)
  • Author(s): Yamada Yoshiji、Horibe Hideki、Oguri Mitsutoshi、Sakuma Jun、Takeuchi Ichiro、Yasukochi Yoshiki、Kato Kimihiko、Sawabe Motoji
  • Journal Title: International Journal of Molecular Medicine Volume: 41 Pages: 2724-32
  • DOI: 10.3892/ijmm.2018.3453
  • NAID: 120007133931
  • Peer Reviewed / Open Access
• [Journal Article] Inverse Association Between Height-Increasing Alleles and Extreme Longevity in Japanese Women. (2018)
  • Author(s): Tanisawa K, Hirose N, Arai Y, Shimokata H, Yamada Y, Kawai H, Kojima M, Obuchi S, Hirano H, Suzuki H, Fujiwara Y, Taniguchi Y, Shinkai S, Ihara K, Sugaya M, Higuchi M, Arai T, Mori S, Sawabe M, Sato N, Muramatsu M, Tanaka M.
  • Journal Title: J Gerontol A Biol Sci Med Sci Volume: 73(5) Issue: 5 Pages: 588-595
  • DOI: 10.1093/gerona/glx155
  • Peer Reviewed / Open Access
• [Journal Article] Identification of five genetic variants as novel determinants of type 2 diabetes mellitus in Japanese by exome-wide association studies (2017)
  • Author(s): Yamada Yoshiji、Sakuma Jun、Takeuchi Ichiro、Yasukochi Yoshiki、Kato Kimihiko、Oguri Mitsutoshi、Fujimaki Tetsuo、Horibe Hideki、Muramatsu Masaaki、Sawabe Motoji、Fujiwara Yoshinori、Taniguchi Yu、Obuchi Shuichi、Kawai Hisashi、Shinkai Shoji、Mori Seijiro、Arai Tomio、Tanaka Masashi
  • Journal Title: Oncotarget Volume: 8 Issue: 46 Pages: 80492-80505
  • DOI: 10.18632/oncotarget.19287
  • NAID: 120007134713
  • Peer Reviewed / Open Access
• [Journal Article] Identification of STXBP2 as a novel susceptibility locus for myocardial infarction in Japanese individuals by an exome-wide association study (2017)
  • Author(s): Yoshiji Yamada, Jun Sakuma, Ichiro Takeuchi, Yoshiki Yasukochi, Kimihiko Kato, Mitsutoshi Oguri, Tetsuo Fujimaki, Hideki Horibe, Masaaki Muramatsu, Motoji Sawabe, Yoshinori Fujiwara, Yu Taniguchi, Shuichi Obuchi, Hisashi Kawai, Shoji Shinkai, Seijiro Mori, Tomio Arai, Masashi Tanaka
  • Journal Title: Oncotarget Volume: 印刷中 Issue: 20 Pages: 33527-33535
  • DOI: 10.18632/oncotarget.16536
  • NAID: 120007129044
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Identification of C21orf59 and ATG2A as novel determinants of renal function-related traits in Japanese individuals by exome-wide association studies (2017)
  • Author(s): Yoshiji Yamada, Jun Sakuma, Ichiro Takeuchi, Yoshiki Yasukochi, Kimihiko Kato, Mitsutoshi Oguri, Tetsuo Fujimaki, Hideki Horibe, Masaaki Muramatsu, Motoji Sawabe, Yoshinori Fujiwara, Yu Taniguchi, Shuichi Obuchi, Hisashi Kawai, Shoji Shinkai, Seijiro Mori, Tomio Arai, Masashi Tanaka
  • Journal Title: Oncotarget Volume: 印刷中 Issue: 28 Pages: 45259-45273
  • DOI: 10.18632/oncotarget.16696
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Identification of rs7350481 at chromosome 11q23.3 as a novel susceptibility locus for metabolic syndrome in Japanese individuals by an exome-wide association study (2017)
  • Author(s): Yoshiji Yamada, Jun Sakuma, Ichiro Takeuchi, Yoshiki Yasukochi, Kimihiko Kato, Mitsutoshi Oguri, Tetsuo Fujimaki, Hideki Horibe, Masaaki Muramatsu, Motoji Sawabe, Yoshinori Fujiwara, Yu Taniguchi, Shuichi Obuchi, Hisashi Kawai, Shoji Shinkai, Seijiro Mori, Tomio Arai, Masashi Tanaka
  • Journal Title: Oncotarget Volume: 印刷中 Issue: 24 Pages: 39296-39308
  • DOI: 10.18632/oncotarget.16945
  • NAID: 120007128952
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Identification of eight genetic variants as novel determinants of dyslipidemia in Japanese by exome-wide association studies (2017)
  • Author(s): Yoshiji Yamada, Jun Sakuma, Ichiro Takeuchi, Yoshiki Yasukochi, Kimihiko Kato, Mitsutoshi Oguri, Tetsuo Fujimaki, Hideki Horibe, Masaaki Muramatsu, Motoji Sawabe, Yoshinori Fujiwara, Yu Taniguchi, Shuichi Obuchi, Hisashi Kawai, Shoji Shinkai, Seijiro Mori, Tomio Arai, Masashi Tanaka
  • Journal Title: Oncotarget Volume: 印刷中 Issue: 24 Pages: 38950-38961
  • DOI: 10.18632/oncotarget.17159
  • NAID: 120007128954
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Identification of six polymorphisms as novel susceptibility loci for ischemic or hemorrhagic stroke by exome-wide association studies (2017)
  • Author(s): Yoshiji Yamada, Jun Sakuma, Ichiro Takeuchi, Yoshiki Yasukochi, Kimihiko Kato, Mitsutoshi Oguri, Tetsuo Fujimaki, Hideki Horibe, Masaaki Muramatsu, Motoji Sawabe, Yoshinori Fujiwara, Yu Taniguchi, Shuichi Obuchi, Hisashi Kawai, Shoji Shinkai, Seijiro Mori, Tomio Arai, Masashi Tanaka
  • Journal Title: Int J Mol Med Volume: 39 Issue: 6 Pages: 1477-1491
  • DOI: 10.3892/ijmm.2017.2972
  • NAID: 120007129063
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Identification of polymorphisms in 12q24.1, <i>ACAD10</i>, and <i>BRAP</i> as novel genetic determinants of blood pressure in Japanese by exome-wide association studies (2017)
  • Author(s): Yamada Yoshiji、Sakuma Jun、Takeuchi Ichiro、Yasukochi Yoshiki、Kato Kimihiko、Oguri Mitsutoshi、Fujimaki Tetsuo、Horibe Hideki、Muramatsu Masaaki、Sawabe Motoji、Fujiwara Yoshinori、Taniguchi Yu、Obuchi Shuichi、Kawai Hisashi、Shinkai Shoji、Mori Seijiro、Arai Tomio、Tanaka Masashi
  • Journal Title: Oncotarget Volume: 8 Issue: 26 Pages: 43068-43079
  • DOI: 10.18632/oncotarget.17474
  • NAID: 120007128873
  • Peer Reviewed / Open Access
• [Journal Article] Identification of EGFLAM, SPATC1L, and RNASE13 as novel susceptibility loci for aortic aneurysm in Japanese individuals by exome-wide association studies (2017)
  • Author(s): Yoshiji Yamada, Jun Sakuma, Ichiro Takeuchi, Yoshiki Yasukochi, Kimihiko Kato, Mitsutoshi Oguri, Tetsuo Fujimaki, Hideki Horibe, Masaaki Muramatsu, Motoji Sawabe, Yoshinori Fujiwara, Yu Taniguchi, Shuichi Obuchi, Hisashi Kawai, Shoji Shinkai, Seijiro Mori, Tomio Arai, Masashi Tanaka
  • Journal Title: Int J Mol Med Volume: 39 Issue: 5 Pages: 1091-1100
  • DOI: 10.3892/ijmm.2017.2927
  • NAID: 120007129065
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Identification of TNFSF13, SPATC1L, SLC22A25 and SALL4 as novel susceptibility loci for atrial fibrillation by an exome-wide association study (2017)
  • Author(s): Yamada Yoshiji、Sakuma Jun、Takeuchi Ichiro、Yasukochi Yoshiki、Kato Kimihiko、Oguri Mitsutoshi、Fujimaki Tetsuo、Horibe Hideki、Muramatsu Masaaki、Sawabe Motoji、Fujiwara Yoshinori、Taniguchi Yu、Obuchi Shuichi、Kawai Hisashi、Shinkai Shoji、Mori Seijiro、Arai Tomio、Tanaka Masashi
  • Journal Title: Molecular Medicine Reports Volume: 16 Issue: 5 Pages: 5823-5832
  • DOI: 10.3892/mmr.2017.7334
  • NAID: 120007128795
  • Peer Reviewed / Open Access
• [Journal Article] Association of ZFHX3 gene variation with atrial fibrillation, cerebral infarction, and lung thromboembolism: An autopsy study. (2016)
  • Author(s): Zaw KT, Sato N, Ikeda S, Thu KS, Mieno MN, Arai T, Mori S, Furukawa T, Sasano T, Sawabe M, Tanaka M, Muramatsu M.
  • Journal Title: J Cardiol Volume: S0914-5087 Issue: 2 Pages: 30290-30298
  • DOI: 10.1016/j.jjcc.2016.11.005
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Exome-wide Association Study Identifies CLEC3B Missense Variant p.S106G as Being Associated with Extreme Longevity in East Asian Populations (2016)
  • Author(s): Kumpei Tanisawa, Masashi Tanaka, et al.
  • Journal Title: J Gerontol A Biol Sci Med Sci Volume: 00 Pages: 1-10
  • DOI: 10.1093/gerona/glw074
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] ヒト大動脈老化のプロテオミクス解析：アクチン関連タンパク質の変動および抗酸化タンパク質の増加 (2020)
  • Author(s): 沢辺元司, 三浦ゆり, 津元裕樹, 岩本真知子, 副島友莉恵, 吉田祥子, 戸田年総) 、新井冨生, 濱松晶彦, 遠藤玉夫
  • Organizer: 第109回日本病理学会総会
  • Invited
• [Presentation] 左室駆出率が保たれた心不全のヒト心筋プロテオーム解析 (2019)
  • Author(s): 佐藤 瑞穂, 津元 裕樹, 鳥羽 梓弓, 梅澤 啓太郎, 川上 恭司郎, 副島 友莉恵, 新井 冨生, 原田 和昌, 三浦 ゆり, 沢辺 元司
  • Organizer: 日本プロテオーム学会2019年大会
• [Presentation] 胆道上皮内腫瘍におけるα6β4, αvβ6インテグリンの発現 (2019)
  • Author(s): 副島 友莉恵, 高槻 祐菜, 中嶋 裕, 今田 安津子, 明石 巧, 小林 正典, 田邉 稔, 沢辺 元司, 福里 利夫
  • Organizer: 第108回日本病理学会総会
• [Presentation] ヒト悪性腫瘍におけるapolipopoprotein(a)の免疫組織化学的検討 (2018)
  • Author(s): 沢辺元司、副島友莉恵、明石 巧
  • Organizer: 第107回日本病理学会総会