Association between lifestyle and disease risk: Mendelian randomization studies in a genome cohort

• Project/Area Number: 19K10659
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 58030:Hygiene and public health-related: excluding laboratory approach
• Research Institution: Nagoya University
• Principal Investigator: Wakai Kenji 名古屋大学, 医学系研究科, 教授 (50270989)
• Co-Investigator(Kenkyū-buntansha): 松尾 恵太郎 愛知県がんセンター(研究所), がん予防研究分野, 分野長 (80393122)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 遺伝子多型 / ゲノムワイド関連解析 / 生活習慣 / がん / 媒介分析 / 野菜 / 果物 / コホート研究 / 膵臓がん / 飲酒 / 症例対照研究 / メンデルランダム化 / 肥満 / 食事 / 喫煙 / 横断研究

Outline of Research at the Start

生活習慣と病気の関係を調べることは、病気の予防のために重要ですが、生活習慣同士が絡み合っていたり、病気自体の影響で生活習慣が変わったりするために、研究が難しいという問題があります。そこで本研究では生活習慣が遺伝にも一部影響される（例：生まれつきお酒が飲めない人がいる）ことを利用し（「メンデルランダム化」という方法を用います）、全国で10万人以上が参加している一時点の調査および追跡調査により、生活習慣と病気との関係を検討します。

Outline of Final Research Achievements

In the investigation in the J-MICC Study, several loci related to vegetable or fruit consumption have been suggested. In addition, polymorphisms associated with BMI at middle age were different from those correlated with BMI at age 20.
In a case-control study with a mediation analysis in the Aichi Cancer Center, ALDH2 polymorphism showed both indirect effect (by affecting alcohol drinking habit) and direct one in the association between the genotype and the risk of pancreatic cancer. Indirect and direct effects were also found in the association of ADH1B polymorphism and the risk of esophageal cancer.

Academic Significance and Societal Importance of the Research Achievements

食事や肥満に影響を及ぼす遺伝的要因の解明に繋がるとともに、野菜・果物摂取と疾患との関連を検討する際に、これらの摂取に関連する遺伝子多型を用いることで、両者の関連をより明確にしうる可能性がある。
またALDH2遺伝子多型が膵臓がんリスクに及ぼす影響、およびADH1B遺伝子多型が食道がんリスクに及ぼす影響に、飲酒習慣への影響を介さない経路（直接効果）があることが示されたことは、飲酒が膵臓がんおよび食道がんのリスクを高めるメカニズムを解明する上で重要である。

Research Products

• [Journal Article] Mediation analysis unveils a carcinogenic effect of ADH1B rs1229984 through mechanisms other than change in drinking intensity: oesophageal cancer case-control study (2023)
  • Author(s): Sugimoto Yukihiro、Koyanagi Yuriko N、Kawakatsu Yukino、Oze Isao、Taniyama Yukari、Kasugai Yumiko、Tanaka Tsutomu、Abe Tetsuya、Tajika Masahiro、Shimizu Yasuhiro、Ito Hidemi、Wakai Kenji、Matsuo Keitaro
  • Journal Title: Japanese Journal of Clinical Oncology Volume: - Issue: 7 Pages: 581-588
  • DOI: 10.1093/jjco/hyad028
  • Peer Reviewed / Open Access
• [Journal Article] Assessing the Relationship Between High-sensitivity C-reactive Protein and Kidney Function Employing Mendelian Randomization in the Japanese Community-based J-MICC Study (2022)
  • Author(s): Fujii Ryosuke、Hishida Asahi、Nishiyama Takeshi、Matsuo Keitaro、Wakai Kenji et al.
  • Journal Title: Journal of Epidemiology Volume: 32 Issue: 11 Pages: 483-488
  • DOI: 10.2188/jea.JE20200540
  • NAID: 130007988449
  • ISSN: 0917-5040, 1349-9092
  • Year and Date: 2022-11-05
  • Peer Reviewed / Open Access
• [Journal Article] New insights into the genetic contribution of ALDH2 rs671 in pancreatic carcinogenesis: evaluation by mediation analysis (2022)
  • Author(s): Yuriko N. Koyanagi, Isao Oze, Yumiko Kasugai, Yukino Kawakatsu, Yukari Taniyama, Kazuo Hara, Yasuhiro Shimizu, Issei Imoto, Hidemi Ito, Keitaro Matsuo
  • Journal Title: Cancer Science Volume: 113 Issue: 4 Pages: 1441-1450
  • DOI: 10.1111/cas.15286
  • Peer Reviewed / Open Access
• [Journal Article] Association between germline pathogenic variants and breast cancer risk in Japanese women : the HERPACC study (2022)
  • Author(s): Kasugai Y, Kohmoto T, Taniyama Y, Koyanagi YN, Usui Y, Iwase M, Oze I, Yamaguchi R, Ito H, Imoto I, Matsuo K.
  • Journal Title: Cancer Sci Volume: 113 Issue: 4 Pages: 1451-1462
  • DOI: 10.1111/cas.15312
  • Peer Reviewed / Open Access
• [Journal Article] Differential Effect of Polymorphisms on Body Mass Index Across the Life Course of Japanese: The Japan Multi-Institutional Collaborative Cohort Study (2021)
  • Author(s): Iwase M, Matsuo K, Nakatochi M, Oze I, Ito H, Koyanagi Y, et al
  • Journal Title: Journal of Epidemiology Volume: 31 Issue: 3 Pages: 172-179
  • DOI: 10.2188/jea.JE20190296
  • NAID: 130007995132
  • ISSN: 0917-5040, 1349-9092
  • Year and Date: 2021-03-05
  • Peer Reviewed / Open Access
• [Journal Article] A genome-wide association study on meat consumption in a Japanese population : the Japan Multi-Institutional Collaborative Cohort study (2021)
  • Author(s): Nakamura Y, Narita A, Sutoh Y, et al.
  • Journal Title: J Nutr Sci Volume: 10 Pages: e61
  • DOI: 10.1017/jns.2021.49
  • NAID: 120007169590
  • URL: https://tokushima-u.repo.nii.ac.jp/records/2009810
  • Peer Reviewed / Open Access
• [Journal Article] Body mass index and colorectal cancer risk: A Mendelian randomization study (2021)
  • Author(s): Suzuki Shiori, Goto Atsushi, Nakatochi Masahiro, et al.
  • Journal Title: Cancer Science Volume: 112 Issue: 4 Pages: 1579-1588
  • DOI: 10.1111/cas.14824
  • NAID: 120007147665
  • Peer Reviewed / Open Access
• [Journal Article] Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus. (2020)
  • Author(s): Xianyong Yin, et al.
  • Journal Title: Ann Rheum Dis. Volume: 80(5) Issue: 5 Pages: 632-640
  • DOI: 10.1136/annrheumdis-2020-219209
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A genome-wide association study on fish consumption in a Japanese population?the Japan Multi-Institutional Collaborative Cohort study (2020)
  • Author(s): Suzuki Taro、for the J-MICC Research Group、Nakamura Yasuyuki、Matsuo Keitaro、Wakai Kenji et al.
  • Journal Title: European Journal of Clinical Nutrition Volume: 75 Issue: 3 Pages: 480-488
  • DOI: 10.1038/s41430-020-00702-7
  • Peer Reviewed / Open Access
• [Journal Article] European polygenic risk score for prediction of breast cancer shows similar performance in Asian women (2020)
  • Author(s): Ho Weang-Kee、Tan Min-Min、Mavaddat Nasim、Tai Mei-Chee、Matsuo Keitaro et al.
  • Journal Title: Nature Communications Volume: 11 Issue: 1
  • DOI: 10.1038/s41467-020-17680-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genome-wide association meta-analysis identifies GP2 gene risk variants for pancreatic cancer (2020)
  • Author(s): Lin Y, Nakatochi M, Hosono Y, Ito H, Kamatani Y, Inoko A, Sakamoto H, Kinoshita F, Kobayashi Y, Ishii H, Yamaji T,et al.
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 3175-3175
  • DOI: 10.1038/s41467-020-16711-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Subtype-specific gout susceptibility loci and enrichment of selection pressure on ABCG2 and ALDH2 identified by subtype genome-wide meta-analyses of clinically defined gout patients. (2020)
  • Author(s): Nakayama A, Takada T, et al.
  • Journal Title: Ann Rheum Dis. Volume: 79 Issue: 5 Pages: 657665-657665
  • DOI: 10.1136/annrheumdis-2019-216644
  • NAID: 120007042436
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A genome-wide association study in Japanese identified one variant associated with a preference for a Japanese dietary pattern (2020)
  • Author(s): Suzuki Harumitsu、Nakamura Yasuyuki、Matsuo Keitaro、Imaeda Nahomi、Goto Chiho、Wakai Kenji et al.
  • Journal Title: European Journal of Clinical Nutrition Volume: - Issue: 6 Pages: 937-945
  • DOI: 10.1038/s41430-020-00823-z
  • Peer Reviewed
• [Journal Article] Across-Site Differences in the Mechanism of Alcohol-Induced Digestive Tract Carcinogenesis: An Evaluation by Mediation Analysis (2020)
  • Author(s): Koyanagi Yuriko N.、Suzuki Etsuji、Imoto Issei、Kasugai Yumiko、Oze Isao、Ugai Tomotaka、Iwase Madoka、Usui Yoshiaki、Kawakatsu Yukino、Sawabe Michi、Hirayama Yutaka、Tanaka Tsutomu、Abe Tetsuya、Ito Seiji、Komori Koji、Hanai Nobuhiro、Tajika Masahiro、Shimizu Yasuhiro、Niwa Yasumasa、Ito Hidemi、Matsuo Keitaro
  • Journal Title: Cancer Research Volume: 80 Issue: 7 Pages: 1601-1610
  • DOI: 10.1158/0008-5472.can-19-2685
  • Peer Reviewed
• [Journal Article] Impact of PSCA polymorphisms on the risk of duodenal ulcer (2019)
  • Author(s): Usui Y, Matsuo K, Oze I, Ugai T, Koyanagi Y, Maeda Y, Ito H, Hishida A, Takeuchi K, Tamura T, Tsukamoto M, Kadomatsu Y, Hara M, Wakai K, et al
  • Journal Title: J Epidemiol Volume: 31 Issue: 1 Pages: 12-20
  • DOI: 10.2188/jea.je20190184
  • NAID: 130007965897
  • Description: in press
  • Peer Reviewed / Open Access
• [Journal Article] Cluster of differentiation 36 gene polymorphism (rs1761667) is associated with dietary MUFA intake and hypertension in a Japanese population (2019)
  • Author(s): Fujii Ryosuke、Hishida Asahi、Suzuki Koji、Imaeda Nahomi、Goto Chiho、Hamajima Nobuyuki、Wakai Kenji、Kondo Takaaki
  • Journal Title: British Journal of Nutrition Volume: 121 Issue: 11 Pages: 1215-1222
  • DOI: 10.1017/s0007114519000679
  • NAID: 120006765163
  • Peer Reviewed
• [Presentation] ADH1B rs1229984は飲酒強度の変化以外の機序でも食道がんリスクを上げる：媒介解析の結果 (2023)
  • Author(s): 小柳 友理子、杉本 幸弘、川勝 雪乃、尾瀬 功、谷山 祐 香里、春日井 由美子、伊藤 秀美、若井 建志、松尾 恵太郎
  • Organizer: 第33回 日本疫学会学術総会
• [Presentation] Dissecting carcinogenic effects of ALDH2 rs671: new insights from causal mediation analysis (2022)
  • Author(s): 小柳 友理子、尾瀬 功、春日井 由美子、川勝 雪乃、谷山 祐香里、井本 逸勢、伊藤 秀美、松尾 恵太郎
  • Organizer: 第81回 日本癌学会学術総会
  • Invited
• [Presentation] Introduction of mediation analysis utilizing genetic information (2020)
  • Author(s): Matsuo K
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] 魚摂取量に関連する遺伝子多型について：J-MICC Study (2020)
  • Author(s): 鈴木太朗、中村保幸、松尾恵太郎、尾瀬 功、土居幸雄、松井健志、門田 文、三浦克之、高嶋直敬、喜多義邦、若井建志、J-MICC Study Group
  • Organizer: 第30回 日本疫学会学術総会