縦断的エクソン全領域関連解析による生活習慣病の個別化予防システムの開発

2015 Fiscal Year Annual Research Report

• Project/Area Number: 15H04772
• Research Institution: Mie University
• Principal Investigator: 山田 芳司 三重大学, 生命科学研究支援センター, 教授 (90333286)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: エクソン全領域関連解析 / 個別化予防 / 高血圧 / 2型糖尿病 / 脂質異常症 / 慢性腎臓病 / 肥満 / メタボリックシンドローム

Outline of Annual Research Achievements

本研究の目的は、一般住民6048名においてエクソームアレイを用いた縦断的エクソン全領域関連解析を行なうことにより6種類の生活習慣病（高血圧・2型糖尿病・脂質異常症・慢性腎臓病・肥満・メタボリックシンドローム）の発症に関連する「効果の大きい新規の機能的一塩基多型群（SNPs）」を同定することにある。これらのSNPs情報に加え、年齢、性別、臨床情報、生活習慣（食事・運動・喫煙・飲酒・ストレスなど）情報を加えた個別化予防システムを開発することにより、中高年者の健康維持・健康長寿・生活の質の向上・ねたきり防止に貢献することが本研究の最終目標である。
平成27年度は、高血圧、2型糖尿病、脂質異常症（高中性脂肪血症・低HDLコレステロール血症・高LDLコレステロール血症）、慢性腎臓病、肥満、メタボリックシンドームについて、いなべ健康長寿研究の縦断的疫学データベースの整備を行った。また、ゲノムDNA 4526検体について、エクソームアレイ（HumanExome-12 v1.2 DNA Analysis BeadChip、イルミナ社）およびマイクロアレイスキャナー（iScan、イルミナ社）を用いてInfinium genotyping法によりSNPs解析を行なった。得られたSNPsデータについては厳密なクオリティーコントロールを以下の手順で行った。（i）Genotypeデータのcall rateを算出し、call rate < 97%のサンプルは除外した。（ii）Gender specificationをチェックし、不一致のサンプルを除外した。（iii）Cryptic relatednessをチェックし、identity by descent > 0.185のペアは一方のサンプルを除外した。（iv）Heterozygosityを算出し、mean ± 3SDからはずれたサンプルを除外した。

Current Status of Research Progress

1: Research has progressed more than it was originally planned.

Reason

エクソームアレイによるDNAサンプルの解析は、予定より約1500検体多く解析した。さらに解析したデータについても、call rateが99.9%とクオリティーが高く、除外データが極めて少なかった。縦断的疫学データの整備も完了した。研究計画としては、6ヶ月程度前倒しで進んでいる。

Strategy for Future Research Activity

残りの1522検体についてエクソームアレイを用いた解析を行い、平成27年度に解析した4526検体と合わせて合計6048検体のエクソームアレイ解析を完了する。 平成28年度後半以降は、得られたSNPsデータおよび背景・臨床情報を用いて、6種類の生活習慣病についてエクソン全領域関連解析を行ない、それぞれの生活習慣病の発症に強く関連する遺伝子およびSNPsを同定する。さらに、これらのSNPs情報に加え、年齢、性別、臨床情報、生活習慣（食事・運動・喫煙・飲酒・ストレスなど）情報を加えた個別化予防システムを開発する。

Research Products

• [Journal Article] Association of genetic variants with atrial fibrillation (2016)
  • Author(s): Yuichiro Yamase, Kimihiko Kato, Hideki Horibe, Chikara Ueyama, Tetsuo Fujimaki, Mitsutoshi Oguri, Masazumi Arai, Sachiro Watanabe, Toyoaki Murohara, Yoshiji Yamada
  • Journal Title: Biomed Rep Volume: 4 Pages: 178-182
  • DOI: 10.3892/br.2015.551
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Association of a transcription factor 21 gene polymorphism with hypertension (2015)
  • Author(s): Tetsuo Fujimaki, Mitsutoshi Oguri, Hideki Horibe, Kimihiko Kato, Reiko Matsuoka, Shintaro Abe, Fumitaka Tokoro, Masazumi Arai, Toshiyuki Noda, Sachiro Watanabe, Yoshiji Yamada
  • Journal Title: Biomed Rep Volume: 3 Pages: 118-122
  • DOI: 10.3892/br.2014.371
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Association of a genetic variant of the ZPR1 zinc finger gene with type 2 diabetes mellitus (2015)
  • Author(s): Fumitaka Tokoro, Reiko Matsuoka, Shintaro Abe, Masazumi Arai, Toshiyuki Noda, Sachiro Watanabe, Hideki Horibe, Tetsuo Fujimaki, Mitsutoshi Oguri, Kimihiko Kato, Shinya Minatoguchi, Yoshiji Yamada
  • Journal Title: Biomed Rep Volume: 3 Pages: 88-92
  • DOI: 10.3892/br.2014.379
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Association of six genetic variants with myocardial infarction (2015)
  • Author(s): Reiko Matsuoka, Shintaro Abe, Fumitaka Tokoro, Masazumi Arai, Toshiyuki Noda, Sachiro Watanabe, Hideki Horibe, Tetsuo Fujimaki, Mitsutoshi Oguri, Kimihiko Kato, Shinya Minatoguchi, Yoshiji Yamada
  • Journal Title: Int J Mol Med Volume: 35 Pages: 1451-1459
  • DOI: 10.3892/ijmm.2015.2115
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Association of genetic variants with dyslipidemia (2015)
  • Author(s): Shintaro Abe, Fumitaka Tokoro, Reiko Matsuoka, Masazumi Arai, Toshiyuki Noda, Sachiro Watanabe, Hideki Horibe, Tetsuo Fujimaki, Mitsutoshi Oguri, Kimihiko Kato, Shinya Minatoguchi, Yoshiji Yamada
  • Journal Title: Mol Med Rep Volume: 12 Pages: 5429-5436
  • DOI: 10.3892/mmr.2015.4081
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Association of a polymorphism of the interleukin 6 receptor gene with chronic kidney disease in Japanese individuals (2015)
  • Author(s): Hideki Horibe, Tetsuo Fujimaki, Mitsutoshi Oguri, Kimihiko Kato, Reiko Matsuoka, Shintaro Abe, Fumitaka Tokoro, Masazumi Arai, Toshiyuki Noda, Sachiro Watanabe, Yoshiji Yamada
  • Journal Title: Nephrology Volume: 20 Pages: 273-278
  • DOI: 10.1111/nep.12381
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Association of genetic variants with hypertension in a longitudinal population-based genetic epidemiological study (2015)
  • Author(s): Yoshiji Yamada, Kota Matsui, Ichiro Takeuchi, Mitsutoshi Oguri, Tetsuo Fujimaki
  • Journal Title: Int J Mol Med Volume: 35 Pages: 1189-1198
  • DOI: 10.3892/ijmm.2015.2151
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Association of genetic variants of the alpha-kinase 1 gene with type 2 diabetes mellitus in a longitudinal population-based genetic epidemiological study (2015)
  • Author(s): Yoshiji Yamada, Kota Matsui, Ichiro Takeuchi, Mitsutoshi Oguri, Tetsuo Fujimaki
  • Journal Title: Biomed Rep Volume: 3 Pages: 347-354
  • DOI: 0.3892/br.2015.439
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Association of genetic variants with coronary artery disease and ischemic stroke in a longitudinal population-based genetic epidemiological study (2015)
  • Author(s): Yoshiji Yamada, Kota Matsui, Ichiro Takeuchi, Tetsuo Fujimaki
  • Journal Title: Biomed Rep Volume: 3 Pages: 413-419
  • DOI: 10.3892/br.2015.440
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Association of genetic variants with dyslipidemia and chronic kidney disease in a longitudinal population-based genetic epidemiological study (2015)
  • Author(s): Yoshiji Yamada, Kota Matsui, Ichiro Takeuchi, Tetsuo Fujimaki
  • Journal Title: Int J Mol Med Volume: 35 Pages: 1290-1300
  • DOI: 10.3892/ijmm.2015.2152
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Association of polymorphisms of TOMM40 and SLC22A4 with ischemic stroke (2015)
  • Author(s): Yuichiro Yamase, Hideki Horibe, Chikara Ueyama, Tetsuo Fujimaki, Mitsutoshi Oguri, Kimihiko Kato, Masazumi Arai, Sachiro Watanabe, Yoshiji Yamada
  • Journal Title: Biomed Rep Volume: 3 Pages: 491-498
  • DOI: 10.3892/br.2015.457
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Association of polymorphisms of FURIN and ZPR1 with metabolic syndrome (2015)
  • Author(s): Chikara Ueyama, Hideki Horibe, Yuichiro Yamase, Tetsuo Fujimaki, Mitsutoshi Oguri, Kimihiko Kato, Masazumi Arai, Sachiro Watanabe, Toyoaki Murohara, Yoshiji Yamada
  • Journal Title: Biomed Rep Volume: 3 Pages: 641-647
  • DOI: 10.3892/br.2015.484
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Age-related changes in clinical parameters and their relations to common complex diseases (2015)
  • Author(s): Yoshiko Murakata, Tetsuo Fujimaki, Yoshiji Yamada
  • Journal Title: Biomed Rep Volume: 3 Pages: 767-777
  • DOI: 10.3892/br.2015.505
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Privacy-preserving genome-wide association studies on cloud environment using fully homomorphic encryption (2015)
  • Author(s): Wen-jie Lu, Yoshiji Yamada, Jun Sakuma
  • Journal Title: BMC Med Inform Decis Mak Volume: 15(Suppl 5) Pages: S1
  • DOI: 10.1186/1472-6947-15-S5-S1
  • Peer Reviewed / Open Access
• [Journal Article] Molecular genetics of coronary artery disease and ischemic stroke (2015)
  • Author(s): Yoshiji Yamada
  • Journal Title: Personalized Medicine Universe Volume: 4 Pages: 4-12
  • DOI: 10.1016/j.pmu.2015.03.002
  • Peer Reviewed
• [Journal Article] 生活習慣が肥満・高血圧・2型糖尿病・脂質異常症に及ぼす影響：いなべ健康長寿研究のアンケート調査による検討 (2015)
  • Author(s): 村方好子、藤巻哲夫、山田芳司
  • Journal Title: 臨床と研究 Volume: 92 Pages: 615-624
  • Peer Reviewed
• [Presentation] Association of genetic variants of the alpha-kinase 1 gene with type 2 diabetes mellitus in a longitudinal population-based genetic epidemiological study (2016)
  • Author(s): Mitsutoshi Oguri, Tetsuo Fujimaki, Hideki Horibe, Kimihiko Kato, Toyoaki Murohara, Yoshiji Yamada
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際センター（宮城県・仙台市）
  • Year and Date: 2016-03-18 – 2016-03-20
• [Presentation] Association of body mass index with clinical parameters and conditions in a longitudinal population-based epidemiological study (2016)
  • Author(s): Mitsutoshi Oguri, Tetsuo Fujimaki, Hideki Horibe, Kimihiko Kato, Toyoaki Murohara, Yoshiji Yamada
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際センター（宮城県・仙台市）
  • Year and Date: 2016-03-18 – 2016-03-20
• [Presentation] Association of renal function with clinical parameters and conditions in a longitudinal population-based epidemiological study (2016)
  • Author(s): Takuya Sumi, Mitsutoshi Oguri, Tetsuo Fujimaki, Hideki Horibe, Kimihiko Kato, Toyoaki Murohara, Yoshiji Yamada
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際センター（宮城県・仙台市）
  • Year and Date: 2016-03-18 – 2016-03-20
• [Presentation] Association of genetic variants with hypertension in a longitudinal population-based genetic epidemiological study (2016)
  • Author(s): Takuya Sumi, Mitsutoshi Oguri, Tetsuo Fujimaki, Hideki Horibe, Kimihiko Kato, Toyoaki Murohara, Yoshiji Yamada
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際センター（宮城県・仙台市）
  • Year and Date: 2016-03-18 – 2016-03-20
• [Presentation] Association of genetic variants with dyslipidemia and chronic kidney disease in a longitudinal population-based genetic epidemiological study (2016)
  • Author(s): Tetsuo Fujimaki, Mitsutoshi Oguri, Hideki Horibe, Kimihiko Kato, Nobuyuki Ohte, Yoshiji Yamada
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際センター（宮城県・仙台市）
  • Year and Date: 2016-03-18 – 2016-03-20
• [Presentation] Association of genetic variants with coronary artery disease and ischemic stroke in a longitudinal population-based genetic epidemiological study (2016)
  • Author(s): Tetsuo Fujimaki, Mitsutoshi Oguri, Hideki Horibe, Kimihiko Kato, Nobuyuki Ohte, Yoshiji Yamada
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際センター（宮城県・仙台市）
  • Year and Date: 2016-03-18 – 2016-03-20
• [Presentation] The association of serum uric acid level with the prevalence of atrial fibrillation in Japanese individuals (2016)
  • Author(s): Yuichiro Yamase, Chikara Ueyama, Hideki Horibe, Tetsuo Fujimaki, Mitsutoshi Oguri, Kimihiko Kato, Toyoaki Murohara, Yoshiji Yamada
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際センター（宮城県・仙台市）
  • Year and Date: 2016-03-18 – 2016-03-20
• [Presentation] Association of genetic variants with atrial fibrillation in Japanese individuals (2015)
  • Author(s): Kimihiko Kato, Tetsuo Fujimaki, Mitsutoshi Oguri, Hideki Horibe, Masazumi Arai, Toshiyuki Noda, Sachiro Watanabe, Toyoaki Murohara, Yoshiji Yamada
  • Organizer: European Society of Cardiology Congress 2015
  • Place of Presentation: London, United Kingdom
  • Year and Date: 2015-08-29 – 2015-09-02
  • Int'l Joint Research
• [Presentation] Association of polymorphisms of FURIN and ZPR1 with metabolic syndrome in Japanese individuals (2015)
  • Author(s): Hideki Horibe, Chikara Ueyama, Yuichiro Yamase, Tetsuo Fujimaki, Mitsutoshi Oguri, Kimihiko Kato, Masazumi Arai, Sachiro Watanabe, Toyoaki Murohara, Yoshiji Yamada
  • Organizer: European Society of Cardiology Congress 2015
  • Place of Presentation: London, United Kingdom
  • Year and Date: 2015-08-29 – 2015-09-02
  • Int'l Joint Research
• [Presentation] Association of polymorphisms of TOMM40 and SLC22A4 with ischemic stroke (2015)
  • Author(s): Hideki Horibe, Yuichiro Yamase, Chikara Ueyama, Tetsuo Fujimaki, Mitsutoshi Oguri, Kimihiko Kato, Masazumi Arai, Sachiro Watanabe, Toyoaki Murohara, Yoshiji Yamada
  • Organizer: European Society of Cardiology Congress 2015
  • Place of Presentation: London, United Kingdom
  • Year and Date: 2015-08-29 – 2015-09-02
  • Int'l Joint Research
• [Presentation] Association of genetic variants of the alpha-kinase 1 gene with type 2 diabetes mellitus in a longitudinal population-based genetic epidemiological study (2015)
  • Author(s): Mitsutoshi Oguri, Tetsuo Fujimaki, Hideki Horibe, Kimihiko Kato, Toyoaki Murohara, Kota Matsui, Ichiro Takeuchi, Yoshiji Yamada
  • Organizer: European Society of Cardiology Congress 2015
  • Place of Presentation: London, United Kingdom
  • Year and Date: 2015-08-29 – 2015-09-02
  • Int'l Joint Research
• [Presentation] Association of genetic variants with atrial fibrillation in Japanese individuals (2015)
  • Author(s): Kimihiko Kato, Tetsuo Fujimaki, Tetsuro Yoshida, Mitsutoshi Oguri, Takeshi Hibino, Hideki Horibe, Kiyoshi Yokoi, Toyoaki Murohara, Yoshiji Yamada
  • Organizer: 第79回日本循環器学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府・大阪市）
  • Year and Date: 2015-04-24 – 2015-04-26
• [Presentation] Association of a polymorphism of the butyrophilin, subfamily 2, member A1 gene (BTN2A1) with hypertension in community-dwelling individuals (2015)
  • Author(s): Tetsuo Fujimaki, Yoshiji Yamada
  • Organizer: 第79回日本循環器学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府・大阪市）
  • Year and Date: 2015-04-24 – 2015-04-26
• [Presentation] Association of a polymorphism of the transcription factor 21 gene (TCF21) with hypertension in Japanese individuals (2015)
  • Author(s): Tetsuo Fujimaki, Mitsutoshi Oguri, Hideki Horibe, Kimihiko Kato, Reiko Matsuoka, Shintaro Abe, Fumitaka Tokoro, Masazumi Arai, Toshiyuki Noda, Sachiro Watanabe, Yoshiji Yamada
  • Organizer: 第79回日本循環器学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府・大阪市）
  • Year and Date: 2015-04-24 – 2015-04-26
• [Presentation] Association of six genetic variants with myocardial infarction in Japanese individuals (2015)
  • Author(s): Reiko Matsuoka, Shintaro Abe, Fumitaka Tokoro, Masazumi Arai, Toshiyuki Noda, Sachiro Watanabe, Tetsuo Fujimaki, Mitsutoshi Oguri, Kimihiko Kato, Yoshiji Yamada
  • Organizer: 第79回日本循環器学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府・大阪市）
  • Year and Date: 2015-04-24 – 2015-04-26
• [Presentation] Clinical significance of a polymorphism of CDKN2B-AS1 in the pathogenetic factors triggering myocardial infarction (2015)
  • Author(s): Reiko Matsuoka, Shintaro Abe, Fumitaka Tokoro, Masazumi Arai, Toshiyuki Noda, Sachiro Watanabe, Tetsuo Fujimaki, Mitsutoshi Oguri, Kimihiko Kato, Yoshiji Yamada
  • Organizer: 第79回日本循環器学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府・大阪市）
  • Year and Date: 2015-04-24 – 2015-04-26
• [Presentation] Association of a polymorphism of the zinc finger protein 259 gene (ZNF259) with dislipidemia in Japanese individuals (2015)
  • Author(s): Shintaro Abe, Fumitaka Tokoro, Reiko Matsuoka, Masazumi Arai, Toshiyuki Noda, Sachiro Watanabe, Tetsuo Fujimaki, Mitsutoshi Oguri, Kimihiko Kato, Yoshiji Yamada
  • Organizer: 第79回日本循環器学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府・大阪市）
  • Year and Date: 2015-04-24 – 2015-04-26
• [Presentation] Association of a polymorphism of IL6R with chronic kidney disease in Japanese individuals (2015)
  • Author(s): Hideki Horibe, Chikara Ueyama, Yuichiro Yamase, Kiyoshi Yokoi, Tetsuo Fujimaki, Mitsutoshi Oguri, Kimihiko Kato, Reiko Matsuoka, Shintaro Abe, Fumitaka Tokoro, Masazumi Arai, Toshiyuki Noda, Sachiro Watanabe, Yoshiji Yamada
  • Organizer: 第79回日本循環器学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府・大阪市）
  • Year and Date: 2015-04-24 – 2015-04-26
• [Presentation] Association of polymorphisms of FURIN and ZPR1 with metabolic syndrome in Japanese individuals (2015)
  • Author(s): Chikara Ueyama, Hideki Horibe, Yuichiro Yamase, Kiyoshi Yokoi, Tetsuo Fujimaki, Mitsutoshi Oguri, Kimihiko Kato, Reiko Matsuoka, Shintaro Abe, Fumitaka Tokoro, Masazumi Arai, Toshiyuki Noda, Sachiro Watanabe, Yoshiji Yamada
  • Organizer: 第79回日本循環器学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府・大阪市）
  • Year and Date: 2015-04-24 – 2015-04-26
• [Presentation] Association of polymorphisms of TOMM40 and SLC22A4 with cerebral infarction (2015)
  • Author(s): Yuichiro Yamase, Hideki Horibe, Chikara Ueyama, Kiyoshi Yokoi, Tetsuo Fujimaki, Mitsutoshi Oguri, Kimihiko Kato, Reiko Matsuoka, Shintaro Abe, Fumitaka Tokoro, Masazumi Arai, Toshiyuki Noda, Sachiro Watanabe, Yoshiji Yamada
  • Organizer: 第79回日本循環器学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府・大阪市）
  • Year and Date: 2015-04-24 – 2015-04-26
• [Book] 新・血栓止血血管学―検査と診療 (2015)
  • Author(s): 山田芳司
  • Total Pages: 208
  • Publisher: 金芳堂
• [Book] Genomic Medicine: Priciple and Practice (2015)
  • Author(s): Yoshiji Yamada
  • Total Pages: 814
  • Publisher: Oxford University Press
• [Remarks] 三重大学生命科学研究支援センターヒト機能ゲノミクス部門
  • URL: http://www.lsrc.mie-u.ac.jp/human/
• [Remarks] 三重大学疾患ゲノム研究センター
  • URL: http://www.mie-u.ac.jp/research/intro/ct0002-00.html
• [Remarks] 三重大学医学系研究科基礎医学系講座遺伝子病態制御学
  • URL: http://www.medic.mie-u.ac.jp/organization/course/lsrc_human/index.php