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SNPs in BRAP associated with risk of myocardial infarction in Asian populations

Nature Genetics volume 41, pages 329–333 (2009)Cite this article

Abstract

Myocardial infarction is a common disease and among the leading causes of death in the world. We previously reported association of variants in LGALS2, encoding galectin-2, with myocardial infarction susceptibility in a case-control association study in a Japanese population1. Here we identify BRAP (BRCA1-associated protein) as a galectin-2–binding protein. We report an association of SNPs in BRAP with myocardial infarction risk in a large Japanese cohort (P = 3.0 × 10−18, OR = 1.48, 2,475 cases and 2,778 controls), with replication in additional Japanese and Taiwanese cohorts (P = 4.4 × 10−6, 862 cases and 1,113 controls and P = 4.7 × 10−3, 349 cases and 994 controls, respectively). BRAP expression was observed in smooth muscle cells (SMCs) and macrophages in human atherosclerotic lesions. BRAP knockdown by siRNA using cultured coronary endothelial cells suppressed activation of NF-κB, a central mediator of inflammation.

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Figure 1: Galectin-2 interacts with BRAP.
Figure 2: LD map of BRAP locus.
Figure 3: Colocalization of galectin-2 and BRAP in HCASMC and atherosclerotic lesion of coronary artery.
Figure 4: Functional analyses of the intron 3 SNP (rs11066001) of BRAP.

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References

  1. Ozaki, K. et al. Functional SNPs in the lymphotoxin-α gene that are associated with susceptibility to myocardial infarction. Nat. Genet. 32, 650–654 (2002).

    Article  CAS  Google Scholar 

  2. Ozaki, K. et al. Functional variation in LGALS2 confers risk of myocardial infarction and regulates lymphotoxin-alpha secretion in vitro. Nature 429, 72–75 (2004).

    Article  CAS  Google Scholar 

  3. PROCARDIS Consortium. A trio family study showing association of the lymphotoxin-alpha N26 (804A) allele with coronary artery disease. Eur. J. Hum. Genet. 12, 770–774 (2004).

  4. Clarke, R. et al. Lymphotoxin-alpha gene and risk of myocardial infarction in 6,928 cases and 2,712 controls in the ISIS case-control study. PLoS. Genet. 2, e107 (2006).

    Article  Google Scholar 

  5. Asselbergs, F.W. et al. Effects of lymphotoxin-alpha gene and galectin-2 gene polymorphisms on inflammatory biomarkers, cellular adhesion molecules and risk of coronary heart disease. Clin. Sci. 112, 291–298 (2007).

    Article  CAS  Google Scholar 

  6. Mangino, M. et al. LGALS2 functional variant rs7291467 is not associated with susceptibility to myocardial infarction in Caucasians. Atherosclerosis 194, 112–115 (2007).

    Article  CAS  Google Scholar 

  7. Rigaut, G. et al. A generic protein purification method for protein complex characterization and proteome exploration. Nat. Biotechnol. 17, 1030–1032 (1999).

    Article  CAS  Google Scholar 

  8. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Article  CAS  Google Scholar 

  9. Tregouet, D.A. & Garelle, V. A new JAVA interface implementation of THESIAS: testing haplotype effects in association studies. Bioinformatics 23, 1038–1039 (2007).

    Article  CAS  Google Scholar 

  10. International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).

  11. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  12. Cordell, H.J. & Clayton, D.G. A unified stepwise regression procedure for evaluating the relative effects of polymorphisms within a gene using case/control or family data: application to HLA in type 1 diabetes. Am. J. Hum. Genet. 70, 124–141 (2002).

    Article  CAS  Google Scholar 

  13. Ozaki, K. et al. A functional SNP in PSMA6 confers risk of myocardial infarction in the Japanese population. Nat. Genet. 38, 921–925 (2006).

    Article  CAS  Google Scholar 

  14. Heinemeyer, T. et al. Databases on transcriptional regulation: TRANSFAC, TRRD, and COMPEL. Nucleic Acids Res. 26, 362–367 (1998).

    Article  CAS  Google Scholar 

  15. Li, S. et al. Identification of a novel cytoplasmic protein that specifically binds to nuclear localization signal motifs. J. Biol. Chem. 273, 6183–6189 (1998).

    Article  CAS  Google Scholar 

  16. Matheny, S.A. et al. Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP. Nature 427, 256–260 (2004).

    Article  CAS  Google Scholar 

  17. Ory, S. & Morrison, D.K. Signal transduction: implications for Ras-dependent ERK signaling. Curr. Biol. 14, R277–R278 (2004).

    Article  CAS  Google Scholar 

  18. O'Neill, L.A. Targeting signal transduction as a strategy to treat inflammatory diseases. Nat. Rev. Drug Discov. 5, 549–563 (2006).

    Article  CAS  Google Scholar 

  19. Karin, M. & Delhase, M. The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling. Semin. Immunol. 12, 85–98 (2000).

    Article  CAS  Google Scholar 

  20. Breslow, J.L. Cardiovascular disease burden increases, NIH funding decreases. Nat. Med. 3, 600–601 (1997).

    Article  CAS  Google Scholar 

  21. Mizuno, H. et al. Impact of atherosclerosis-related gene polymorphisms on mortality and recurrent events after myocardial infarction. Atherosclerosis 185, 400–405 (2006).

    Article  CAS  Google Scholar 

  22. Andrews, N.C. & Faller, D.V. A rapid micropreparation teqhnique fore extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucleic Acids Res. 19, 2499 (1991).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Takahashi, M. Yoshii, S. Abiko, W. Yamanobe, R. Ohishi, M. Watabe and T. Furusho for their assistance. We also thank all the other members of Center for Genomic Medicine, RIKEN and OACIS for their contribution to the completion of our study. We are also grateful to members of The Rotary Club of Osaka-Midosuji District 2660 Rotary International in Japan for supporting our study. This work was supported in part by grants from the Takeda Science Foundation, the Uehara Science Foundation, the Japanese Millennium Project and the Ministry of Education, Science, Sports, Culture and Technology of Japan and NHRI-Ex96-9607PI (Taiwan).

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Authors and Affiliations

  1. Laboratory for Cardiovascular Diseases, Center for Genomic Medicine, RIKEN, Yokohama, 230-0045, Japan

    Kouichi Ozaki, Asako Aoki, Yoshihiro Onouchi & Toshihiro Tanaka

  2. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan

    Hiroshi Sato, Yasuhiko Sakata, Hiroya Mizuno & Masatsugu Hori

  3. Department of Cardiology, Kokura Memorial Hospital, Kitakyushu, 802-8555, Japan

    Katsumi Inoue, Keita Odashiro & Masakiyo Nobuyoshi

  4. Laboratory for Medical Informatics, Center for Genomic Medicine, RIKEN, Yokohama, 230-0045, Japan

    Tatsuhiko Tsunoda

  5. Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan

    Tsung-Hsien Lin & Sheng-Hsiung Sheu

  6. Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan

    Tsung-Hsien Lin & Sheng-Hsiung Sheu

  7. Laboratory for Bone and Joint Disease, Center for Genomic Medicine, RIKEN, Tokyo, 108-8639, Japan

    Yoshinari Miyamoto & Shiro Ikegawa

  8. Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan

    Suh-Hang H Juo

  9. Graduate Institute of Medical Genetics, Kaohsiung Medical University, Kaohsiung, 807, Taiwan

    Suh-Hang H Juo

  10. Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan

    Suh-Hang H Juo

  11. Center for Genomic Medicine, RIKEN, Yokohama, 230-0045, Japan

    Yusuke Nakamura

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  1. Kouichi Ozaki
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Contributions

K. Ozaki performed most of the experiments and wrote the manuscript; H.S., Y.S., H.M., T.-H.L., Y.M., S.-H.S., S.I., S.-H.H.J. and M.H. managed DNA samples and clinical information; K.I., K. Odashiro and M.N. performed the immunohistochemistry; T. Tsunoda performed the statistical analyses; A.A. and Y.O. performed the data analyses; Y.N. contributed to SNP discovery and preparation of the manuscript; and T. Tanaka supervised this study.

Corresponding author

Correspondence to Toshihiro Tanaka.

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Supplementary Tables 1–7, Supplementary Figures 1 and 2 and Supplementary Note (PDF 703 kb)

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Ozaki, K., Sato, H., Inoue, K. et al. SNPs in BRAP associated with risk of myocardial infarction in Asian populations. Nat Genet 41, 329–333 (2009). https://doi.org/10.1038/ng.326

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