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A functional SNP in PSMA6 confers risk of myocardial infarction in the Japanese population

Nature Genetics 38, 921–925 (2006) | Download Citation

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Abstract

Inflammation is now considered critical in the pathogenesis of myocardial infarction. One of the mechanisms regulating the inflammatory process is the ubiquitin-proteasome system. We investigated whether variants of the 20S proteasome are associated with susceptibility to myocardial infarction and found a common SNP (minor allele frequency of 0.35) in the proteasome subunit α type 6 gene (PSMA6) conferring risk of myocardial infarction in the Japanese population (χ2 = 21.1, P = 0.0000044, 2,592 affected individuals versus 2,851 controls). We replicated this association in another panel of myocardial infarction and control subjects, although its relevance to other ethnic groups remains to be clarified. The SNP, located in the 5′ untranslated region of exon 1 in this gene, enhanced the transcription of PSMA6. Moreover, suppression of PSMA6 expression using short interfering RNA in cultured cells reduced activation of the transcription factor NF-κB by stabilizing phosphorylated IκB. Our results implicate this PSMA6 SNP as a previously unknown genetic risk factor for myocardial infarction.

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Acknowledgements

We thank M. Takahashi, M. Yoshii, S. Abiko, W. Yamanobe, M. Omotezako, Y. Ariji, R. Ohishi, M. Watabe, K. Tabei and S. Manabe for their assistance and A. Suzuki and K. Kobayashi for advice on allele-specific gene expression experiments. We also thank all the other members of SNP Research Center, 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 and the Japanese Millennium Project.

Author information

Affiliations

  1. Laboratory for Cardiovascular Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.

    • Kouichi Ozaki
    •  & Toshihiro Tanaka

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

    • Hiroshi Sato
    • , Hiroya Mizuno
    •  & Masatsugu Hori

  3. Laboratory for Pharmacogenetics, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.

    • Aritoshi Iida
    •  & Yusuke Nakamura

  4. Laboratory for Statistical Analysis, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.

    • Takahiro Nakamura
    • , Atsushi Takahashi
    •  & Naoyuki Kamatani

  5. Laboratory for Bone and Joint Disease, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.

    • Yoshinari Miyamoto
    •  & Shiro Ikegawa

  6. Laboratory for Medical Informatics, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 1-7-22 Suehiro-cho, Tsurumi-ku,Yokohama 230-0045, Japan.

    • Tatsuhiko Tsunoda

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Contributions

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

Note: Supplementary information is available on the Nature Genetics website.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Toshihiro Tanaka.

Supplementary information

PDF files

  1. 1.

    Supplementary Table 1

    Association analyses between myocardial infarction and SNPs in genes encoding 20S proteasome α and β subunits.

  2. 2.

    Supplementary Table 2

    Pairwise LD coefficients (upper; r2; lower; D1) among SNPs in PSMA6 region.

  3. 3.

    Supplementary Table 3

    Association analyses of haplotypes in PSMA6 region with MI.

  4. 4.

    Supplementary Table 4

    No association of HT, smoking and past history of MI with the PSMA6 SNP.

  5. 5.

    Supplementary Table 5

    Clinical parameters of MI patients and the PSMA6 SNP genotype.

  6. 6.

    Supplementary Table 6

    Replication of association with the second panel.

  7. 7.

    Supplementary Table 7

    Primer sequences used in the study.

  8. 8.

    Supplementary Note

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DOI

https://doi.org/10.1038/ng1846

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