Letter | Published:

A nonsynonymous SNP in PRKCH (protein kinase C η) increases the risk of cerebral infarction

Nature Genetics volume 39, pages 212217 (2007) | Download Citation

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Abstract

Cerebral infarction is the most common type of stroke and often causes long-term disability. To investigate the genetic contribution to cerebral infarction, we conducted a case-control study using 52,608 gene-based tag SNPs selected from the JSNP database. Here we report that a nonsynonymous SNP in a member of protein kinase C (PKC) family, PRKCH, was significantly associated with lacunar infarction in two independent Japanese samples (P = 5.1 × 10−7, crude odds ratio of 1.40). This SNP is likely to affect PKC activity. Furthermore, a 14-year follow-up cohort study in Hisayama (Fukuoka, Japan) supported involvement of this SNP in the development of cerebral infarction (P = 0.03, age- and sex-adjusted hazard ratio of 2.83). We also found that PKCη was expressed mainly in vascular endothelial cells and foamy macrophages in human atherosclerotic lesions, and its expression increased as the lesion type progressed. Our results support a role for PRKCH in the pathogenesis of cerebral infarction.

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Acknowledgements

We thank the residents of Hisayama and the patients with cerebral infarction for their participation; T. Omae and the staff of the Division of Health and Welfare of Hisayama for their cooperation and many members of the Hisayama study for assistance. For collecting clinical samples, we thank T. Ago, H. Ooboshi, M. Kamouchi, H. Sugimori, J. Kuroda, Y. Kumai, N. Hagiwara and S. Yoshimura (Kyushu University Hospital); K. Tamaki and Y. Wakugawa (Hakujyuji Hospital); K. Fujii (Fukuoka Red Cross Hospital); Y. Okada and K. Toyoda (National Hospital Organization, Kyushu Medical Center); T. Nagao (Imazu Red Cross Hospital); H. Nakane (National Hospital Organization, Fukuoka Higashi Medical Center) and Y. Yamashita and K. Kusuda (Seiai Rehabilitation Hospital). We thank K. Chida (Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo) for technical advice. This study was supported in part by a Special Coordination Fund for Promoting Science and a Fund for Technology and Innovative Development Project in Life Sciences from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Author information

Affiliations

  1. Department of Environmental Medicine, Kyushu University, Fukuoka 812-8582, Japan.

    • Michiaki Kubo
    • , Jun Hata
    • , Toshiharu Ninomiya
    • , Koji Yonemoto
    •  & Yutaka Kiyohara
  2. Department of Medicine and Clinical Science, Kyushu University, Fukuoka 812-8582, Japan.

    • Michiaki Kubo
    • , Jun Hata
    • , Toshiharu Ninomiya
    • , Toshiaki Nakano
    • , Tomonaga Matsushita
    • , Takanari Kitazono
    • , Setsuro Ibayashi
    •  & Mitsuo Iida
  3. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.

    • Michiaki Kubo
    • , Jun Hata
    • , Koichi Matsuda
    • , Tomonaga Matsushita
    • , Keiko Yamazaki
    •  & Yusuke Nakamura
  4. Pathophysiological and Experimental Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

    • Toshiaki Nakano
    •  & Katsuo Sueishi
  5. Laboratory for Genotyping, SNP Research Center, the Institute of Physical and Chemical Research (RIKEN), Yokohama 230-0045, Japan.

    • Yozo Ohnishi
    •  & Susumu Saito

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Contributions

M.K., J.H., T.M. and K. Yamazaki performed SNP genotyping; T. Ninomiya and K. Yonemoto provided Hisayama samples and carried out statistical analyses; T. Nakano and K.S. performed immunohistochemical experiments; M.K., K. Yamazaki and K.M. performed protein blotting experiments; Y.O. and S.S. performed genotyping of genome-wide screening samples; T.K. and S.I. provided clinical information and samples of individuals with cerebral infarction; Y.N. provided BioBank Japan samples; M.K. performed all other experiments and wrote the manuscript with contributions from K.S., Y.N. and Y.K.; T. Ninomiya, K. Yonemoto, Y.K. helped with revisions and M.I., Y.N. and Y.K. jointly directed the project.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Michiaki Kubo.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Stratification analysis of screening samples.

  2. 2.

    Supplementary Fig. 2

    Kaplan-Meier estimate of the incidence of lacunar infarction by 1425G→A genotype in the Hisayama study.

  3. 3.

    Supplementary Fig. 3

    Age- and sex-adjusted cumulative incidence of coronary heart disease by 1425G→A genotype in the Hisayama study.

  4. 4.

    Supplementary Fig. 4

    Relative mRNA expression of PKCη in various human tissues.

  5. 5.

    Supplementary Fig. 5

    Flow diagram of the study.

  6. 6.

    Supplementary Table 1

    Case-control association results of 45 SNPs in PRKCH for lacunar infarction.

  7. 7.

    Supplementary Table 2

    Multivariate logistic analysis of nonsynonymous SNPs in PRKCH among cases with lacunar infarction and age- and sex-matched controls.

  8. 8.

    Supplementary Table 3

    Clinical characteristics of the study population in the case-control study.

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DOI

https://doi.org/10.1038/ng1945

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