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Genetic variants of TNFSF4 and risk for carotid artery disease and stroke

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Abstract

In two independent human cohorts, the minor allele of SNP rs3850641 in TNFSF4 was significantly more frequent in individuals with myocardial infarction than in controls. In mice, Tnfsf4 expression is associated with increased atherosclerosis. The expression of TNFSF4 in human atherosclerosis and the association between genotype and cerebrovascular disease have not yet been investigated. TNFSF4 messenger RNA (mRNA) levels were significantly higher in human atherosclerotic lesions compared with controls (730 ± 30 vs 330 ± 65 arbitrary units, p < 0.01). TNFSF4 was mainly expressed by macrophages in atherosclerotic lesions. In cell culture, endothelial cells upregulated TNFSF4 in response to tumor necrosis factor alpha (TNF-α; 460 ± 110 vs 133 ± 8 arbitrary units, p < 0.001 after 6 h of stimulation). We analyzed the TNFSF4 gene in 239 patients who had undergone carotid endarterectomy and 138 matching controls from The Biobank of Karolinska Carotid Endarterectomies and Stockholm Heart Epidemiology Program cohorts and 929 patients and 1,382 matching controls from the Sahlgrenska Academy Study on Ischemic Stroke and Case Control Study of Stroke cohorts, limiting inclusion to patients with ischemic stroke. Participants were genotyped for the rs3850641 SNP in TNFSF4. Genotype associations were neither found with TNFSF4 mRNA levels nor with atherosclerosis associated systemic factors or risk for stroke. This study shows that TNFSF4 is expressed on antigen-presenting cells in human carotid atherosclerotic lesions but provides no evidence for an association of TNFSF4 gene variation with the risk for ischemic stroke.

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Acknowledgments

The authors thank the investigators, staff, and participants in the BiKE, SHEEP, CASTRO, and SAHLSIS cohorts.

Funding sources

This study was supported by the Swedish Heart-Lung foundation (project 20070634), Swedish Medical Research Council (projects 6816, 8691 and 14121), the Leducq Transatlantic Network of Excellence on Atherothrombosis Research, the MOLSTROKE and PROCARDIS (LSHM-CT-2007–037273) integrated projects, the European Vascular Genomics Network sponsored by the European Commission, the Stockholm County Council (projects 20060768 and 560183), and the AFA insurance company.

Disclosures

The authors have no conflicting financial interests.

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Authors and Affiliations

  1. Center for Molecular Medicine, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

    P. S. Olofsson, L. Å. Söderström, M. Ria, E. Sundler, J. Öhrvik, U. Hedin, G. Paulsson-Berne, A. Hamsten, P. Eriksson & G. K. Hansson

  2. Department of Anesthesiology and Intensive Care Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

    P. S. Olofsson

  3. Institute of Neuroscience and Physiology, Department of Clinical Neuroscience and Rehabilitation, The Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden

    C. Jern

  4. Department of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden

    A. Sirsjö

  5. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    M. Ria

  6. Institute of Environmental Medicine, Karolinska Institutet, and Department of Cardiology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

    U. de Faire

  7. Department of Medicine, Umeå University, Umeå, Sweden

    P. G. Wiklund

  8. Center for Molecular Medicine L8:03, Karolinska University Hospital, 17176, Stockholm, Sweden

    P. S. Olofsson

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  1. P. S. Olofsson
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  2. L. Å. Söderström
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  3. C. Jern
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  4. A. Sirsjö
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  5. M. Ria
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  6. E. Sundler
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  7. U. de Faire
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  8. P. G. Wiklund
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  9. J. Öhrvik
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  10. U. Hedin
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  11. G. Paulsson-Berne
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  12. A. Hamsten
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  13. P. Eriksson
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  14. G. K. Hansson
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Correspondence to P. S. Olofsson.

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Olofsson, P.S., Söderström, L.Å., Jern, C. et al. Genetic variants of TNFSF4 and risk for carotid artery disease and stroke. J Mol Med 87, 337–346 (2009). https://doi.org/10.1007/s00109-008-0412-5

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  • DOI: https://doi.org/10.1007/s00109-008-0412-5

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