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Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility

Nature Genetics volume 37, pages 365–372 (2005)Cite this article

Abstract

Ath1 is a quantitative trait locus on mouse chromosome 1 that renders C57BL/6 mice susceptible and C3H/He mice resistant to diet-induced atherosclerosis. The quantitative trait locus region encompasses 11 known genes, including Tnfsf4 (also called Ox40l or Cd134l), which encodes OX40 ligand. Here we report that mice with targeted mutations of Tnfsf4 had significantly (P ≤ 0.05) smaller atherosclerotic lesions than did control mice. In addition, mice overexpressing Tnfsf4 had significantly (P ≤ 0.05) larger atherosclerotic lesions than did control mice. In two independent human populations, the less common allele of SNP rs3850641 in TNFSF4 was significantly more frequent (P ≤ 0.05) in individuals with myocardial infarction than in controls. We therefore conclude that Tnfsf4 underlies Ath1 in mice and that polymorphisms in its human homolog TNFSF4 increase the risk of myocardial infarction in humans.

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Figure 1: Genes in the Ath1 region.
Figure 2: mRNA expression of Tnfsf6 and Tnfsf4.
Figure 3: Diet-induced atherosclerosis and plasma lipid levels in Tnfsf6 or Tnfsf4 mutant mice, in transgenic mice overexpressing Tnfsf4 and in their respective controls.
Figure 4: Immunohistochemical localization of OX40L protein in mouse atherosclerotic lesions.

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Acknowledgements

We thank C. McFarland for technical assistance and R. Lambert for helping to prepare the manuscript. This study was supported by AstraZeneca (Sweden), grants from the US National Institutes of Health and grants from the Swedish Heart-Lung Foundation, the Swedish Medical Research Council, the Torsten and Ragnar Söderberg foundation, AFA insurance, the Stockholm County Council, the Wallenberg Consortium North, the Swedish Society for Medical Research and the Karolinska Institute.

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Author notes

  1. Xiaosong Wang and Massimiliano Ria: These authors contributed equally to this work.

Authors and Affiliations

  1. The Jackson Laboratory, 600 Main Street, Bar Harbor, 04609, Maine, USA

    Xiaosong Wang, Peter M Kelmenson, David C Higgins, Christina Petros, Jarod Rollins & Beverly Paigen

  2. Department of Medicine, Atherosclerosis Research Unit, King Gustaf V Research Institute, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden

    Massimiliano Ria, Per Eriksson, Ann Samnegård, Anders Hamsten & Jacob Lagercrantz

  3. Division of Cardiovascular Epidemiology, Institute for Environmental Medicine, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden

    Anna M Bennet & Ulf de Faire

  4. Division of Clinical Chemistry and Blood Coagulation, Department of Surgical Sciences, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden

    Björn Wiman

  5. Department of Cardiology, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden

    Ulf de Faire

  6. Department of Molecular Biology, AstraZeneca R&D, Mölndal, Sweden

    Charlotte Wennberg, Per G Olsson & Kristina Forsman-Semb

  7. Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Naoto Ishii & Kazuo Sugamura

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Supplementary information

Supplementary Table 1

Differences in 5′ upstream sequences between B6 and C3H Ox40l. (PDF 22 kb)

Supplementary Table 2

Allele frequencies and pairwise linkage disequilibrium coefficients for the SNPs in the OX40L gene in control subjects. (PDF 19 kb)

Supplementary Table 3

Association of the 110NN haplotype with the levels of plasma lipids and serum amyloid A in control subjects. (PDF 20 kb)

Supplementary Table 4

Primers for genotyping, RT-PCR and sequencing. (PDF 21 kb)

Supplementary Table 5

OX40L sequencing primers (PDF 17 kb)

Supplementary Table 6

Pyrosequencing© primers for OX40L (PDF 18 kb)

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Wang, X., Ria, M., Kelmenson, P. et al. Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility. Nat Genet 37, 365–372 (2005). https://doi.org/10.1038/ng1524

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