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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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References

  1. Paigen, B., Morrow, A., Brandon, C., Mitchell, D. & Holmes, P. Variation in susceptibility to atherosclerosis among inbred strains of mice. Atherosclerosis 57, 65–73 (1985).

    Article  CAS  Google Scholar 

  2. Paigen, B. et al. Ath-1, a gene determining atherosclerosis susceptibility and high density lipoprotein levels in mice. Proc. Natl. Acad. Sci. USA 84, 3763–3767 (1987).

    Article  CAS  Google Scholar 

  3. Paigen, B., Albee, D., Holmes, P.A. & Mitchell, D. Genetic analysis of murine strains C57BL/6J and C3H/HeJ to confirm the map position of Ath-1, a gene determining atherosclerosis susceptibility. Biochem. Genet. 25, 501–511 (1987).

    Article  CAS  Google Scholar 

  4. Phelan, S.A., Beier, D.R., Higgins, D.C. & Paigen, B. Confirmation and high resolution mapping of an atherosclerosis susceptibility gene in mice on Chromosome 1. Mamm. Genome 13, 548–553 (2002).

    Article  CAS  Google Scholar 

  5. Wang, X. et al. Mice with targeted mutation of peroxiredoxin 6 develop normally but are susceptible to oxidative stress. J. Biol. Chem. 278, 25179–25190 (2003).

    Article  CAS  Google Scholar 

  6. Phelan, S.A., Wang, X., Wallbrandt, P., Forsman-Semb, K. & Paigen, B. Overexpression of Prdx6 reduces H2O2 but does not prevent diet-induced atherosclerosis in the aortic root. Free Radic. Biol. Med. 35, 1110–1120 (2003).

    Article  CAS  Google Scholar 

  7. Wang, X. et al. Peroxiredoxin 6 deficiency and atherosclerosis susceptibility in mice: significance of genetic background for assessing atherosclerosis. Atherosclerosis 177, 61–70 (2004).

    Article  CAS  Google Scholar 

  8. Geng, Y.J. Biologic effect and molecular regulation of vascular apoptosis in atherosclerosis. Curr. Atheroscler. Rep. 3, 234–242 (2001).

    Article  CAS  Google Scholar 

  9. Weinberg, A.D. OX40: targeted immunotherapy–implications for tempering autoimmunity and enhancing vaccines. Trends Immunol. 23, 102–109 (2002).

    Article  CAS  Google Scholar 

  10. Hansson, G.K., Libby, P., Schonbeck, U. & Yan, Z.Q. Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circ. Res. 91, 281–291 (2002).

    Article  CAS  Google Scholar 

  11. Shi, W. et al. Genetic backgrounds but not sizes of atherosclerotic lesions determine medial destruction in the aortic root of apolipoprotein E-deficient mice. Arterioscler. Thromb. Vasc. Biol. 23, 1901–1906 (2003).

    Article  CAS  Google Scholar 

  12. Mehrabian, M. et al. Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice. Circ. Res. 91, 120–126 (2002).

    Article  CAS  Google Scholar 

  13. Emeson, E.E., Shen, M.L., Bell, C.G. & Qureshi, A. Inhibition of atherosclerosis in CD4 T-cell-ablated and nude (nu/nu) C57BL/6 hyperlipidemic mice. Am. J. Pathol. 149, 675–685 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Nakai, Y. et al. Natural killer T cells accelerate atherogenesis in mice. Blood 104, 2051–2059 (2004).

    Article  CAS  Google Scholar 

  15. Major, A.S., Fazio, S. & Linton, M.F. B-lymphocyte deficiency increases atherosclerosis in LDL receptor-null mice. Arterioscler. Thromb. Vasc. Biol. 22, 1892–1898 (2002).

    Article  CAS  Google Scholar 

  16. Caligiuri, G., Nicoletti, A., Poirier, B. & Hansson, G.K. Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice. J. Clin. Invest. 109, 745–753 (2002).

    Article  CAS  Google Scholar 

  17. Reardon, C.A. et al. Effect of immune deficiency on lipoproteins and atherosclerosis in male apolipoprotein E-deficient mice. Arterioscler. Thromb. Vasc. Biol. 21, 1011–1016 (2001).

    Article  CAS  Google Scholar 

  18. Song, L., Leung, C. & Schindler, C. Lymphocytes are important in early atherosclerosis. J. Clin. Invest. 108, 251–259 (2001).

    Article  CAS  Google Scholar 

  19. Dansky, H.M., Charlton, S.A., Harper, M.M. & Smith, J.D. T and B lymphocytes play a minor role in atherosclerotic plaque formation in the apolipoprotein E-deficient mouse. Proc. Natl. Acad. Sci. USA 94, 4642–4646 (1997).

    Article  CAS  Google Scholar 

  20. Geng, Y.J. & Libby, P. Progression of atheroma: a struggle between death and procreation. Arterioscler. Thromb. Vasc. Biol. 22, 1370–1380 (2002).

    Article  CAS  Google Scholar 

  21. Yang, J. et al. Endothelial overexpression of Fas ligand decreases atherosclerosis in apolipoprotein E-deficient mice. Arterioscler. Thromb. Vasc. Biol. 24, 1466–1473 (2004).

    Article  CAS  Google Scholar 

  22. Aprahamian, T. et al. Impaired clearance of apoptotic cells promotes synergy between atherogenesis and autoimmune disease. J. Exp. Med. 199, 1121–1131 (2004).

    Article  CAS  Google Scholar 

  23. Schneider, D.B. et al. Expression of Fas ligand in arteries of hypercholesterolemic rabbits accelerates atherosclerotic lesion formation. Arterioscler. Thromb. Vasc. Biol. 20, 298–308 (2000).

    Article  CAS  Google Scholar 

  24. Kotani, A., Hori, T., Matsumura, Y. & Uchiyama, T. Signaling of gp34 (OX40 ligand) induces vascular endothelial cells to produce a CC chemokine RANTES/CCL5. Immunol. Lett. 84, 1–7 (2002).

    Article  CAS  Google Scholar 

  25. Kawai, T. et al. Selective diapedesis of Th1 cells induced by endothelial cell RANTES. J. Immunol. 163, 3269–3278 (1999).

    CAS  PubMed  Google Scholar 

  26. Welch, C.L. et al. Localization of atherosclerosis susceptibility loci to chromosomes 4 and 6 using the Ldlr knockout mouse model. Proc. Natl. Acad. Sci. USA 98, 7946–7951 (2001).

    Article  CAS  Google Scholar 

  27. Hauser, E.R. et al. A genomewide scan for early-onset coronary artery disease in 438 families: the GENECARD Study. Am. J. Hum. Genet. 75, 436–447 (2004).

    Article  CAS  Google Scholar 

  28. Wang, Q. et al. Premature myocardial infarction novel susceptibility locus on chromosome 1p34-36 identified by genomewide linkage analysis. Am. J. Hum. Genet. 74, 262–271 (2004).

    Article  CAS  Google Scholar 

  29. Abiola, O. et al. The nature and identification of quantitative trait loci: a community's view. Nat. Rev. Genet. 4, 911–916 (2003).

    PubMed  Google Scholar 

  30. Stary, H.C. et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 92, 1355–1374 (1995).

    Article  CAS  Google Scholar 

  31. Edfeldt, K. et al. Association of hypo-responsive toll-like receptor 4 variants with risk of myocardial infarction. Eur. Heart J. 25, 1447–1453 (2004).

    Article  CAS  Google Scholar 

  32. Paigen, B., Holmes, P.A., Mitchell, D. & Albee, D. Comparison of atherosclerotic lesions and HDL-lipid levels in male, female, and testosterone-treated female mice from strains C57BL/6, BALB/c, and C3H. Atherosclerosis 64, 215–221 (1987).

    Article  CAS  Google Scholar 

  33. Sugamura, K., Ishii, N. & Weinberg, A.D. Therapeutic targeting of the effector T-cell co-stimulatory molecule OX40. Nat. Rev. Immunol. 4, 420–431 (2004).

    Article  CAS  Google Scholar 

  34. Murata, K. et al. Impairment of antigen-presenting cell function in mice lacking expression of OX40 ligand. J. Exp. Med. 191, 365–374 (2000).

    Article  CAS  Google Scholar 

  35. Nishina, P.M., Verstuyft, J. & Paigen, B. Synthetic low and high fat diets for the study of atherosclerosis in the mouse. J. Lipid Res. 31, 859–869 (1990).

    CAS  PubMed  Google Scholar 

  36. Paigen, B. et al. Ath-1, a gene determining atherosclerosis susceptibility and high density lipoprotein levels in mice. Proc. Natl. Acad. Sci. USA 84, 3763–3767 (1987).

    Article  CAS  Google Scholar 

  37. Paigen, B., Mitchell, D., Holmes, P.A. & Albee, D. Genetic analysis of strains C57BL/6J and BALB/cJ for Ath-1, a gene determining atherosclerosis susceptibility in mice. Biochem. Genet. 25, 881–892 (1987).

    Article  CAS  Google Scholar 

  38. Paigen, B., Albee, D., Holmes, P.A. & Mitchell, D. Genetic analysis of murine strains C57BL/6J and C3H/HeJ to confirm the map position of Ath-1, a gene determining atherosclerosis susceptibility. Biochem. Genet. 25, 501–511 (1987).

    Article  CAS  Google Scholar 

  39. Paigen, B., Morrow, A., Holmes, P.A., Mitchell, D. & Williams, R.A. Quantitative assessment of atherosclerotic lesions in mice. Atherosclerosis 68, 231–240 (1987).

    Article  CAS  Google Scholar 

  40. Wang, X. et al. Using advanced intercross lines for high-resolution mapping of HDL cholesterol quantitative trait loci. Genome. Res. 13, 1654–1664 (2003).

    Article  CAS  Google Scholar 

  41. Eriksson, P. et al. Human evidence that the cystatin C gene is implicated in focal progression of coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 24, 551–557 (2004).

    Article  CAS  Google Scholar 

  42. Reuterwall, C. et al. Higher relative, but lower absolute risks of myocardial infarction in women than in men: analysis of some major risk factors in the SHEEP study. The SHEEP Study Group. J. Intern. Med. 246, 161–174 (1999).

    Article  CAS  Google Scholar 

  43. Boquist, S. et al. Alimentary lipemia, postprandial triglyceride-rich lipoproteins, and common carotid intima-media thickness in healthy, middle-aged men. Circulation 100, 723–728 (1999).

    Article  CAS  Google Scholar 

  44. Austen, W.G. et al. A reporting system on patients evaluated for coronary artery disease. Report of the Ad Hoc Committee for Grading of Coronary Artery Disease, Council on Cardiovascular Surgery, American Heart Association. Circulation 51, 5–40 (1975).

    Article  CAS  Google Scholar 

  45. Ronaghi, M., Uhlen, M. & Nyren, P. A sequencing method based on real-time pyrophosphate. Science 281, 363–365 (1998).

    Article  CAS  Google Scholar 

  46. Niu, T., Qin, Z.S., Xu, X. & Liu, J.S. Bayesian haplotype inference for multiple linked single-nucleotide polymorphisms. Am. J. Hum. Genet. 70, 157–169 (2002).

    Article  CAS  Google Scholar 

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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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