Nature Genetics
37, 365 - 372 (2005)
Published online: 6 March 2005; | doi:10.1038/ng1524
Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibilityXiaosong Wang1, 8, Massimiliano Ria2, 8, Peter M Kelmenson1, Per Eriksson2, David C Higgins1, Ann Samnegård2, Christina Petros1, Jarod Rollins1, Anna M Bennet3, Björn Wiman4, Ulf de Faire3, 5, Charlotte Wennberg6, Per G Olsson6, Naoto Ishii7, Kazuo Sugamura7, Anders Hamsten2, Kristina Forsman-Semb6, Jacob Lagercrantz2
& Beverly Paigen11
The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA. 2
Atherosclerosis Research Unit, King Gustaf V Research Institute, Department of Medicine, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden. 3
Division of Cardiovascular Epidemiology, Institute for Environmental Medicine, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden. 4
Division of Clinical Chemistry and Blood Coagulation, Department of Surgical Sciences, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden. 5
Department of Cardiology, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden. 6
Department of Molecular Biology, AstraZeneca R&D, Mölndal, Sweden. 7
Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan. 8
These authors contributed equally to this work.
Correspondence should be addressed to Xiaosong Wang xw@jax.org
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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