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

Xiaosong Wang; Massimiliano Ria; Peter M. Kelmenson; Per Eriksson; David C. Higgins; Ann Samnegård; Christina Petros; Jarod Rollins; Anna M. Bennet; Björn Wiman; Ulf De Faire; Charlotte Wennberg; Per G. Olsson; Naoto Ishii; Kazuo Sugamura; Anders Hamsten; Kristina Forsman-Semb; Jacob Lagercrantz; Beverly Paigen

doi:10.1038/ng1524

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

Xiaosong Wang, Massimiliano Ria, Peter M. Kelmenson, Per Eriksson, David C. Higgins, Ann Samnegård, Christina Petros, Jarod Rollins, Anna M. Bennet, Björn Wiman, Ulf De Faire, Charlotte Wennberg, Per G. Olsson, Naoto Ishii, Kazuo Sugamura, Anders Hamsten, Kristina Forsman-Semb, Jacob Lagercrantz, Beverly Paigen

MED - Medical Sciences

Research output: Contribution to journal › Article › peer-review

260 Citations (Scopus)

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 Ox40I or Cd134I), 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.

Original language	English
Pages (from-to)	365-372
Number of pages	8
Journal	Nature Genetics
Volume	37
Issue number	4
DOIs	https://doi.org/10.1038/ng1524
Publication status	Published - 2005 Apr

ASJC Scopus subject areas

Genetics

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Wang, X., Ria, M., Kelmenson, P. M., Eriksson, P., Higgins, D. C., Samnegård, A., Petros, C., Rollins, J., Bennet, A. M., Wiman, B., De Faire, U., Wennberg, C., Olsson, P. G., Ishii, N., Sugamura, K., Hamsten, A., Forsman-Semb, K., Lagercrantz, J., & Paigen, B. (2005). Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility. Nature Genetics, 37(4), 365-372. https://doi.org/10.1038/ng1524

Wang, X, Ria, M, Kelmenson, PM, Eriksson, P, Higgins, DC, Samnegård, A, Petros, C, Rollins, J, Bennet, AM, Wiman, B, De Faire, U, Wennberg, C, Olsson, PG, Ishii, N, Sugamura, K, Hamsten, A, Forsman-Semb, K, Lagercrantz, J & Paigen, B 2005, 'Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility', Nature Genetics, vol. 37, no. 4, pp. 365-372. https://doi.org/10.1038/ng1524

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

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 Ox40I or Cd134I), 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.",

author = "Xiaosong Wang and Massimiliano Ria and Kelmenson, {Peter M.} and Per Eriksson and Higgins, {David C.} and Ann Samneg{\aa}rd and Christina Petros and Jarod Rollins and Bennet, {Anna M.} and Bj{\"o}rn Wiman and {De Faire}, Ulf and Charlotte Wennberg and Olsson, {Per G.} and Naoto Ishii and Kazuo Sugamura and Anders Hamsten and Kristina Forsman-Semb and Jacob Lagercrantz and Beverly Paigen",

note = "Funding Information: 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 S{\"o}derberg 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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T1 - Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility

AU - Wang, Xiaosong

AU - Ria, Massimiliano

AU - Kelmenson, Peter M.

AU - Eriksson, Per

AU - Higgins, David C.

AU - Samnegård, Ann

AU - Petros, Christina

AU - Rollins, Jarod

AU - Bennet, Anna M.

AU - Wiman, Björn

AU - De Faire, Ulf

AU - Wennberg, Charlotte

AU - Olsson, Per G.

AU - Ishii, Naoto

AU - Sugamura, Kazuo

AU - Hamsten, Anders

AU - Forsman-Semb, Kristina

AU - Lagercrantz, Jacob

AU - Paigen, Beverly

N1 - Funding Information: 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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N2 - 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 Ox40I or Cd134I), 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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Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility

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