Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility.
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 <or= 0.05) smaller atherosclerotic lesions than did control mice. In addition, mice overexpressing Tnfsf4 had significantly (P <or= 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 <or= 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.
Wang
Xiaosong
X
The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA. xw@jax.org
Ria
Massimiliano
M
Kelmenson
Peter M
PM
Eriksson
Per
P
Higgins
David C
DC
Samnegård
Ann
A
Petros
Christina
C
Rollins
Jarod
J
Bennet
Anna M
AM
Wiman
Björn
B
de Faire
Ulf
U
Wennberg
Charlotte
C
Olsson
Per G
PG
Ishii
Naoto
N
Sugamura
Kazuo
K
Hamsten
Anders
A
Forsman-Semb
Kristina
K
Lagercrantz
Jacob
J
Paigen
Beverly
B
D000368:Aged; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics / Q000502:physiology; D001161:Arteriosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002791:Cholesterol, Dietary; D003433:Crosses, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D053278:OX40 Ligand; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000502:physiology; D048069:Tumor Necrosis Factors
D001057:Apolipoproteins E; D002791:Cholesterol, Dietary; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; C089251:TNFSF4 protein, human; C504586:Tnfsf4 protein, mouse; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D048069:Tumor Necrosis Factors