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

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

doi:10.1038/ng1524

Cited by 257 publications

(253 citation statements)

References 42 publications

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“…Emerging evidence supports a role of OX40-OX40L in atherosclerosis [21]. Furthermore, in the present study, OX40L was found to be up-regulated in PBMCs from children and young adults with FH.…”

Section: Regulation Of Mmp-9 By Ox40 Ox40l and Oxldl In Thp-1 Monocytessupporting

confidence: 87%

“…The gene encoding OX40L has been found to influence the development of atherosclerosis in both mice and humans [21]; in the present study we have shown that PBMCs from children and young adults with FH have enhanced expression of OX40L compared with those from matched healthy controls. Moreover, OX40, acting through OX40L, enhanced the oxLDL-induced expression of MMP-9 in THP-1 monocytes.…”

Section: Discussionsupporting

confidence: 59%

“…TNFSF/TNFRSF members regulate immune and inflammatory responses, and are associated with various autoimmune and inflammatory disorders [24,25], including atherosclerosis [11,21]. However, to the best of our knowledge, this is the first report to show altered expression of several TNFSF/TNFRSF members in PBMCs from children and young adults with FH.…”

Section: Discussionmentioning

confidence: 78%

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Oxidized LDL level is related to gene expression of tumour necrosis factor super family members in children and young adults with familial hypercholesterolaemia

et al. 2012

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Objective. Familial hypercholesterolaemia (FH) is associated with increased risk of premature atherosclerosis. Inflammation is a key event in atherogenesis, and we have previously reported an inflammatory imbalance between tumour necrosis factor (TNF)a and interleukin-10 in children with FH. Based on the potential role of TNF-related molecules in inflammation, we investigated the regulation of other members of the TNF superfamily (TNFSF)/TNF receptor superfamily (TNFRSF) in children and young adults with FH and matched healthy controls.Methods. Expression of TNFSF/TNFRSF genes in peripheral blood mononuclear cells (PBMCs) was quantified in children and young adults with FH prior to (n = 42) and after statin treatment (n = 10) and in controls (n = 25) by quantitative real-time polymerase chain reaction.Results. First we found that, compared with controls, the mRNA levels of OX40L, BAFFR and TRAILR1 were significantly higher, whereas TRAIL and TRAILR3 were significantly lower in children and young adults with FH. Secondly, levels of oxidized low-density lipoprotein (oxLDL) were significantly raised in the FH group, and correlated with the expression of OX40L, BAFFR and TRAILR1. Thirdly, oxLDL increased mRNA levels of BAFFR, TRAILR1 and TRAILR4 in PBMCs ex vivo from individuals with FH. Fourthly, OX40, acting through OX40L, enhanced the oxLDL-induced expression of matrix metalloproteinase-9 in THP-1 monocytes in vitro. Finally, after statin treatment in children with FH (n = 10), mRNA levels of OX40L and TRAILR1 decreased, whereas levels BAFF, TRAIL and TRAILR3 increased.Conclusion. Our findings suggest the involvement of some TNFSF/TNFRSF members and oxLDL in the early stages of atherogenesis; this may potentially contribute to the accelerated rate of atherosclerosis observed in individuals with FH.

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Section: Regulation Of Mmp-9 By Ox40 Ox40l and Oxldl In Thp-1 Monocytessupporting

confidence: 87%

Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 78%

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Oxidized LDL level is related to gene expression of tumour necrosis factor super family members in children and young adults with familial hypercholesterolaemia

et al. 2012

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“…For example, evidence from QTL mapping and analyses of knockouts implicates Tnfsf4 in diet-induced atherosclerosis in mice (Wang et al 2005b); however, genetic association studies have not provided consistent evidence for its involvement in humans (Koch et al 2008). Similar difficulties are found for the involvement of type II SH2 domain-containing inositol 5-phosphatase in the metabolic syndrome (Kaisaki et al 2004;Marcano et al 2007) and regulators of G protein signaling in anxiety (Fullerton et al 2008).…”

Section: How Much Does Genetic Architecture Vary Between Phenotypes?mentioning

confidence: 99%

Genetic architecture of quantitative traits in mice, flies, and humans

Flint¹,

Mackay²

2009

Genome Res.

409

364

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We compare and contrast the genetic architecture of quantitative phenotypes in two genetically well-characterized model organisms, the laboratory mouse, Mus musculus, and the fruit fly, Drosophila melanogaster, with that found in our own species from recent successes in genome-wide association studies. We show that the current model of large numbers of loci, each of small effect, is true for all species examined, and that discrepancies can be largely explained by differences in the experimental designs used. We argue that the distribution of effect size of common variants is the same for all phenotypes regardless of species, and we discuss the importance of epistasis, pleiotropy, and gene by environment interactions. Despite substantial advances in mapping quantitative trait loci, the identification of the quantitative trait genes and ultimately the sequence variants has proved more difficult, so that our information on the molecular basis of quantitative variation remains limited. Nevertheless, available data indicate that many variants lie outside genes, presumably in regulatory regions of the genome, where they act by altering gene expression. As yet there are very few instances where homologous quantitative trait loci, or quantitative trait genes, have been identified in multiple species, but the availability of high-resolution mapping data will soon make it possible to test the degree of overlap between species.Recent successes in mapping quantitative trait loci (QTLs) that contribute to phenotypic variation in humans and model organisms make it possible to address important questions about the genetic architecture of quantitative phenotypes, such as the likely number of loci, their mode of genetic action, and interaction with each other and with the environment. An understanding of the genetic architecture of quantitative traits is not only important in its own right, it will also inform studies that seek to proceed to the identification of the quantitative trait genes (QTGs) and the quantitative trait nucleotide (QTN) variants, the functional changes in DNA sequence that contribute to trait variation.In this work we use examples from two genetically wellcharacterized model organisms, the laboratory mouse, Mus musculus, and the fruit fly, Drosophila melanogaster, to discuss how an understanding of the genetic architecture of quantitative phenotypes in model organisms informs mapping experiments in human genetics. In our discussion of the latter, we draw upon the recent successful application of genome-wide association studies (GWAS) to both quantitative phenotypes (such as height and weight) and disease phenotypes (assuming that the genetic architecture of common disease is similar, if not identical, to that of quantitative phenotypes).Genetic architecture has been the subject of a number of recent reviews, most of which deal with information from a single model organism (Mackay 2004) or review a small number of phenotypes (Kendler and Greenspan 2006). Here, our purpose is different. We tackle three relate...

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“…3 Several large-scale association studies using a large number of genetic variations, including single nucleotide polymorphisms (SNPs), have recently identified the susceptibility genes and loci for CAD. [4][5][6][7][8][9][10][11][12] However, not all of the reported associations could be replicated in other studies even if middle-to large-sized samples were investigated in the original reports, suggesting that the contribution of genetic factors was not large enough to be replicated in some cases. 13 Validation studies for the association in other populations are, therefore, crucial to establish the role of diseaserelated genes.…”

Section: Introductionmentioning

confidence: 99%

Validation of eight genetic risk factors in East Asian populations replicated the association of BRAP with coronary artery disease

et al. 2009

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Coronary artery disease (CAD) is caused by a thrombotic occlusion or spasm of the coronary artery. Association of genetic variants with susceptibility to CAD has been reported in various populations, but the association should be replicated in other populations to establish the role of genetic variants in CAD. We conducted a case-control study with a total of 1480 CAD cases and 2115 controls from two East Asian populations, Japanese and Korean, to validate the associations of CAD with eight single nucleotide polymorphisms (SNPs) in eight loci, which were identified from large-scale whole-genome association studies in Europeans or East Asians. Among the tested SNPs, one SNP in BRAP (rs11066001) showed a significant association in allele frequency distribution with CAD in both the Japanese (Odds ratio (OR)¼1.63, 95% confidence interval (CI); 1.41-1.89, P¼5.0Â10 À11 , corrected P (Pc)¼4.0Â10 À10 ) and Korean populations (OR¼1.68, 95% CI; 1.41-2.00, P¼6.5Â10 À9 , Pc¼5.2Â10 À9 ), and a meta-analysis showed a significant association in the East Asian populations (OR¼1.65, 95% CI; 1.48-1.85, P¼1.8Â10 À18 , Pc¼1.4Â10 À17 ), whereas no evidence of association was found for the other SNPs. In addition, a combined analysis of BRAP and another CAD locus on 9p21 suggested that these loci had a synergistic role in the susceptibility. Failure to replicate the association with the other SNPs, which were reported in the European populations, suggested that their contributions to CAD were not large enough to be readily captured in the East Asian populations.

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

Cited by 257 publications

References 42 publications

Oxidized LDL level is related to gene expression of tumour necrosis factor super family members in children and young adults with familial hypercholesterolaemia

Oxidized LDL level is related to gene expression of tumour necrosis factor super family members in children and young adults with familial hypercholesterolaemia

Genetic architecture of quantitative traits in mice, flies, and humans

Validation of eight genetic risk factors in East Asian populations replicated the association of BRAP with coronary artery disease

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