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Human genetic evidence for involvement of CD137 in atherosclerosis.

ABSTRACT: Atherosclerosis is an inflammatory disease and the main cause of cardiovascular disease. Inflammation promotes plaque instability and clinical disease, such as myocardial infarction, stroke and peripheral vascular disease. Subclinical atherosclerosis begins with thickening of the arterial intimal layer, and increased intima-media thickness (IMT) in the carotid artery is a widely used measurement of subclinical atherosclerosis. Activation of CD137 (tumor necrosis factor receptor super family 9) promotes inflammation and disease development in murine atherosclerosis. CD137 is expressed in human atherosclerosis, but its role is largely unknown. This study uses a genetic approach to investigate CD137 in human atherosclerotic disease. In publicly available data on genotype and gene expression from the HapMap project, the minor T allele of rs2453021, a single nucleotide polymorphism in CD137, was significantly associated with CD137 gene expression. In the PROCARDIS and Wellcome Trust Case Control Consortium (WTCCC) cohorts of 13,029 cases and controls, no significant association was detected between the minor T allele of rs2453021 and risk for coronary artery disease or myocardial infarction. However, in the IMPROVE multicenter study of 3,418 individuals, the minor T allele of rs2453021 was associated with increased IMT of the common carotid artery (CCA), as measured by ultrasonography, with presence of plaque in CCA and with increased incidence of adverse noncardiac vascular events. Taken together, this study shows that the minor T allele of rs2453021 is associated with increased IMT in the CCA and increased risk of incident noncardiac vascular events, thus providing the first human genetic evidence for involvement of CD137 in atherosclerosis.

SUBMITTER: Soderstrom LA

PROVIDER: S-EPMC4212009 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Human genetic evidence for involvement of CD137 in atherosclerosis.

Söderström Leif Å LÅ Gertow Karl K Folkersen Lasse L Sabater-Lleal Maria M Sundman Eva E Sheikine Yuri Y Goel Anuj A Baldassarre Damiano D Humphries Steve E SE de Faire Ulf U Watkins Hugh H Tremoli Elena E Veglia Fabrizio F Hamsten Anders A Hansson Göran K GK Olofsson Peder S PS

Molecular medicine (Cambridge, Mass.) 20141014

Atherosclerosis is an inflammatory disease and the main cause of cardiovascular disease. Inflammation promotes plaque instability and clinical disease, such as myocardial infarction, stroke and peripheral vascular disease. Subclinical atherosclerosis begins with thickening of the arterial intimal layer, and increased intima-media thickness (IMT) in the carotid artery is a widely used measurement of subclinical atherosclerosis. Activation of CD137 (tumor necrosis factor receptor super family 9) p ...[more]

PMID: 25032953

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Project description:Bilateral retinoblastoma has served as a critical model for studying genetic predisposition to cancer, however international incidence of unilateral retinoblastoma is variable across populations suggesting the involvement of environmental factors. DNA from Human Papilloma Virus (HPV) has been found in human retinoblastoma tissue through polymerase chain reaction based methods in several independent reports. To search for HPV oncoproteins and characterize transcriptional profiles in retinoblastoma, we analyzed tumor tissue obtained after enucleation and cultured for one week from 13 previously untreated Mexican children with retinoblastoma. We identified the presence of E7 HPV oncoproteins using western blot analysis in HPV positive tumors, and using non-supervised methods of classification on gene expression microarrays data, tumors clustered according to the presence or absence of HPV DNA identified by PCR. These methods were unable to discriminate retinoblastoma tissues by laterality. 2,404 genes were differentially expressed between HPV positive and HPV negative retinoblastoma, including a group of genes involved in a transcriptional response to viral infection. This molecular evidence supports the hypothesis that HPV is involved in the molecular pathogenesis of these tumors. The 13 children and tumors examined here, are incident cases participating in a larger case-control study at two Pediatric Hospitals of third level of medical attention in Mexico City, that form part of the public health system. Nine different tumors positive and four negative to HPV by PCR were included in the experimental design. From these, seven are unilateral and six are bilateral and are considered biological replicas. Two unilateral and two bilateral cases were chosen to make technical replicas. From the surgical specimens, two tumor portions were obtained, one was frozen, DNA was extracted from it, and HPV status was assigned using MY09 and MY11 primers by PCR. Another portion of tumor tissue was used to grow in culture, separating viable cells from non viable cells through a ficoll gradient. In the eye, retinoblastoma usually grows into the vitreous which has no cells, and thus the tissue obtained is predominantly formed by tumor cells and few endothelial cells from capillaries in the tumor. Retinoblastoma grow in culture as non adherent cells, and when adherent cells were also present, cell suspension was moved to a new dish to keep retinoblastoma cells as the main or only cellular type as possible. We used a two channel platform with in house spotted microarrays. Since retinoblastoma has known classes: uni and bilateral, we sought to verify these classes or discover new, we used a class discovery approach and a reference experimental design. As the reference sample we used RNA form exponentially growing Saccharomyces cerevisiae because major signaling pathways and basic cellular processes among Saccharomyces cerevisiae and mammalian cells including cell cycle control and DNA repair mechanisms have a high degree of conservation. Also because yeast is easy to grow, and thus a reliable and robust source of reference RNA.

Dataset Information

Human genetic evidence for involvement of CD137 in atherosclerosis.

Publications

Human genetic evidence for involvement of CD137 in atherosclerosis.

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