Human Genetic Evidence for Involvement of CD137 in Atherosclerosis
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.
This study was supported by the Swedish Heart-Lung Foundation, the Wenner-Gren Foundation, Karolinska Institutet, Stiftelsen för Gamla Tjänarinnor, the Swedish Research Council (projects 0593, 6816 and 8691 and Linnaeus support 8703), the Swedish Foundation for Strategic Research, the Cardiovascular and Diabetes Programmes of the Karolinska Institutet and Stockholm County Council, the Knut and Alice Wallenberg Foundation and the European Commission (AtheroRemo, PROCARDIS and IMPROVE collaborative projects), the Academy of Finland, the Ministry of Education and Culture of Finland, the City of Kuopio, the British Heart Foundation and the Italian Ministry of Health (Ricerca Corrente). SE Humphries is supported by the British Heart Foundation (PG08/008).
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