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 SuperFamily 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 (SNP) in CD137, was significantly associated with CD137 gene expression. In the PROCARDIS and WTCCC cohorts of 13029 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 3418 individuals, the minor T allele of rs2453021 was associated with increased intima-media thickness (IMT) of the common carotid artery (CCA), as measured by ultrasonography, with presence of plaque in CCA, and with increased incidence of adverse non-cardiac 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 non-cardiac vascular events, thus providing the first human genetic evidence for involvement of CD137 in atherosclerosis.