RANTES/CCL5 and risk for coronary events: Results from the MONICA/KORA Augsburg case-cohort, Athero-express and CARDIoGRAM studies

Sekar Kathiresan, Muredach P. Reilly, Nilesh J. Samani, Heribert Schunkert, Jeanette Erdmann, Themistocles L. Assimes, Eric Boerwinkle, Alistair Hall, Christian Hengstenberg, Inke R. König, Reijo Laaksonen, Ruth McPherson, John R. Thompson, Unnur Thorsteinsdottir, Andreas Ziegler, Devin Absher, Li Chen, L. Adrienne Cupples, Eran Halperin, Mingyao LiKiran Musunuru, Michael Preuss, Arne Schillert, Gudmar Thorleifsson, Benjamin F. Voight, George A. Wells, Panos Deloukas, Hilma Holm, Robert Roberts, Alexandre F R Stewart, Stephen Fortmann, Alan Go, Mark Hlatky, Carlos Iribarren, Joshua Knowles, Richard Myers, Thomas Quertermous, Steven Sidney, Neil Risch, Hua Tang, Stefan Blankenberg, Tanja Zeller, Philipp Wild, Renate Schnabel, Christoph Sinning, Karl Lackner, Laurence Tiret, Viviane Nicaud, Francois Cambien, Christoph Bickel, Hans J. Rupprecht, Claire Perret, Carole Proust, Thomas Münzel, Maja Barbalic, Joshua Bis, Ida Yii Der Chen, Abbas Dehghan, Serkalem Demissie-Banjaw, Aaron Folsom, Nicole Glazer, Vilmundur Gudnason, Tamara Harris, Susan Heckbert, Daniel Levy, Thomas Lumley, Kristin Marciante, Alanna Morrison, Christopher J. O'Donnell, Bruce M. Psaty, Kenneth Rice, Jerome I. Rotter, David S. Siscovick, Nicholas Smith, Albert Smith, Kent D. Taylor, Cornelia van Duijn, Kelly Volcik, Jaqueline Whitteman, Vasan Ramachandran, Albert Hofman, Andre Uitterlinden, Solveig Gretarsdottir, Jeffrey R. Gulcher, Augustine Kong, Kari Stefansson, Gudmundur Thorgeirsson, Karl Andersen, Marcus Fischer, Anika Grosshennig, Wolfgang Lieb, Patrick Linsel-Nitschke, Klaus Stark, Stefan Schreiber, H. Erich Wichmann, Zouhair Aherrahrou, Petra Bruse, Angela Doering, Thomas Illig, Norman Klopp, Christina Loley, Anja Medack, Christina Meisinger, Thomas Meitinger, Janja Nahrstedt, Annette Peters, Arnika K. Wagner, Christina Willenborg, Bernhard O. Böhm, Harald Dobnig, Tanja B. Grammer, Michael M. Hoffmann, Marcus Kleber, Winfried März, Andreas Meinitzer, Bernhard R. Winkelmann, Stefan Pilz, Wilfried Renner, Hubert Scharnagl, Tatjana Stojakovic, Andreas Tomaschitz, Karl Winkler, Candace Guiducci, Noel Burtt, Stacey B. Gabriel, Roberto Elosua, Leena Peltonen, Veikko Salomaa, Stephen M. Schwartz, Olle Melander, David Altshuler, Sonny Dandona, Olga Jarinova, Liming Qu, Robert Wilensky, William Matthai, Hakon H. Hakonarson, Joe Devaney, Mary Susan Burnett, Augusto D. Pichard, Kenneth M. Kent, Lowell Satler, Joseph M. Lindsay, Ron Waksman, Christopher W. Knouff, Dawn M. Waterworth, Max C. Walker, Vincent Mooser, Stephen E. Epstein, Daniel J. Rader, Peter S. Braund, Christopher P. Nelson, Benjamin J. Wright, Anthony J. Balmforth, Stephen G. Ball

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Abstract

Background: The chemokine RANTES (regulated on activation, normal T-cell expressed and secreted)/CCL5 is involved in the pathogenesis of cardiovascular disease in mice, whereas less is known in humans. We hypothesised that its relevance for atherosclerosis should be reflected by associations between CCL5 gene variants, RANTES serum concentrations and protein levels in atherosclerotic plaques and risk for coronary events. Methods and Findings: We conducted a case-cohort study within the population-based MONICA/KORA Augsburg studies. Baseline RANTES serum levels were measured in 363 individuals with incident coronary events and 1,908 non-cases (mean follow-up: 10.2±4.8 years). Cox proportional hazard models adjusting for age, sex, body mass index, metabolic factors and lifestyle factors revealed no significant association between RANTES and incident coronary events (HR [95% CI] for increasing RANTES tertiles 1.0, 1.03 [0.75-1.42] and 1.11 [0.81-1.54]). None of six CCL5 single nucleotide polymorphisms and no common haplotype showed significant associations with coronary events. Also in the CARDIoGRAM study (>22,000 cases, >60,000 controls), none of these CCL5 SNPs was significantly associated with coronary artery disease. In the prospective Athero-Express biobank study, RANTES plaque levels were measured in 606 atherosclerotic lesions from patients who underwent carotid endarterectomy. RANTES content in atherosclerotic plaques was positively associated with macrophage infiltration and inversely associated with plaque calcification. However, there was no significant association between RANTES content in plaques and risk for coronary events (mean follow-up 2.8±0.8 years). Conclusions: High RANTES plaque levels were associated with an unstable plaque phenotype. However, the absence of associations between (i) RANTES serum levels, (ii) CCL5 genotypes and (iii) RANTES content in carotid plaques and either coronary artery disease or incident coronary events in our cohorts suggests that RANTES may not be a novel coronary risk biomarker. However, the potential relevance of RANTES levels in platelet-poor plasma needs to be investigated in further studies.

Original languageEnglish (US)
Article numbere25734
JournalPloS one
Volume6
Issue number12
DOIs
StatePublished - Dec 6 2011

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    Kathiresan, S., Reilly, M. P., Samani, N. J., Schunkert, H., Erdmann, J., Assimes, T. L., Boerwinkle, E., Hall, A., Hengstenberg, C., König, I. R., Laaksonen, R., McPherson, R., Thompson, J. R., Thorsteinsdottir, U., Ziegler, A., Absher, D., Chen, L., Cupples, L. A., Halperin, E., ... Ball, S. G. (2011). RANTES/CCL5 and risk for coronary events: Results from the MONICA/KORA Augsburg case-cohort, Athero-express and CARDIoGRAM studies. PloS one, 6(12), [e25734]. https://doi.org/10.1371/journal.pone.0025734