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; groep; 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 Li; Kiran 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; Abbas Dehghan; Cornelia van Duijn; Albert Hofman; Andre Uitterlinden

doi:10.1371/journal.pone.0025734

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
, groep
, 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 Li, Kiran 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, Abbas Dehghan, Cornelia van Duijn, Albert Hofman, Andre Uitterlinden

Massachusetts General Hospital
Massachusetts Institute of Technology
University of Pennsylvania
University of Leicester
Glenfield Hospital
University of Lübeck
Stanford University School of Medicine
University of Texas Health Science Center at Houston
University of Leeds, School of Medicine
University of Regensburg
Tampere University Hospital and Tampere University
University of Ottawa
deCODE Genetics
University of Iceland
HudsonAlpha Institute for Biotechnology
Boston University School of Public Health
The Framingham Heart Study
Tel Aviv University
Hebrew SeniorLife
Skåne University Hospital
Kaiser Permanente Northern California (Oakland)
University of California at San Francisco
Cleveland Clinic Foundation
Johannes Gutenberg University Mainz

Research output: Contribution to journal › Article › Academic › peer-review

48 Citations (Scopus)

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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 language	English
Article number	e25734
Journal	PLoS ONE
Volume	6
Issue number	12
DOIs	https://doi.org/10.1371/journal.pone.0025734
Publication status	Published - 6 Dec 2011

Bibliographical note

Funding:
The MONICA/KORA Augsburg case-cohort study was supported by research grants from the German Research Foundation (TH-784/2-1, TH-784/2-2)
and by additional funds provided by the German Diabetes Center (Du¨sseldorf, Germany); the Federal Ministry of Health (Berlin, Germany); the Federal Ministry of
Education, Science, Research and Technology (National Genome Research Net-2, cardiovascular, 01GS0423; Berlin, Germany); the Ministry of Innovation, Science,
Research and Technology of the state North Rhine-Westphalia (Du¨sseldorf, Germany); Helmholtz Zentrum Mu¨nchen, German Research Center for Environmental
Health, Neuherberg, Germany (formerly GSF National Research Center for Environment and Health; funded by the German Federal Ministry of Education, Science,
Research and Technology and by the State of Bavaria); and the University of Ulm. The MONICA/KORA Augsburg cohort study was financed by the Helmholtz
Zentrum Mu¨nchen and supported by grants from the Federal Ministry of Education and Research, Berlin, Germany. The Athero-Express study was partially funded
by the University Medical Center Utrecht. For the complete list of funders of the CARDIoGRAM Consortium and their support information, please refer to our
supplementary file entitled ‘‘Text S2. Funding information and competing interests of the CARDIoGRAM Consortium’’. The funders had no role in study design,
data collection and analysis, decision to publish, or preparation of the manuscript.

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SDG 3 Good Health and Well-being

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10.1371/journal.pone.0025734

RANTES CCL5 and Risk for Coronary Events Results from the MONICA KORA Augsburg Case-Cohort, Athero-Express and CARDIoGRAM StudiesFinal published version, 176 KB

Cite this

Kathiresan, S., Reilly, M. P., groep, 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., ... Uitterlinden, A. (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), Article e25734. https://doi.org/10.1371/journal.pone.0025734

@article{3d32e4e9e63b4565a5e3e27215441280,

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

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.",

author = "Sekar Kathiresan and Reilly, \{Muredach P.\} and groep and Samani, \{Nilesh J.\} and Heribert Schunkert and Jeanette Erdmann and Assimes, \{Themistocles L.\} and Eric Boerwinkle and Alistair Hall and Christian Hengstenberg and K{\"o}nig, \{Inke R.\} and Reijo Laaksonen and Ruth McPherson and Thompson, \{John R.\} and Unnur Thorsteinsdottir and Andreas Ziegler and Devin Absher and Li Chen and Cupples, \{L. Adrienne\} and Eran Halperin and Mingyao Li and Kiran Musunuru and Michael Preuss and Arne Schillert and Gudmar Thorleifsson and Voight, \{Benjamin F.\} and Wells, \{George A.\} and Panos Deloukas and Hilma Holm and Robert Roberts and Stewart, \{Alexandre F.R.\} and Stephen Fortmann and Alan Go and Mark Hlatky and Carlos Iribarren and Joshua Knowles and Richard Myers and Thomas Quertermous and Steven Sidney and Neil Risch and Hua Tang and Stefan Blankenberg and Tanja Zeller and Philipp Wild and Renate Schnabel and Christoph Sinning and Karl Lackner and Abbas Dehghan and \{van Duijn\}, Cornelia and Albert Hofman and Andre Uitterlinden",

note = "Funding: The MONICA/KORA Augsburg case-cohort study was supported by research grants from the German Research Foundation (TH-784/2-1, TH-784/2-2) and by additional funds provided by the German Diabetes Center (Du¨sseldorf, Germany); the Federal Ministry of Health (Berlin, Germany); the Federal Ministry of Education, Science, Research and Technology (National Genome Research Net-2, cardiovascular, 01GS0423; Berlin, Germany); the Ministry of Innovation, Science, Research and Technology of the state North Rhine-Westphalia (Du¨sseldorf, Germany); Helmholtz Zentrum Mu¨nchen, German Research Center for Environmental Health, Neuherberg, Germany (formerly GSF National Research Center for Environment and Health; funded by the German Federal Ministry of Education, Science, Research and Technology and by the State of Bavaria); and the University of Ulm. The MONICA/KORA Augsburg cohort study was financed by the Helmholtz Zentrum Mu¨nchen and supported by grants from the Federal Ministry of Education and Research, Berlin, Germany. The Athero-Express study was partially funded by the University Medical Center Utrecht. For the complete list of funders of the CARDIoGRAM Consortium and their support information, please refer to our supplementary file entitled {\textquoteleft}{\textquoteleft}Text S2. Funding information and competing interests of the CARDIoGRAM Consortium{\textquoteright}{\textquoteright}. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.",

year = "2011",

month = dec,

day = "6",

doi = "10.1371/journal.pone.0025734",

language = "English",

volume = "6",

journal = "PLoS ONE",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "12",

}

Kathiresan, S, Reilly, MP, groep, Samani, NJ, Schunkert, H, Erdmann, J, Assimes, TL, Boerwinkle, E, Hall, A, Hengstenberg, C, König, IR, Laaksonen, R, McPherson, R, Thompson, JR, Thorsteinsdottir, U, Ziegler, A, Absher, D, Chen, L, Cupples, LA, Halperin, E, Li, M, Musunuru, K, Preuss, M, Schillert, A, Thorleifsson, G, Voight, BF, Wells, GA, Deloukas, P, Holm, H, Roberts, R, Stewart, AFR, Fortmann, S, Go, A, Hlatky, M, Iribarren, C, Knowles, J, Myers, R, Quertermous, T, Sidney, S, Risch, N, Tang, H, Blankenberg, S, Zeller, T, Wild, P, Schnabel, R, Sinning, C, Lackner, K, Dehghan, A, van Duijn, C, Hofman, A & Uitterlinden, A 2011, 'RANTES/CCL5 and risk for coronary events: Results from the MONICA/KORA Augsburg case-cohort, Athero-express and CARDIoGRAM studies', PLoS ONE, vol. 6, no. 12, e25734. https://doi.org/10.1371/journal.pone.0025734

TY - JOUR

T1 - RANTES/CCL5 and risk for coronary events

T2 - Results from the MONICA/KORA Augsburg case-cohort, Athero-express and CARDIoGRAM studies

AU - Kathiresan, Sekar

AU - Reilly, Muredach P.

AU - groep

AU - Samani, Nilesh J.

AU - Schunkert, Heribert

AU - Erdmann, Jeanette

AU - Assimes, Themistocles L.

AU - Boerwinkle, Eric

AU - Hall, Alistair

AU - Hengstenberg, Christian

AU - König, Inke R.

AU - Laaksonen, Reijo

AU - McPherson, Ruth

AU - Thompson, John R.

AU - Thorsteinsdottir, Unnur

AU - Ziegler, Andreas

AU - Absher, Devin

AU - Chen, Li

AU - Cupples, L. Adrienne

AU - Halperin, Eran

AU - Li, Mingyao

AU - Musunuru, Kiran

AU - Preuss, Michael

AU - Schillert, Arne

AU - Thorleifsson, Gudmar

AU - Voight, Benjamin F.

AU - Wells, George A.

AU - Deloukas, Panos

AU - Holm, Hilma

AU - Roberts, Robert

AU - Stewart, Alexandre F.R.

AU - Fortmann, Stephen

AU - Go, Alan

AU - Hlatky, Mark

AU - Iribarren, Carlos

AU - Knowles, Joshua

AU - Myers, Richard

AU - Quertermous, Thomas

AU - Sidney, Steven

AU - Risch, Neil

AU - Tang, Hua

AU - Blankenberg, Stefan

AU - Zeller, Tanja

AU - Wild, Philipp

AU - Schnabel, Renate

AU - Sinning, Christoph

AU - Lackner, Karl

AU - Dehghan, Abbas

AU - van Duijn, Cornelia

AU - Hofman, Albert

AU - Uitterlinden, Andre

N1 - Funding: The MONICA/KORA Augsburg case-cohort study was supported by research grants from the German Research Foundation (TH-784/2-1, TH-784/2-2) and by additional funds provided by the German Diabetes Center (Du¨sseldorf, Germany); the Federal Ministry of Health (Berlin, Germany); the Federal Ministry of Education, Science, Research and Technology (National Genome Research Net-2, cardiovascular, 01GS0423; Berlin, Germany); the Ministry of Innovation, Science, Research and Technology of the state North Rhine-Westphalia (Du¨sseldorf, Germany); Helmholtz Zentrum Mu¨nchen, German Research Center for Environmental Health, Neuherberg, Germany (formerly GSF National Research Center for Environment and Health; funded by the German Federal Ministry of Education, Science, Research and Technology and by the State of Bavaria); and the University of Ulm. The MONICA/KORA Augsburg cohort study was financed by the Helmholtz Zentrum Mu¨nchen and supported by grants from the Federal Ministry of Education and Research, Berlin, Germany. The Athero-Express study was partially funded by the University Medical Center Utrecht. For the complete list of funders of the CARDIoGRAM Consortium and their support information, please refer to our supplementary file entitled ‘‘Text S2. Funding information and competing interests of the CARDIoGRAM Consortium’’. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

PY - 2011/12/6

Y1 - 2011/12/6

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84880505530

U2 - 10.1371/journal.pone.0025734

DO - 10.1371/journal.pone.0025734

M3 - Article

C2 - 22162987

AN - SCOPUS:84880505530

SN - 1932-6203

VL - 6

JO - PLoS ONE

JF - PLoS ONE

IS - 12

M1 - e25734

ER -

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

Abstract

Bibliographical note

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