Abstract
Background: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods: In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings: The minor allele frequency of Asp358Ala was 39. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3 (95 CI 30·4-38·2) and of interleukin 6 by 14·6 (10·7-18·4), and mean concentration of C-reactive protein was reduced by 7·5 (5·9-9·1) and of fibrinogen by 1·0 (0·7-1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4 (1·8-5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation: Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease. Funding: British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1205-1213 |
| Number of pages | 9 |
| Journal | The Lancet |
| Volume | 379 |
| Issue number | 9822 |
| DOIs | |
| State | Published - Mar 1 2012 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Medicine(all)
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Interleukin-6 receptor pathways in coronary heart disease : A collaborative meta-analysis of 82 studies. / Members of the IL6R Genetics Consortium and the Emerging Risk Factors Collaboration.
In: The Lancet, Vol. 379, No. 9822, 01.03.2012, p. 1205-1213.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Interleukin-6 receptor pathways in coronary heart disease
T2 - A collaborative meta-analysis of 82 studies
AU - Members of the IL6R Genetics Consortium and the Emerging Risk Factors Collaboration
AU - Sarwar, Nadeem
AU - Butterworth, Adam S.
AU - Freitag, D. F.
AU - Gregson, J.
AU - Willeit, P.
AU - Gorman, D. N.
AU - Gao, P.
AU - Saleheen, D.
AU - Rendon, A.
AU - Nelson, C. P.
AU - Braund, P. S.
AU - Hall, A. S.
AU - Chasman, D. I.
AU - Tybjærg-Hansen, A.
AU - Chambers, J. C.
AU - Benjamin, E. J.
AU - Franks, P. W.
AU - Clarke, R.
AU - Wilde, A. A.
AU - Trip, M. D.
AU - Steri, M.
AU - Witteman, J. C.
AU - Qi, L.
AU - van der Schoot, C. E.
AU - de Faire, U.
AU - Erdmann, J.
AU - Stringham, H. M.
AU - Koenig, W.
AU - Rader, D. J.
AU - Melzer, D.
AU - Reich, D.
AU - Psaty, B. M.
AU - Kleber, M. E.
AU - Panagiotakos, D. B.
AU - Willeit, J.
AU - Wennberg, P.
AU - Woodward, M.
AU - Adamovic, S.
AU - Rimm, E. B.
AU - Meade, T. W.
AU - Gillum, R. F.
AU - Shaffer, J. A.
AU - Hofman, A.
AU - Onat, A.
AU - Sundström, J.
AU - Wassertheil-Smoller, S.
AU - Mellström, D.
AU - Gallacher, J.
AU - Cushman, M.
AU - Fontes, Joao Daniel T.
PY - 2012/3/1
Y1 - 2012/3/1
N2 - Background: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods: In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings: The minor allele frequency of Asp358Ala was 39. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3 (95 CI 30·4-38·2) and of interleukin 6 by 14·6 (10·7-18·4), and mean concentration of C-reactive protein was reduced by 7·5 (5·9-9·1) and of fibrinogen by 1·0 (0·7-1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4 (1·8-5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation: Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease. Funding: British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.
AB - Background: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods: In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings: The minor allele frequency of Asp358Ala was 39. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3 (95 CI 30·4-38·2) and of interleukin 6 by 14·6 (10·7-18·4), and mean concentration of C-reactive protein was reduced by 7·5 (5·9-9·1) and of fibrinogen by 1·0 (0·7-1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4 (1·8-5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation: Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease. Funding: British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.
UR - http://www.scopus.com/inward/record.url?scp=84859210770&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84859210770&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(11)61931-4
DO - 10.1016/S0140-6736(11)61931-4
M3 - Article
C2 - 22421339
AN - SCOPUS:84859210770
VL - 379
SP - 1205
EP - 1213
JO - The Lancet
JF - The Lancet
SN - 0140-6736
IS - 9822
ER -