Lancet. 2012 Mar 31;379(9822):1205-13. doi: 10.1016/S0140-6736(11)61931-4. Epub 2012 Mar 14.
Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies.
IL6R Genetics Consortium Emerging Risk Factors Collaboration,
Sarwar N,
Butterworth AS,
Freitag DF,
Gregson J,
Willeit P,
Gorman DN,
Gao P,
Saleheen D,
Rendon A,
Nelson CP,
Braund PS,
Hall AS,
Chasman DI,
Tybjærg-Hansen A,
Chambers JC,
Benjamin EJ,
Franks PW,
Clarke R,
Wilde AA,
Trip MD,
Steri M,
Witteman JC,
Qi L,
van der Schoot CE,
de Faire U,
Erdmann J,
Stringham HM,
Koenig W,
Rader DJ,
Melzer D,
Reich D,
Psaty BM,
Kleber ME,
Panagiotakos DB,
Willeit J,
Wennberg P,
Woodward M,
Adamovic S,
Rimm EB,
Meade TW,
Gillum RF,
Shaffer JA,
Hofman A,
Onat A,
Sundström J,
Wassertheil-Smoller S,
Mellström D,
Gallacher J,
Cushman M,
Tracy RP,
Kauhanen J,
Karlsson M,
Salonen JT,
Wilhelmsen L,
Amouyel P,
Cantin B,
Best LG,
Ben-Shlomo Y,
Manson JE,
Davey-Smith G,
de Bakker PI,
O'Donnell CJ,
Wilson JF,
Wilson AG,
Assimes TL,
Jansson JO,
Ohlsson C,
Tivesten Å,
Ljunggren Ö,
Reilly MP,
Hamsten A,
Ingelsson E,
Cambien F,
Hung J,
Thomas GN,
Boehnke M,
Schunkert H,
Asselbergs FW,
Kastelein JJ,
Gudnason V,
Salomaa V,
Harris TB,
Kooner JS,
Allin KH,
Nordestgaard BG,
Hopewell JC,
Goodall AH,
Ridker PM,
Hólm H,
Watkins H,
Ouwehand WH,
Samani NJ,
Kaptoge S,
Di Angelantonio E,
Harari O,
Danesh J.
Assimes TL, Quertermous T, Go AS, Hlatky MA, Knowles JW, Gudnason V, Smith AV, Panagiotakos DB, Chrysohoou C, Pitsavos C, Stefanadis C, Nelson CP, Braund PS, Samani NJ, Hall AS, Balmforth AJ, Thompson JR, Rendon A, Wilde AA, Trip MD, van der Schoot CE, Kastelein JJ, Ouwehand WH, Sivapalaratnam S, Maiwald S, Basart H, Motazacker M, de Jong JS, Dekker LR, Tanck M, Bezzina CR, Whincup PH, Morris RW, Wannamethee SG, Willeit J, Kiechl S, Gallacher J, Yarnell JW, Lowe G, Rumley A, Samani NJ, Goodall AH, Cambien F, Cushman M, Mukamal KJ, Nordestgaard BG, Tybjærg-Hansen A, Allin KH, Salomaa V, Havulinna AS, Lokki ML, Nieminen MS, Ripatti S, Sinisalo J, Hung J, McQuillan BM, Beilby JP, Thompson PL, Hólm H, Thorleifsson G, Thorgeirsson G, Thorsteinsdóttir U, Stefansson K, Salomaa V, Jula A, Männistö S, Perola M, Tikkanen E, Asselbergs FW, Boer JM, Onland-Moret NC, van der Schouw YT, Verschuren WM, de Bakker PI, Wennberg P, Jansson JH, Salomaa V, Woodward M, Benjamin EJ, Dupuis J, Fontes JD, Yin X, O'Donnell CJ, Boehnke M, Stringham HM, Tuomilehto J, Schunkert H, Erdmann J, Koenig IR, Nahrstaedt J, Loley C, Stark K, Willenborg C, Hengstenberg C, Schreiber S, Preuss M, Franks PW, Barroso I, Hallmans G, Shungin D, Thomas GN, Cheng KK, Lam TH, Jiang CC, Reich D, Harris TB, Rimm EB, Pai J, Hopewell JC, Collins R, Parish S, Armitage J, Stringham HM, Jackson A, Hveem K, Psaty BM, Wiggins KL, Heckbert SR, Smith NL, Bis JC, Melzer D, Ferrucci L, Guralnik JM, Bandinelli S, Singleton AB, Kauhanen J, Salonen JT, Tuomainen TP, Kurl S, Meade TW, Chambers JC, Kooner JS, Zhang W, Kooner AS, Das D, Kleber ME, März W, Scharnagl H, Böhm BO, Winkelmann BR, Cushman M, Tracy RP, Folsom AR, Psaty BM, Shea SJ, Stringham HM, Laakso M, Kuusisto J, Koenig W, Baumert J, Thorand B, Illig T, Meisinger C, Wilhelmsen L, Rosengren A, Jansson JO, Adamovic S, Karlsson MK, Ljunggren Ö, Mellström D, Ohlsson C, Tivesten Å, Gillum RF, Rimm EB, Manson JE, Qi L, Hu FB, Hankinson SE, Shaffer JA, Davidson KW, Wilson JF, Fraser R, Wild S, Campbell H, Rader DJ, Reilly MP, Qasim A, Qu L, Li M, Ingelsson E, Lind L, Sundström J, Syvänen AC, Amouyel P, Arveiler D, Clarke R, Watkins H, Farrall M, Hopewell JC, Peden JF, Saleheen D, Deloukas P, Sheikh N, Rasheed A, Danesh J, Cantin B, Dagenais GR, Witteman JC, Hofman A, Dehghan A, van Duijn CM, Uitterlinden AG, Steri M, Abecasis GR, Cucca F, Sanna S, Uda M, Schlessinger D, Hamsten A, Sabater-Lleal M, Silveira A, de Faire U, Gigante B, Best LG, Howard BV, Davey-Smith G, Ben-Shlomo Y, Onat A, Ingelsson E, Sundström J, Lind L, Basu S, Syvänen AC, Ridker PM, Chasman DI, Rose LM, Wassertheil-Smoller S, Ridker PM, Buring J.
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.
Copyright © 2012 Elsevier Ltd. All rights reserved.
- PMID:
- 22421339
- [PubMed - indexed for MEDLINE]
- PMCID:
- PMC3316940
Free PMC ArticleFigure 1
IL6R genotypes and circulating concentrations of inflammation markers
Analyses were undertaken with standardised units of measurement for each marker. To enable comparison of the magnitude of associations across several different markers, associations are presented as percentage differences (calculated in reference to the weighted overall mean of each marker among the reference group). The number of participants with information about each marker is shown in the table. Details of the genotypes studied are provided in appendix p 12. Error bars show 95% CI. IL6R=interleukin-6 receptor. *Reference group (represented by a square with an arbitrary fixed size).
Lancet. 2012 March 31;379(9822):1205-1213.
Figure 3
(A) Cross-sectional associations between interleukin 6, C-reactive protein, and fibrinogen concentrations in the general population and (B) associations of interleukin 6, C-reactive protein, and fibrinogen concentrations with incident coronary heart disease
Adjusted for age, sex, smoking, body-mass index, diabetes status, systolic blood pressure, and total cholesterol. Studies included in these analyses had information on at least two of the biomarkers studied and had recorded at least ten incident coronary heart disease events during follow-up. Error bars show 95% CI.
Lancet. 2012 March 31;379(9822):1205-1213.
Figure 2
IL6R genotypes and risk of coronary heart disease
Data are shown for 51 441 cases and 136 226 controls. The odds ratio per minor allele was 0·966 (95% CI 0·950–0·982, p=4·5×10−5). Details of the genotypes studied are provided in appendix p 12. Error bars show 95% CI. *Reference group (represented by a square with in arbitrary fixed size).
Lancet. 2012 March 31;379(9822):1205-1213.
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