The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis
Open accessAbstract
BACKGROUND: A high circulating concentration of interleukin 6 is associated with increased risk of coronary heart disease. Blockade of the interleukin-6 receptor (IL6R) with a monoclonal antibody (tocilizumab) licensed for treatment of rheumatoid arthritis reduces systemic and articular inflammation. However, whether IL6R blockade also reduces risk of coronary heart disease is unknown. METHODS: Applying the mendelian randomisation principle, we used single nucleotide polymorphisms (SNPs) in the gene IL6R to evaluate the likely efficacy and safety of IL6R inhibition for primary prevention of coronary heart disease. We compared genetic findings with the effects of tocilizumab reported in randomised trials in patients with rheumatoid arthritis. FINDINGS: In 40 studies including up to 133,449 individuals, an IL6R SNP (rs7529229) marking a non-synonymous IL6R variant (rs8192284; p.Asp358Ala) was associated with increased circulating log interleukin-6 concentration (increase per allele 9·45%, 95% CI 8·34-10·57) as well as reduced C-reactive protein (decrease per allele 8·35%, 95% CI 7·31-9·38) and fibrinogen concentrations (decrease per allele 0·85%, 95% CI 0·60-1·10). This pattern of effects was consistent with IL6R blockade from infusions of tocilizumab (4-8 mg/kg every 4 weeks) in patients with rheumatoid arthritis studied in randomised trials. In 25,458 coronary heart disease cases and 100,740 controls, the IL6R rs7529229 SNP was associated with a decreased odds of coronary heart disease events (per allele odds ratio 0·95, 95% CI 0·93-0·97, p=1·53×10(-5)). INTERPRETATION: On the basis of genetic evidence in human beings, IL6R signalling seems to have a causal role in development of coronary heart disease. IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials. Genetic studies in populations could be used more widely to help to validate and prioritise novel drug targets or to repurpose existing agents and targets for new therapeutic uses. FUNDING: UK Medical Research Council; British Heart Foundation; Rosetrees Trust; US National Heart, Lung, and Blood Institute; Du Pont Pharma; Chest, Heart and Stroke Scotland; Wellcome Trust; Coronary Thrombosis Trust; Northwick Park Institute for Medical Research; UCLH/UCL Comprehensive Medical Research Centre; US National Institute on Aging; Academy of Finland; Netherlands Organisation for Health Research and Development; SANCO; Dutch Ministry of Public Health, Welfare and Sports; World Cancer Research Fund; Agentschap NL; European Commission; Swedish Heart-Lung Foundation; Swedish Research Council; Strategic Cardiovascular Programme of the Karolinska Institutet; Stockholm County Council; US National Institute of Neurological Disorders and Stroke; MedStar Health Research Institute; GlaxoSmithKline; Dutch Kidney Foundation; US National Institutes of Health; Netherlands Interuniversity Cardiology Institute of the Netherlands; Diabetes UK; European Union Seventh Framework Programme; National Institute for Healthy Ageing; Cancer Research UK; MacArthur Foundation.
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Genetic evidence suggests that IL-6 may be causal for atherosclerotic cardiovascular disease.
“genetic evidence suggests that IL-6 may be causal for atherosclerotic cardiovascular disease, 24,25”
From Comprehensive Long-Term Changes in Cardiovascular Risk Biomarkers With Tirzepatide (2026) · cites this paper as [25]
The Discussion reports strong genetic evidence for a causal role of IL6R signalling in coronary heart disease. The claim broadens that finding to IL-6 itself and to atherosclerotic cardiovascular disease generally; the cited passages do not establish those broader claims. (LLM, conf=0.86)
Experimental — accuracy not yet measuredGWAS, meta-analysis, exome analysis and SNP mapping have associated IL-6, IL-6R and gp130 with inflammatory diseases such as RA and coronary artery disease.
“Genome-wide association studies (GWAS), meta-analysis, exome analysis and single nucleotide polymorphism (SNP) mapping have associated IL-6, IL-6R and gp130 with inflammatory diseases such as RA and coronary artery disease (263–269).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [265]
The Discussion (page not specified) reports that an IL6R variant was associated with reduced coronary heart disease risk, and the Methods describe analysis of IL6R SNPs. The paper discusses rheumatoid arthritis in connection with tocilizumab trials, but does not report genetic associations linking IL6 or gp130 to rheumatoid arthritis, or exome analyses establishing the broader claim. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAssociations were identified between IL6R pQTLs and CAD, rheumatoid arthritis and 7 other disease traits, thereby supporting the findings of the study.
“We also identified associations between IL6R pQTLs and CAD, rheumatoid arthritis and 7 other disease traits (Supplementary Table S12), thereby supporting the findings of the study69.”
From Genetic determinants of plasma protein levels in the Estonian population (2024) · cites this paper as [69]
The Results report an association between an IL6R variant and reduced coronary heart disease risk. The paper discusses rheumatoid arthritis in connection with trials of the IL6R-blocking drug tocilizumab, but does not report an association between IL6R variants and rheumatoid arthritis. The seven other traits are presented as the citing authors’ own findings, not as findings attributed to this source. (LLM, conf=0.86)
Experimental — accuracy not yet measuredOne large study reported a near significant effect (P = 0.06) of a functional variant causing impaired signalling at the IL-6 receptor with reduced risk of developing diabetes mellitus.
“One large study reported a near significant effect ( P = 0.06) of a functional variant causing impaired signalling at the IL-6 receptor with reduced risk of developing diabetes mellitus 44.”
From Type 2 diabetes mellitus and psychological stress — a modifiable risk factor (2017) · cites this paper as [44]
A previous study has shown a link between IL6R and CAD.
“A previous study has shown a link between IL6R and CAD69.”
From Genetic determinants of plasma protein levels in the Estonian population (2024) · cites this paper as [69]
The IL6R SNP rs7529229, marking non-synonymous variant rs8192284 (p.Asp358Ala), is associated with increased circulating IL-6 levels.
“Confirming the role of IL-6 in health, in a large Mendelian randomization analysis, the IL6R SNP rs7529229, marking a non-synonymous IL6R variant (rs8192284; p.Asp358Ala), was associated with increased circulating IL-6 levels24.”
From Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty (2018) · cites this paper as [24]
Variants in IL6R are associated with increased risk of coronary artery disease, rheumatoid arthritis, atrial fibrillation, abdominal aortic aneurysm, asthma, type 1 diabetes, and depression.
“Variants in the IL6R gene have been found to be associated with increased risk of coronary artery disease24, rheumatoid arthritis, atrial fibrillation, and abdominal aortic aneurysm, and with increased susceptibility to asthma, type 1 diabetes, and depression36,37.”
From Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty (2018) · cites this paper as [24]
CETP inhibitors exert their relatively modest cardioprotective effects on the basis that in addition to their HDL-C raising effects, more potent CETP inhibitors also lower apolipoprotein B.
“CETP inhibitors exert their relatively modest cardioprotective effects on the basis that in addition to their HDL-C raising effects, more potent CETP inhibitors also lower apolipoprotein B 22,23,75 .”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [23]
The approach outlined here to obtaining a scaling estimate has generally held true for lipid-lowering therapies and risk of cardiovascular disease, but there are several potential reasons why the derivation of such a scaling for other therapeutic target-indication pairs may pose a challenge.
“The approach outlined here to obtaining a scaling estimate has generally held true for lipid-lowering therapies and risk of cardiovascular disease 22,23,40,92 but there are several potential reasons why the derivation of such a scaling for other therapeutic target-indication pairs may pose a challenge.”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [23]
Using SNPs located in CETP associated with HDL-C at genome-wide significant levels in a drug-target MR suggests that modifying HDL-C via CETP is likely to reduce risk of CHD.
“However, using SNPs located in CETP associated with HDL-C at genome-wide significant levels in a drug-target MR suggests that modifying HDL-C via CETP, is likely to reduce risk of CHD 23,103 .”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [23]
CETP variants associate with risk of CHD; APOA1 variants do not associate with risk of CHD.
“CETP 23 variants associate with of CHD; APOA1 117 variants do not associate with risk of CHD”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [23]
Various statistical methods have been proposed to reduce weak instrument bias due to sample overlap and bias due to winner's curse.
“Various statistical methods have been proposed to reduce weak instrument bias due to sample overlap and bias due to winner’s curse (see Section 3) 43– 45 .”
From Guidelines for performing Mendelian randomization investigations (2020) · cites this paper as [43]
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Cites
Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement
Moher, D., Liberati, A., Tetzlaff, J., Altman, D. G., & for the PRISMA Group (2009) · BMJ · doi:10.1136/bmj.b2535 · Cited by 83,823 · see citing works
Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement
Moher, D., Liberati, A., Tetzlaff, J., Altman, D. G., & The PRISMA Group (2009) · PLoS Medicine · doi:10.1371/journal.pmed.1000097 · Cited by 64,042 · see citing works
Measuring inconsistency in meta-analyses
Higgins, J. P. T., Thompson, S. G., Deeks, J. J., & Altman, D. G. (2003) · BMJ · doi:10.1136/bmj.327.7414.557 · Cited by 63,139 · see citing works
Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement.
(2009) · PubMed Central · Cited by 44,859 · see citing works
Friedewald, W. T., Levy, R. I., & Fredrickson, D. S. (1972) · Clinical Chemistry · doi:10.1093/clinchem/18.6.499 · Cited by 32,423 · see citing works
Atherosclerosis--an inflammatory disease
Ross, R. (1999) · New England Journal of Medicine · doi:10.1056/nejm199901143400207 · Cited by 21,725 · see citing works
Wang, G., Ma, R., Qiao, G., Wada, K., Aizawa, Y., & Satoh, T. (2015) · Integrative Medicine International · doi:10.1159/000368408 · Cited by 18,759 · see citing works
Haploview: analysis and visualization of LD and haplotype maps
Barrett, J., Fry, B., Maller, J., & Daly, M. (2005) · Bioinform. · doi:10.1093/bioinformatics/bth457 · Cited by 15,086 · see citing works
The Human Genome Browser at UCSC
Kent, W. J., Sugnet, C. W., Furey, T. S., Roskin, K. M., Pringle, T. H., Zahler, A. M., & Haussler, A. D. (2002) · Genome Research · doi:10.1101/gr.229102 · Cited by 10,400 · see citing works
Davey Smith, G., & Ebrahim, S. (2003) · International Journal of Epidemiology · doi:10.1093/ije/dyg070 · Cited by 5,882 · see citing works
Hindorff, L. A., Sethupathy, P., Junkins, H. A., Ramos, E. M., Mehta, J. P., Collins, F. S., & Manolio, T. A. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0903103106 · Cited by 4,013 · see citing works
Multi-Ethnic Study of Atherosclerosis: Objectives and Design
Bild, D. E. (2002) · American Journal of Epidemiology · doi:10.1093/aje/kwf113 · Cited by 3,942 · see citing works
The Cardiovascular Health Study: design and rationale.
Fried, L. P., Borhani, N. O., Enright, P., Furberg, C. D., Gardin, J. M., Kronmal, R. A., Kuller, L. H., Manolio, T. A., Mittelmark, M. B., Newman, A., et al. (1991) · Annals of Epidemiology · doi:10.1016/1047-2797(91)90005-w · Cited by 3,652 · see citing works
Ridker, P. M., Rifai, N., Stampfer, M. J., & Hennekens, C. H. (2000) · Circulation · doi:10.1161/01.cir.101.15.1767 · Cited by 2,429 · see citing works
Epidemiological approaches to heart disease: the Framingham study
Dawber, T. R., Meadors, G. F., & Moore, F. E. (1951) · American Journal of Public Health and the Nations Health · doi:10.2105/ajph.41.3.279 · Cited by 2,148 · see citing works
Genomewide Association Analysis of Coronary Artery Disease
Samani, N. J., Erdmann, J., Hall, A. S., Hengstenberg, C., Mangino, M., Mayer, B., Dixon, R. J., Meitinger, T., Braund, P., Wichmann, H.-E., et al. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa072366 · Cited by 2,044 · see citing works
Cardia: study design, recruitment, and some characteristics of the examined subjects
FRIEDMAN, G. D., Cutter, G., Donahue, R. P., Hughes, G. H., Hulley, S. B., Jacobs, D. R., Liu, K., & Savage, P. J. (1988) · Journal of Clinical Epidemiology · doi:10.1016/0895-4356(88)90080-7 · Cited by 1,689 · see citing works
Smolen, J. S., Beaulieu, A. D., Rubbert‐Roth, A., Ramos-Remus, C., Rovensky, J., Alecock, E., WOODWORTH, T. G., & Alten, R. (2008) · The Lancet · doi:10.1016/s0140-6736(08)60453-5 · Cited by 1,399 · see citing works
Fowkes, F. G. R., Housley, E., Cawood, E. H. H., Macintyre, C. C. A., Ruckley, C. V., & Prescott, R. J. (1991) · International Journal of Epidemiology · doi:10.1093/ije/20.2.384 · Cited by 1,179 · see citing works
Emery, P., Keystone, E., Tony, H. P., Cantagrel, A., van Vollenhoven, R., Sanchez, A., Alecock, E., Lee, J., & Kremer, J. (2008) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2008.092932 · Cited by 1,104 · see citing works
Cohort profile: 1958 British birth cohort (National Child Development Study)
Power, C., & Elliott, J. (2005) · International Journal of Epidemiology · doi:10.1093/ije/dyi183 · Cited by 978 · see citing works
Genovese, M. C., McKay, J. D., Nasonov, E. L., Mysler, E. F., da Silva, N. A., Alecock, E., Woodworth, T., & Gomez‐Reino, J. J. (2008) · Arthritis & Rheumatism · doi:10.1002/art.23940 · Cited by 855 · see citing works
the CORGI Consortium, Tomlinson, I., Webb, E., Carvajal-Carmona, L., Broderick, P., Kemp, Z., Spain, S., Penegar, S., Chandler, I., Gorman, M., et al. (2007) · Nature Genetics · doi:10.1038/ng2085 · Cited by 808 · see citing works
Ferrucci, L., Bandinelli, S., Benvenuti, E., Iorio, A. D., Macchi, C., Harris, T. B., & Guralnik, J. M. (2000) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2000.tb03873.x · Cited by 797 · see citing works
Maini, R. N., Taylor, P. C., Szechinski, J., Pavelka, K., Bröll, J., Balint, G., Emery, P., Raemen, F., Petersen, J., Smolen, J., et al. (2006) · Arthritis & Rheumatism · doi:10.1002/art.22033 · Cited by 790 · see citing works
Cohort Profile: The Whitehall II study
Marmot, M. G., & Brunner, E. J. (2004) · International Journal of Epidemiology · doi:10.1093/ije/dyh372 · Cited by 790 · see citing works
Nishimoto, N., Yoshizaki, K., Miyasaka, N., Yamamoto, K., Kawai, S., Takeuchi, T., Hashimoto, J., Azuma, J., & Kishimoto, T. (2004) · Arthritis & Rheumatism · doi:10.1002/art.20303 · Cited by 786 · see citing works
Stacey, S. N., Manolescu, A., Sulem, P., Rafnar, T., Gudmundsson, J., Gudjonsson, S. A., Masson, G., Jakobsdottir, M., Thorlacius, S., Helgason, A., et al. (2007) · Nature Genetics · doi:10.1038/ng2064 · Cited by 786 · see citing works
Nishimoto, N., Terao, K., Mima, T., Nakahara, H., Takagi, N., & Kakehi, T. (2008) · Blood · doi:10.1182/blood-2008-05-155846 · Cited by 781 · see citing works
Implementation of the women's health initiative study design
Anderson, G. L., Manson, J. E., Wallace, R. B., Lund, B., Hall, D., Davis, S., Shumaker, S. A., Wang, C., Stein, E. A., & Prentice, R. L. (2003) · Annals of Epidemiology · doi:10.1016/s1047-2797(03)00043-7 · Cited by 757 · see citing works
The soluble interleukin 6 receptor: mechanisms of production and implications in disease
Jones, S. A., Horiuchi, S., Topley, N., Yamamoto, N., & Fuller, G. M. (2001) · The FASEB Journal · doi:10.1096/fj.99-1003rev · Cited by 684 · see citing works
Danesh, J., Kaptoge, S., Mann, A. G., Sarwar, N., Wood, A., Angleman, S. B., Wensley, F., Higgins, J. P. T., Lennon, L., Eiriksdottir, G., et al. (2008) · PLoS Medicine · doi:10.1371/journal.pmed.0050078 · Cited by 676 · see citing works
C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC) (2011) · BMJ · doi:10.1136/bmj.d548 · Cited by 642 · see citing works
Reilly, M. P., Li, M., He, J., Ferguson, J. F., Stylianou, I. M., Mehta, N. N., Burnett, M. S., Devaney, J. M., Knouff, C. W., Thompson, J. R., et al. (2011) · The Lancet · doi:10.1016/s0140-6736(10)61996-4 · Cited by 539 · see citing works
The soluble interleukin‐6 receptor is generated by shedding
Müllberg, J., Schooltink, H., Stoyan, T., Günther, M., Graeve, L., Buse, G., Mackiewicz, A. A., Heinrich, P. C., & Rose‐John, S. (1993) · European Journal of Immunology · doi:10.1002/eji.1830230226 · Cited by 507 · see citing works
Common genetic variation near MC4R is associated with waist circumference and insulin resistance
Chambers, J. C., Elliott, P., Zabaneh, D., Zhang, W., Li, Y., Froguel, P., Balding, D. J., Scott, J., & Kooner, J. S. (2008) · Nature Genetics · doi:10.1038/ng.156 · Cited by 497 · see citing works
The paradigm of IL-6: from basic science to medicine.
Naka, T., Nishimoto, N., & Kishimoto, T. (2002) · Arthritis Research · doi:10.1186/ar565 · Cited by 480 · see citing works
A genome-wide association study identifies protein quantitative trait loci (pQTLs)
Melzer, D., Perry, J. R. B., Hernandez, D., Corsi, A.-M., Stevens, K., Rafferty, I., Lauretani, F., Murray, A., Gibbs, J. R., Paolisso, G., et al. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.1000072 · Cited by 480 · see citing works
The Familial Aggregation of Obstructive Sleep Apnea
Redline, S., Tishler, P. V., Tosteson, T. D., Williamson, J., Kump, K., Browner, I., Ferrette, V., & Krejci, P. (1995) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/ajrccm/151.3_pt_1.682 · Cited by 473 · see citing works
The design of a prospective study of pravastatin in the elderly at risk (PROSPER)
Shepherd, J., Blauw, G. J., Murphy, M. B., Cobbe, S. M., Bollen, E. L. E. M., Buckley, B. M., Ford, I., Jukema, J. W., Hyland, M., Gaw, A., et al. (1999) · The American Journal of Cardiology · doi:10.1016/s0002-9149(99)00533-0 · Cited by 449 · see citing works
Kremer, J. M., Blanco, R., Brzosko, M., Burgos‐Vargas, R., Halland, A.-M., Vernon, E., Ambs, P., & Fleischmann, R. (2010) · Arthritis & Rheumatism · doi:10.1002/art.30158 · Cited by 405 · see citing works
Schunkert, H., Götz, A., Braund, P. S., McGinnis, R. E., Trégouët, D., Mangino, M., Linsel‐Nitschke, P., Cambien, F., Hengstenberg, C., Stark, K. J., et al. (2008) · Circulation · doi:10.1161/circulationaha.107.730614 · Cited by 385 · see citing works
Keating, B. J., Tischfield, S. E., Murray, S. S., Bhangale, T., Price, T. S., Glessner, J., Galver, L., Barrett, J. C., Grant, S. F. A., Farlow, D., et al. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003583 · Cited by 370 · see citing works
Second Manifestations of ARTerial disease (SMART) study: Rationale and design
Simons, P. C. G., Algra, A., van der Laak, M. F., Grobbee, D. E., & van der Graaf, Y. (1999) · European Journal of Epidemiology · doi:10.1023/a:1007621514757 · Cited by 366 · see citing works
Peasey, A., Bobák, M., Kubínová, R., Malyutina, S. K., Pająk, A., Tamošiūnas, A., Pikhart, H., Nicholson, A., & Marmot, M. G. (2006) · BMC Public Health · doi:10.1186/1471-2458-6-255 · Cited by 357 · see citing works
Thye, T., Vannberg, F. O., Wong, S. H., Owusu‐Dabo, E., Osei, I., Gyapong, J. O., Sirugo, G., Sisay-Joof, F., Enimil, A. K., Chinbuah, M. A., et al. (2010) · Nature Genetics · doi:10.1038/ng.639 · Cited by 354 · see citing works
Mihara, M., Kasutani, K., Okazaki, M., Nakamura, A., Kawai, S., Sugimoto, M., Matsumoto, Y., & Ohsugi, Y. (2005) · International Immunopharmacology · doi:10.1016/j.intimp.2005.05.010 · Cited by 330 · see citing works
Choy, E., & Sattar, N. (2009) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2008.101964 · Cited by 314 · see citing works
Dávila, S., Khor, C. C., Lim, C. C., Hibberd, M. L., Wright, V. J., Inwald, D. P., Nadel, S., Betts, H., Levin, M., Sim, K. S., et al. (2010) · Nature Genetics · doi:10.1038/ng.640 · Cited by 284 · see citing works
Hingorani, A. D., & Humphries, S. E. (2005) · The Lancet · doi:10.1016/s0140-6736(05)67767-7 · Cited by 277 · see citing works
Peters, M. J., Jacobs, S., Ehlers, M., Vollmer, P., Müllberg, J., Wolf, E., Brem, G., Büschenfelde, K. H. M. Z., & Rose‐John, S. (1996) · The Journal of Experimental Medicine · doi:10.1084/jem.183.4.1399 · Cited by 276 · see citing works
The soluble human IL-6 receptor. Mutational characterization of the proteolytic cleavage site.
Müllberg, J., OBERTHÜR, W., Lottspeich, F., Mehl, E., Dittrich, E., Graeve, L., Heinrich, P. C., & Rose‐John, S. (1994) · The Journal of Immunology · doi:10.4049/jimmunol.152.10.4958 · Cited by 269 · see citing works
Novel Breast Cancer Susceptibility Locus at 9q31.2: Results of a Genome-Wide Association Study
Fletcher, O., Johnson, N., Orr, N., Hosking, F. J., Gibson, L. J., Walker, K., Zélénika, D., Gut, I. G., Heath, S. C., Palles, C., et al. (2011) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djq563 · Cited by 230 · see citing works
Cohort Profile: The EPIC-NL study
Beulens, J. W. J., Monninkhof, E. M., Verschuren, W. M. M., van der Schouw, Y. T., Smit, J., Ocké, M. C., Jansen, E. H. J. M., van Dieren, S., Grobbee, D. E., Peeters, P. H. M., et al. (2009) · International Journal of Epidemiology · doi:10.1093/ije/dyp217 · Cited by 205 · see citing works
Insight into the nature of the CRP–coronary event association using Mendelian randomization
Casas, J. P., Shah, T., Cooper, J. A., Hawe, E., McMahon, A. D., Gaffney, D. F., Packard, C. J., O’Reilly, D. S. J., Juhan-Vague, I., Yudkin, J. S., et al. (2006) · International Journal of Epidemiology · doi:10.1093/ije/dyl041 · Cited by 172 · see citing works
Nishimoto, N., Ito, K., & Takagi, N. (2010) · Modern Rheumatology · doi:10.3109/s10165-010-0279-5 · Cited by 172 · see citing works
Lipid Profiles in Patients with Rheumatoid Arthritis: Mechanisms and the Impact of Treatment
Steiner, G. A., & Urowitz, M. B. (2008) · Seminars in Arthritis and Rheumatism · doi:10.1016/j.semarthrit.2008.01.015 · Cited by 167 · see citing works
Oldfield, V., Dhillon, S., & Plosker, G. (2012) · Drugs · doi:10.2165/00003495-200969050-00007 · Cited by 163 · see citing works
Undiagnosed Glucose Intolerance in the Community: the Isle of Ely Diabetes Project
Williams, D. R. R., Wareham, N. J., Brown, D. C., Byrne, C. D., Clark, P. M., Cox, B. D., Cox, L., Day, N., Hales, C. N., Palmer, C. R., et al. (1995) · Diabetic Medicine · doi:10.1111/j.1464-5491.1995.tb02058.x · Cited by 156 · see citing works
Nishimoto, N., Ito, K., & Takagi, N. (2010) · Modern Rheumatology · doi:10.1007/s10165-010-0279-5 · Cited by 154 · see citing works
Galicia, J. C., Tai, H., KOMATSU, Y., Shimada, Y., Akazawa, K., & Yoshie, H. (2004) · Genes and Immunity · doi:10.1038/sj.gene.6364120 · Cited by 145 · see citing works
Fibrinogen and coronary heart disease: test of causality by ‘Mendelian randomization’
Keavney, B. D., Danesh, J., Parish, S., Palmer, A., Clark, S., Youngman, L. D., Délepine, M., Lathrop, M. G., Peto, R., & Collins, R. (2006) · International Journal of Epidemiology · doi:10.1093/ije/dyl114 · Cited by 142 · see citing works
Candidate Gene Association Resource (CARe)
Musunuru, K., Lettre, G., Young, T., Farlow, D., Pirruccello, J. P., Ejebe, K. G., Keating, B. J., Yang, Q., Chen, M., Lapchyk, N., et al. (2010) · Circulation Cardiovascular Genetics · doi:10.1161/circgenetics.109.882696 · Cited by 139 · see citing works
Genetics of the apnea hypopnea index in Caucasians and African Americans: I. Segregation analysis
Buxbaum, S. G., Elston, R. C., Tishler, P. V., & Redline, S. S. (2002) · Genetic Epidemiology · doi:10.1002/gepi.0170 · Cited by 134 · see citing works
Baldassarre, D., Nyyssönen, K., Rauramaa, R., Fairé, U. D., Hamsten, A., Smit, A. J., Mannarino, E., Humphries, S. E., Giral, P., Grossi, E., et al. (2009) · European Heart Journal · doi:10.1093/eurheartj/ehp496 · Cited by 130 · see citing works
Vascular comorbidity in rheumatoid arthritis: potential mechanisms and solutions
Sattar, N. A., & McInnes, I. B. (2005) · Current Opinion in Rheumatology · doi:10.1097/01.bor.0000158150.57154.f9 · Cited by 126 · see citing works
Rafiq, S., Frayling, T. M., Murray, A., Hurst, A. J., Stevens, K. N., Weedon, M. N., Henley, W., Ferrucci, L., Bandinelli, S., Corsi, A.-M., et al. (2007) · Genes and Immunity · doi:10.1038/sj.gene.6364414 · Cited by 124 · see citing works
Kawashiri, S., Kawakami, A., Yamasaki, S., Imazato, T., Iwamoto, N., Fujikawa, K., Aramaki, T., Tamai, M., Nakamura, H., Ida, H., et al. (2009) · Rheumatology International · doi:10.1007/s00296-009-1303-y · Cited by 123 · see citing works
The British Regional Heart Study 1975-2004
Walker, M. (2004) · International Journal of Epidemiology · doi:10.1093/ije/dyh295 · Cited by 115 · see citing works
Dhamrait, S. S. (2004) · European Heart Journal · doi:10.1016/j.ehj.2004.01.007 · Cited by 112 · see citing works
Fleischmann, R., Halland, A., Brzosko, M., Burgos-Vargas, R., Mela, C., Vernon, E., & Kremer, J. (2013) · Journal of Rheumatology · doi:10.3899/jrheum.120447 · Cited by 112 · see citing works
Sofat, R., Hingorani, A. D., Smeeth, L., Humphries, S. E., Talmud, P. J., Cooper, J., Shah, T., Sandhu, M. S., Ricketts, S. L., Boekholdt, S. M., et al. (2010) · Circulation · doi:10.1161/circulationaha.109.865444 · Cited by 104 · see citing works
Miller, G. J., Bauer, K. A., Barzegar, S., Foley, A. J., Mitchell, J. P., Cooper, J. A., & ROSENBERG, R. D. (1995) · Thrombosis and Haemostasis · doi:10.1055/s-0038-1653729 · Cited by 104 · see citing works
Sattar, N. A., Murray, H. M., Welsh, P. I., Blauw, G. J., Buckley, B. M., Cobbe, S. M., de Craen, A. J. M., Lowe, G. D. O., Jukema, J. W., Macfarlane, P. W., et al. (2009) · PLoS Medicine · doi:10.1371/journal.pmed.1000099 · Cited by 101 · see citing works
Tocilizumab for the treatment of rheumatoid arthritis
Tanaka, T., Ogata, A., & Narazaki, M. (2010) · Expert Review of Clinical Immunology · doi:10.1586/eci.10.70 · Cited by 99 · see citing works
IL6 Gene Promoter Polymorphisms and Type 2 Diabetes
Huth, C., Heid, I. M., Vollmert, C., Gieger, C., Grallert, H., DiStefano, J. K., Langer, B., Thorand, B., Klopp, N., Hamid, Y. H., et al. (2006) · Diabetes · doi:10.2337/db06-0600 · Cited by 99 · see citing works
Tocilizumab for rheumatoid arthritis
Singh, J. A., Beg, S., & Lopez-Olivo, M. A. (2010) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd008331.pub2 · Cited by 95 · see citing works
A combined analysis of genome-wide association studies in breast cancer
Li, J., Humphreys, K., Heikkinen, T., Aittomäki, K., BLOMQVIST, C. P., Pharoah, P. D. P., Dunning, A. M., Ahmed, S., Hooning, M. J., Martens, J. W. M., et al. (2010) · Breast Cancer Research and Treatment · doi:10.1007/s10549-010-1172-9 · Cited by 93 · see citing works
Farrall, M., Green, F. R., Peden, J. F., Olsson, P. G., Clarke, R., Hellénius, M.-L., Rust, S., Lagercrantz, J., Franzosi, M. G., Schulte, H., et al. (2006) · PLoS Genetics · doi:10.1371/journal.pgen.0020072 · Cited by 87 · see citing works
Paré, G., Serre, D., Brisson, D., Anand, S. S., Montpetit, A., Tremblay, G., Engert, J. C., Hudson, T. J., & Gaudet, D. (2007) · The American Journal of Human Genetics · doi:10.1086/513286 · Cited by 86 · see citing works
The Siblings With Ischemic Stroke Study (SWISS) Protocol
Meschia, J. F., Brown, R. D., Brott, T. G., Chukwudelunzu, F. E., Hardy, J., & Rich, S. S. (2002) · BMC Medical Genetics · doi:10.1186/1471-2350-3-1 · Cited by 84 · see citing works
Clarke, R., Xu, P., Bennett, D., Lewington, S., Zondervan, K. T., Parish, S., Palmer, A., Clark, S., Cardon, L. R., Peto, R., et al. (2006) · PLoS Genetics · doi:10.1371/journal.pgen.0020107 · Cited by 84 · see citing works
Gardener, E. A., Huppert, F. A., Guralnik, J. M., & Melzer, D. R. (2006) · Journal of General Internal Medicine · doi:10.1111/j.1525-1497.2006.00564.x · Cited by 83 · see citing works
Johnson, N., Fletcher, O., Naceur‐Lombardelli, C., dos‐Santos‐Silva, I., Ashworth, A., & Peto, J. (2005) · The Lancet · doi:10.1016/s0140-6736(05)67627-1 · Cited by 83 · see citing works
ADAM17-mediated shedding of the IL6R induces cleavage of the membrane stub by γ-secretase
Chalaris, A., Gewiese, J., Paliga, K., Fleig, L., Schneede, A., Krieger, K., Rose‐John, S., & Scheller, J. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2009.12.001 · Cited by 75 · see citing works
The Edinburgh Type 2 Diabetes Study: study protocol
Price, J. F., Reynolds, R. M., Mitchell, R. J., Williamson, R. M., Fowkes, F. G. R., Deary, I. J., Lee, A. J., Frier, B. M., Hayes, P. C., & Strachan, M. W. J. (2008) · BMC Endocrine Disorders · doi:10.1186/1472-6823-8-18 · Cited by 68 · see citing works
Huth, C., Illig, T., Herder, C., Gieger, C., Grallert, H., Vollmert, C., Rathmann, W., Hamid, Y. H., Pedersen, O. B., Hansen, T. F., et al. (2008) · Annals of Medicine · doi:10.1080/07853890802337037 · Cited by 57 · see citing works
Heikkilä, K., Silander, K., Salomaa, V. V., Jousilahti, P., Koskinen, S. V. P., Pukkala, ., & Perola, M. (2010) · European Journal of Cancer · doi:10.1016/j.ejca.2010.07.032 · Cited by 56 · see citing works
The Ischemic Stroke Genetics Study (ISGS) Protocol
Meschia, J. F., Brott, T. G., Brown, R. D., Crook, R., Frankel, M., Hardy, J., Merino, J. G., Rich, S. S., Silliman, S. L., & Worrall, B. B. (2003) · BMC Neurology · doi:10.1186/1471-2377-3-4 · Cited by 52 · see citing works
Tang, T. S., Prior, S. L., Li, K., Ireland, H., Bain, S. C., Hurel, S. J., Cooper, J. A., Humphries, S. E., & Stephens, J. W. (2010) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2010.08.001 · Cited by 52 · see citing works
Does High C-reactive Protein Concentration Increase Atherosclerosis? The Whitehall II Study
Mika Kivimaki, B., Lawlor, D. A., Smith, G. D., Meena Kumari, B., Donald, A. E., Britton, A. R., Casas, J. P., Shah, T., Brunner, E. J., Timpson, N. J., et al. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003013 · Cited by 46 · see citing works
Peters, B. J. M., Pett, H., Klungel, O. H., Stricker, B. H. C., Psaty, B. M., Glazer, N. L., Wiggins, K. L., Bis, J. C., de Boer, A., & der Zee, A. H. M. (2011) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2011.06.023 · Cited by 43 · see citing works
Mika Kivimaki, B., Lawlor, D. A., Eklund, C., Smith, G. D., Hurme, M., Lehtimäki, T. J., Viikari, J. S. A., & Raitakari, O. T. (2007) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000258869.48076.14 · Cited by 40 · see citing works
Actemra poised to launch IL-6 inhibitors
Melton, L., & Coombs, A. (2008) · Nature Biotechnology · doi:10.1038/nbt0908-957 · Cited by 37 · see citing works
Genetic Loci Associated With C-Reactive Protein Levels and Risk of Coronary Heart Disease
Elliott, P. (2009) · JAMA · doi:10.1001/jama.2009.954 · Cited by 35 · see citing works
Tocilizumab for rheumatoid arthritis
Singh, J. A., Beg, S., & Lopez-Olivo, M. A. (2010) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd008331 · Cited by 33 · see citing works
Rantala, A., Lajunen, T., Juvonen, R., Silvennoinen-Kassinen, S., Peitso, A., Vainio, O., Saikku, P., & Leinonen, M. (2011) · Human Immunology · doi:10.1016/j.humimm.2010.10.010 · Cited by 24 · see citing works
A pilot genome-wide association study of early-onset breast cancer
Kibriya, M. G., Jasmine, F., Argos, M., Andrulis, I. L., John, E. M., Chang-Claude, J. C., & Ahsan, H. (2008) · Breast Cancer Research and Treatment · doi:10.1007/s10549-008-0039-9 · Cited by 22 · see citing works
Silveira, A. M. V., Hawe, E., Eriksson, P. O., Aillaud, M. F., Juhan-Vague, I., Yudkin, J. S., Margaglione, M., Minno, G. D., Mussoni, L., Tremoli, E., et al. (2004) · Thrombosis and Haemostasis · doi:10.1160/th04-06-0339 · Cited by 12 · see citing works
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Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease
Ridker, P. M., Everett, B. M., Thuren, T., MacFadyen, J. G., Chang, W. H., Ballantyne, C., Fonseca, F., Nicolau, J., Koenig, W., Anker, S. D., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1707914 · Cited by 9,482 · see citing works
Mendelian Randomization Analysis With Multiple Genetic Variants Using Summarized Data
Burgess, S., Butterworth, A., & Thompson, S. G. (2013) · Genetic Epidemiology · doi:10.1002/gepi.21758 · Cited by 6,050 · see citing works
Mendelian randomization: genetic anchors for causal inference in epidemiological studies
Davey Smith, G., & Hemani, G. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu328 · Cited by 4,677 · see citing works
Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty
Ferrucci, L., & Fabbri, E. (2018) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0064-2 · Cited by 3,690 · see citing works
Guidelines for performing Mendelian randomization investigations
Burgess, S., Smith, G. D., Davies, N. M., Dudbridge, F., Gill, D., Glymour, M. M., Hartwig, F. P., Holmes, M. V., Minelli, C., Relton, C. L., et al. (2019) · Wellcome Open Research · doi:10.12688/wellcomeopenres.15555.1 · Cited by 1,816 · see citing works
Cohort profile: The English longitudinal study of ageing
Steptoe, A., Breeze, E., Banks, J., & Nazroo, J. (2013) · International Journal of Epidemiology · doi:10.1093/ije/dys168 · Cited by 1,779 · see citing works
EPIC- InterAct Consortium, Burgess, S., Scott, R. A., Timpson, N. J., Davey Smith, G., & Thompson, S. G. (2015) · European Journal of Epidemiology · doi:10.1007/s10654-015-0011-z · Cited by 1,803 · see citing works
IL-6 in inflammation, autoimmunity and cancer
Hirano, T. (2021) · International Immunology · doi:10.1093/intimm/dxaa078 · Cited by 1,453 · see citing works
Guzik, T. J., MOHIDDIN, S. A., Dimarco, A. D., Patel, V., Savvatis, K., Marelli‐Berg, F. M., Madhur, M. S., Tomaszewski, M., Maffia, P., D’Acquisto, F., et al. (2020) · Cardiovascular Research · doi:10.1093/cvr/cvaa106 · Cited by 1,451 · see citing works
Ridker, P. M., MacFadyen, J. G., Thuren, T., Everett, B. M., Libby, P., Glynn, R. J., Ridker, P., Lorenzatti, A., Krum, H., Varigos, J., et al. (2017) · The Lancet · doi:10.1016/s0140-6736(17)32247-x · Cited by 1,344 · see citing works
Stress and cardiovascular disease
Steptoe, A., & Kivimäki, M. (2012) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2012.45 · Cited by 1,321 · see citing works
Guidelines for performing Mendelian randomization investigations
Burgess, S., Davey Smith, G., Davies, N. M., Dudbridge, F., Gill, D., Glymour, M. M., Hartwig, F. P., Holmes, M. V., Minelli, C., Relton, C. L., et al. (2020) · Wellcome Open Research · doi:10.12688/wellcomeopenres.15555.2 · Cited by 1,273 · see citing works
Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines
Rea, I. M., Gibson, D. S., McGilligan, V., McNerlan, S. E., Alexander, H. D., & Ross, O. A. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00586 · Cited by 1,267 · see citing works
Recent Developments in Mendelian Randomization Studies
Zheng, J., Baird, D. A., Borges, M. C., Bowden, J., Hemani, G., Haycock, P., Evans, D. M., & Smith, G. D. (2017) · Current Epidemiology Reports · doi:10.1007/s40471-017-0128-6 · Cited by 1,132 · see citing works
JAK and STAT Signaling Molecules in Immunoregulation and Immune-Mediated Disease
O’Shea, J. J., & Plenge, R. M. (2012) · Immunity · doi:10.1016/j.immuni.2012.03.014 · Cited by 1,146 · see citing works
The druggable genome and support for target identification and validation in drug development
Finan, C., Gaulton, A., Krüger, F. A., Lumbers, R. T., Shah, T., Engmann, J., Galver, L., Kelley, R., Karlsson, A., Santos, R., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aag1166 · Cited by 1,011 · see citing works
Rose-John, S. (2012) · International Journal of Biological Sciences · doi:10.7150/ijbs.4989 · Cited by 1,040 · see citing works
“In two recent publications, it was shown that a single nucleotide polymorphism in the IL-6R gene changing glutamine 258 into alanine resulted in higher serum concentrations of sIL-6R was connected to a lower risk of coronary heart disease [71, 72].”
BackgroundTargeting inflammation in atherosclerosis — from experimental insights to the clinic
Soehnlein, O., & Libby, P. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00198-1 · Cited by 1,042 · see citing works
Ridker, P. M. (2016) · Circulation Research · doi:10.1161/circresaha.115.306656 · Cited by 1,002 · see citing works
Tocilizumab in patients with severe COVID-19: a retrospective cohort study
Guaraldi, G., Meschiari, M., Cozzi-Lepri, A., Milic, J., Tonelli, R., Menozzi, M., Franceschini, E., Cuomo, G., Orlando, G., Borghi, V., et al. (2020) · The Lancet Rheumatology · doi:10.1016/s2665-9913(20)30173-9 · Cited by 939 · see citing works
Ong, S., Hernández‐Reséndiz, S., Crespo-Avilan, G. E., Талгатовна, М. Р., Kwek, X.-Y., Cabrera-Fuentes, H. A., & Hausenloy, D. J. (2018) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.01.001 · Cited by 925 · see citing works
Mendelian Randomization: Concepts and Scope
Richmond, R. C., & Davey Smith, G. (2022) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a040501 · Cited by 841 · see citing works
Zheng, J., Haberland, V., Baird, D., Walker, V., Haycock, P., Hurle, M., Gutteridge, A., Erola, P., Liu, Y., Luo, S., et al. (2019) · doi:10.1101/627398 · Cited by 812 · see citing works
Connecting genetic risk to disease end points through the human blood plasma proteome
Suhre, K., Arnold, M., Bhagwat, A. M., Cotton, R. J., Engelke, R., Raffler, J., Sarwath, H., Thareja, G., Wahl, A., DeLisle, R. K., et al. (2017) · Nature Communications · doi:10.1038/ncomms14357 · Cited by 800 · see citing works
Osimo, E. F., Baxter, L. J., Lewis, G., Jones, P. B., & Khandaker, G. M. (2019) · Psychological Medicine · doi:10.1017/s0033291719001454 · Cited by 774 · see citing works
Ridker, P. M., Devalaraja, M., Baeres, F. M. M., Engelmann, M. D. M., Hovingh, G. K., Ivkovic, M., Lo, L., Kling, D. F., Pérgola, P. E., Raj, D. S., et al. (2021) · The Lancet · doi:10.1016/s0140-6736(21)00520-1 · Cited by 763 · see citing works
Mendelian randomization for cardiovascular diseases: Principles and applications
Larsson, S. C., Butterworth, A. S., & Burgess, S. (2023) · European Heart Journal · doi:10.1093/eurheartj/ehad736 · Cited by 735 · see citing works
Guidelines for performing Mendelian randomization investigations: update for summer 2023
Burgess, S., Smith, G. D., Davies, N. M., Dudbridge, F., Gill, D., Glymour, M. M., Hartwig, F. P., Kutalik, Z., Holmes, M. V., Minelli, C., et al. (2023) · Wellcome Open Research · doi:10.12688/wellcomeopenres.15555.3 · Cited by 737 · see citing works
Swerdlow, D. I., Preiss, D., Kuchenbaecker, K. B., Holmes, M. V., Engmann, J. E. L., Shah, T., Sofat, R., Stender, S., Johnson, P. C. D., Scott, R. A., et al. (2015) · The Lancet · doi:10.1016/s0140-6736(14)61183-1 · Cited by 680 · see citing works
Self-citationValidating therapeutic targets through human genetics
Plenge, R. M., Scolnick, E. M., & Altshuler, D. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4051 · Cited by 712 · see citing works
Interleukin-6 Signaling and Anti-Interleukin-6 Therapeutics in Cardiovascular Disease
Ridker, P. M., & Rane, M. A. (2021) · Circulation Research · doi:10.1161/circresaha.121.319077 · Cited by 715 · see citing works
Mendelian randomization in cardiometabolic disease: challenges in evaluating causality
Holmes, M. V., Ala-Korpela, M., & Smith, G. D. (2017) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2017.78 · Cited by 679 · see citing works
Kaptoge, S. K., Seshasai, S. R. K., Gao, P., Freitag, D. F., Butterworth, A. S., Borglykke, A., Angelantonio, E. D., Gudnason, V. G., Rumley, A., Lowe, G. D. O., et al. (2013) · European Heart Journal · doi:10.1093/eurheartj/eht367 · Cited by 696 · see citing works
Fuster, J. J., Ouchi, N., Gokce, N., & Walsh, K. X. (2016) · Circulation Research · doi:10.1161/circresaha.115.306885 · Cited by 669 · see citing works
High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis
Syndicate, B. I. R. A. G. A. G. S., Eyre, S., Wellcome Trust Case Control Consortium, Bowes, J., Diogo, D., Lee, A., Barton, A., Martin, P., Zhernakova, A., Stahl, E., et al. (2012) · Nature Genetics · doi:10.1038/ng.2462 · Cited by 653 · see citing works
Interleukin-6: designing specific therapeutics for a complex cytokine
Garbers, C., Heink, S., Korn, T., & Rose-John, S. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.45 · Cited by 643 · see citing works
Interleukin-1 Beta as a Target for Atherosclerosis Therapy
Libby, P. (2017) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2017.09.028 · Cited by 629 · see citing works
Interleukin-6 and its receptors: a highly regulated and dynamic system
Wolf, J., Rose-John, S., & Garbers, C. (2014) · Cytokine · doi:10.1016/j.cyto.2014.05.024 · Cited by 618 · see citing works
Mendelian randomization studies: a review of the approaches used and the quality of reporting
Boef, A. G. C., Dekkers, O. M., & le Cessie, S. (2015) · International Journal of Epidemiology · doi:10.1093/ije/dyv071 · Cited by 610 · see citing works
Haycock, P., Burgess, S., Wade, K. H., Bowden, J., Relton, C. L., & Smith, G. D. (2016) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.115.118216 · Cited by 602 · see citing works
May, M., Gompels, M. M., Delpech, V., Porter, K., Orkin, C. M., Kegg, S., Hay, P., Johnson, M. A., Palfreeman, A., Gilson, R. J. C., et al. (2014) · AIDS · doi:10.1097/qad.0000000000000243 · Cited by 598 · see citing works
Genetic drug target validation using Mendelian randomisation
Schmidt, A. F., Finan, C., Gordillo‐Marañón, M., Asselbergs, F. W., Freitag, D. F., Patel, R. S., Tyl, B., Chopade, S., Faraway, R., Zwierzyna, M., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16969-0 · Cited by 564 · see citing works
Ridker, P. M., Libby, P., MacFadyen, J. G., Thuren, T. Y., Ballantyne, C. M., Fonseca, F. A. H., Köenig, W., Shimokawa, H., Everett, B. M., & Glynn, R. J. (2018) · European Heart Journal · doi:10.1093/eurheartj/ehy310 · Cited by 556 · see citing works
Anti-inflammatory therapies for cardiovascular disease
Ridker, P. M., & Lüscher, T. F. (2014) · European Heart Journal · doi:10.1093/eurheartj/ehu203 · Cited by 558 · see citing works
Metalloproteinases and their natural inhibitors in inflammation and immunity
Khokha, R., Murthy, A., & Weiss, A. (2013) · Nature reviews. Immunology · doi:10.1038/nri3499 · Cited by 552 · see citing works
Inflammation, Immunity, and Infection in Atherothrombosis
Libby, P., Loscalzo, J., Ridker, P. M., Farkouh, M. E., Hsue, P. Y., Fuster, V., Hasan, A. A., & Amar, S. (2018) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2018.08.1043 · Cited by 548 · see citing works
Pleiotropy and specificity: insights from the interleukin 6 family of cytokines
Murakami, M., Kamimura, D., & Hirano, T. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.027 · Cited by 533 · see citing works
Mendelian Randomization: New Applications in the Coming Age of Hypothesis-Free Causality
Evans, D. M., & Smith, G. D. (2015) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-090314-050016 · Cited by 524 · see citing works
Ridker, P. M., Howard, C. P., Walter, V., Everett, B., Libby, P., Hensen, J., & Thuren, T. (2012) · Circulation · doi:10.1161/circulationaha.112.122556 · Cited by 530 · see citing works
Type 2 diabetes mellitus and psychological stress — a modifiable risk factor
Hackett, R. A., & Steptoe, A. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.64 · Cited by 480 · see citing works
Use of allele scores as instrumental variables for Mendelian randomization
Burgess, S., & Thompson, S. G. (2013) · International Journal of Epidemiology · doi:10.1093/ije/dyt093 · Cited by 452 · see citing works
Targeting cardiovascular inflammation: next steps in clinical translation
Lawler, P. R., Bhatt, D. L., Godoy, L. C., Lüscher, T. F., Bonow, R. O., Verma, S., & Ridker, P. M. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehaa099 · Cited by 454 · see citing works
Role of inflammation in the pathogenesis of atherosclerosis and therapeutic interventions
Raggi, P., Genest, J. J., Giles, J. T., Rayner, K. J., Dwivedi, G., Beanlands, R. S., & Gupta, M. (2018) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2018.07.014 · Cited by 434 · see citing works
Monocytes and macrophages in abdominal aortic aneurysm
Raffort, J., Lareyre, F., Clément, M., Hassen‐Khodja, R., Chinetti, G., & Mallat, Z. (2017) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2017.52 · Cited by 426 · see citing works
The IL-6/gp130/STAT3 signaling axis: recent advances towards specific inhibition
Garbers, C., Aparicio-Siegmund, S., & Rose‐John, S. (2015) · Current Opinion in Immunology · doi:10.1016/j.coi.2015.02.008 · Cited by 432 · see citing works
Genetic Interleukin 6 Signaling Deficiency Attenuates Cardiovascular Risk in Clonal Hematopoiesis
Bick, A. G., Pirruccello, J. P., Griffin, G. K., Gupta, N., Gabriel, S., Saleheen, D., Libby, P., Kathiresan, S., & Natarajan, P. (2019) · Circulation · doi:10.1161/circulationaha.119.044362 · Cited by 418 · see citing works
Therapeutic strategies targeting inflammation and immunity in atherosclerosis: how to proceed?
Engelen, S. E., Robinson, A., Zurke, Y.-X., & Monaco, C. G. (2022) · Nature Reviews Cardiology · doi:10.1038/s41569-021-00668-4 · Cited by 442 · see citing works
Ridker, P. M. (2016) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2015.11.037 · Cited by 414 · see citing works
Kleveland, O., Kunszt, G., Bratlie, M., Ueland, T., Broch, K., Holte, E., Michelsen, A. E., Bendz, B., Amundsen, B. H., Espevik, T., et al. (2016) · European Heart Journal · doi:10.1093/eurheartj/ehw171 · Cited by 403 · see citing works
Svensson, E. C., Madar, A., Campbell, C. D., He, Y., Sultan, M., Healey, M. L., Xu, H., D’Aco, K., Fernandez, A., Wache-Mainier, C., et al. (2022) · JAMA Cardiology · doi:10.1001/jamacardio.2022.0386 · Cited by 395 · see citing works
Genome-wide association studies of cancer: current insights and future perspectives
Sud, A., Kinnersley, B., & Houlston, R. S. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2017.82 · Cited by 383 · see citing works
PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study
Schmidt, A. F., Swerdlow, D. I., Holmes, M. V., Patel, R. S., Fairhurst-Hunter, Z., Lyall, D. M., Hartwig, F. P., Horta, B. L., Hyppönen, E., Power, C., et al. (2017) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(16)30396-5 · Cited by 380 · see citing works
Self-citationSelecting instruments for Mendelian randomization in the wake of genome-wide association studies.
Swerdlow, D. I., Kuchenbaecker, K. B., Shah, S., Sofat, R., Holmes, M. V., White, J., Mindell, J. S., Kivimaki, M., Brunner, E. J., Whittaker, J. C., et al. (2016) · International Journal of Epidemiology · doi:10.1093/ije/dyw088 · Cited by 387 · see citing works
Self-citationInterplay between interleukin-6 signaling and the vascular endothelium in cytokine storms
Kang, S., & Kishimoto, T. (2021) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00649-0 · Cited by 382 · see citing works
Hamer, M., Lavoie, K., & Bacon, S. (2013) · British Journal of Sports Medicine · doi:10.1136/bjsports-2013-092993 · Cited by 374 · see citing works
Historical overview of the interleukin-6 family cytokine
Kang, S., Narazaki, M., Metwally, H., & Kishimoto, T. (2020) · Journal of Experimental Medicine · doi:10.1084/jem.20190347 · Cited by 360 · see citing works
Milaneschi, Y., Kappelmann, N., Ye, Z., Lamers, F., Moser, S., Jones, P. B., Burgess, S., Penninx, B. W. J. H., & Khandaker, G. M. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01188-w · Cited by 371 · see citing works
Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease
Folkersen, L., Fauman, E., Sabater-Lleal, M., Strawbridge, R. J., Frånberg, M., Sennblad, B., Baldassarre, D., Veglia, F., Humphries, S. E., Rauramaa, R., et al. (2017) · PLOS Genetics · doi:10.1371/journal.pgen.1006706 · Cited by 343 · see citing works
Inflamm-ageing: the role of inflammation in age-dependent cardiovascular disease
Liberale, L., Montecucco, F., Tardif, J., Libby, P., & Camici, G. G. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz961 · Cited by 347 · see citing works
Critical roles of inflammation in atherosclerosis
Moriya, J. (2018) · Journal of Cardiology · doi:10.1016/j.jjcc.2018.05.010 · Cited by 340 · see citing works
The varying faces of IL-6: from cardiac protection to cardiac failure
Fontes, J. A., Rose, N., & Čiháková, D. (2015) · Cytokine · doi:10.1016/j.cyto.2014.12.024 · Cited by 334 · see citing works
Flavonoids as Cytokine Modulators: A Possible Therapy for Inflammation-Related Diseases
Leyva-López, N., Gutierrez-Grijalva, E., Ambriz-Perez, D., & Heredia, J. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17060921 · Cited by 337 · see citing works
The shedding protease ADAM17: Physiology and pathophysiology
Zunke, F., & Rose‐John, S. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2017.07.001 · Cited by 337 · see citing works
McInnes, I. B., Thompson, L., Giles, J. T., Bathon, J. M., Salmon, J. E., Beaulieu, A. D., Codding, C. E., Carlson, T. H., Delles, C., Lee, J. S., et al. (2013) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2013-204345 · Cited by 325 · see citing works
Koenig, W. (2013) · International Journal of Cardiology · doi:10.1016/j.ijcard.2013.07.113 · Cited by 315 · see citing works
Ferreira, R. C., Freitag, D. F., Cutler, A. J., Howson, J. M. M., Rainbow, D. B., Smyth, D. J., Kaptoge, S., Clarke, P., Boreham, C., Coulson, R. M., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003444 · Cited by 316 · see citing works
Mendelian randomization: where are we now and where are we going?
Burgess, S., Timpson, N. J., Ebrahim, S. B. J., & Smith, G. D. (2015) · International Journal of Epidemiology · doi:10.1093/ije/dyv108 · Cited by 308 · see citing works
Residual Cardiovascular Risk at Low LDL: Remnants, Lipoprotein(a), and Inflammation
Hoogeveen, R. C., & Ballantyne, C. M. (2020) · Clinical Chemistry · doi:10.1093/clinchem/hvaa252 · Cited by 316 · see citing works
Inflammation and Brain Structure in Schizophrenia and Other Neuropsychiatric Disorders
Williams, J. A., Burgess, S., Suckling, J., Lalousis, P. A., Batool, F., Griffiths, S. L., Palmer, E. R., Karwath, A., Barsky, A., Gkoutos, G. V., et al. (2022) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2022.0407 · Cited by 310 · see citing works
Choy, E., Ganeshalingam, K., Semb, A., Szekanecz, Z., & Nurmohamed, M. (2014) · Rheumatology · doi:10.1093/rheumatology/keu224 · Cited by 320 · see citing works
Burgess, S., Foley, C. N., & Zuber, V. (2018) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-083117-021731 · Cited by 287 · see citing works
van Diepen, J. A., Berbée, J. F. P., Havekes, L. M., & Rensen, P. C. N. (2013) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2013.02.028 · Cited by 292 · see citing works
Khandaker, G. M., Zuber, V., Rees, J. M. B., Carvalho, L. A., Mason, A. M., Foley, C. N., Gkatzionis, A., Jones, P. B., & Burgess, S. (2019) · Molecular Psychiatry · doi:10.1038/s41380-019-0395-3 · Cited by 279 · see citing works
Inflammatory risk factors, biomarkers and associated therapy in ischaemic stroke
Esenwa, C. C., & Elkind, M. S. V. (2016) · Nature Reviews Neurology · doi:10.1038/nrneurol.2016.125 · Cited by 282 · see citing works
Hamer, M., Sabia, S., Batty, G. D., Shipley, M. J., Tabák, A. G., Singh-Manoux, A., & Kivimaki, M. (2012) · Circulation · doi:10.1161/circulationaha.112.103879 · Cited by 280 · see citing works
Role of Inflammation in Heart Failure
Shirazi, L. F., Bissett, J. K., Romeo, F., & Mehta, J. L. (2017) · Current Atherosclerosis Reports · doi:10.1007/s11883-017-0660-3 · Cited by 280 · see citing works
LDL cholesterol: controversies and future therapeutic directions
Ridker, P. M. (2014) · The Lancet · doi:10.1016/s0140-6736(14)61009-6 · Cited by 274 · see citing works
Anticytokine Agents: Targeting Interleukin Signaling Pathways for the Treatment of Atherothrombosis
Ridker, P. M. (2019) · Circulation Research · doi:10.1161/circresaha.118.313129 · Cited by 260 · see citing works
“randomization studies have also implicated the IL-6 signaling system in both atherogenesis and acute plaque rupture.(34,35)”
BackgroundDepression and inflammation among children and adolescents: A meta-analysis
Colasanto, M., Madigan, S. L., & Korczak, D. J. (2020) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.09.025 · Cited by 278 · see citing works
Changes in lipid levels with inflammation and therapy in RA: a maturing paradigm
Robertson, J., Peters, M., Mcinnes, I., & Sattar, N. (2013) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2013.91 · Cited by 256 · see citing works
Esser, N., Paquot, N., & Scheen, A. J. (2014) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2015.974804 · Cited by 252 · see citing works
Improving the odds of drug development success through human genomics: modelling study
Hingorani, A. D., Kuan, V., Finan, C., Krüger, F. A., Gaulton, A., Chopade, S., Sofat, R., MacAllister, R. J., Overington, J. P., Hemingway, H., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-54849-w · Cited by 242 · see citing works
Targeting Interleukin-6: All the Way to Treat Autoimmune and Inflammatory Diseases
Tanaka, T., & Kishimoto, T. (2012) · International Journal of Biological Sciences · doi:10.7150/ijbs.4666 · Cited by 245 · see citing works
Libby (2019) · doi:10.1016/j.jacc.2019.06.007 · Cited by 247 · see citing works
Dietary Inflammatory Potential and Risk of Cardiovascular Disease Among Men and Women in the U.S.
Li, J., Lee, D. H., Hu, J., Tabung, F. K., Li, Y., Bhupathiraju, S. N., Rimm, E. B., Rexrode, K. M., Manson, J. E., Willett, W. C., et al. (2020) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2020.09.535 · Cited by 252 · see citing works
Inflammation, Cytokines and Insulin Resistance: A Clinical Perspective
Wieser, V. E., Moschen, A. R., & Tilg, H. (2013) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-012-0210-1 · Cited by 241 · see citing works
Ridker, P. M., MacFadyen, J. G., Thuren, T. Y., & Libby, P. (2019) · European Heart Journal · doi:10.1093/eurheartj/ehz542 · Cited by 241 · see citing works
Giles, J., Sattar, N., Gabriel, S., Ridker, P., Gay, S., Warne, C., Musselman, D., Brockwell, L., Shittu, E., Klearman, M., et al. (2019) · Arthritis & Rheumatology · doi:10.1002/art.41095 · Cited by 208 · see citing works
Worldwide Exposures to Cardiovascular Risk Factors and Associated Health Effects
Tzoulaki, I., Elliott, P., Kontis, V., & Ezzati, M. (2016) · Circulation · doi:10.1161/circulationaha.115.008718 · Cited by 236 · see citing works
Gaziano, L., Giambartolomei, C., Pereira, A. C., Gaulton, A., Posner, D. C., Swanson, S. A., Ho, Y.-L. A., Iyengar, S. K., Kosik, N., Vujković, M., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01310-z · Cited by 225 · see citing works
- Authors
- Swerdlow, D. I.
- Affiliations
- University College London (GB)
- Corresponding author
- Daniel I. Swerdlow
- ORCID
- Daniel I. Swerdlow
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 379
- Issue
- 9822
- Pages
- 1214-1224
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- PMC
- PMC3316968
- OpenAlex
- W2143727405
- Cited by
- 1,146
- References
- 100
- Citations by year
- 2026: 78 · 2025: 86 · 2024: 94 · 2023: 89 · 2022: 84 · 2021: 110 · 2020: 89 · 2019: 80 · 2018: 74 · 2017: 77 · 2016: 67 · 2015: 56 · 2014: 63 · 2013: 65 · 2012: 32
- FWCI
- 8.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Lancet (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Bristol Research (University of Bristol) (publishedVersion, cc-by)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Lithuanian University of Health Sciences (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- MRC population health scientist fellowship (G0802432)
- National Institutes of Health (NIH), the MRC, and the British Heart Foundation (BHF (RG/10/12/28456)
- BHF (Schillingford) clinical training fellowship (FS/07/011)
- US National Heart, Lung, and Blood Institute (HHSN268200900009C)
- National Human Genome Research Institute (U01HG005152)
- Cancer Research UK (C1298/A8362, C150/A5660)
- IKEM (Czech Republic) (00023001)
- National Institute for Healthy Ageing (05060810)
- NIH/NHLBI (5215810-55000000041)
- BHF (RG 08/008 and PG/07/133/24260, RG/04/003)
- Netherlands Organisation for Health Research and Development (90700342)
- BHF senior fellowship (FS 05/125)
- British Heart Foundation (RG/10/12/28456)
- contract no. (HHSN268200625226C)
- NHLBI in collaboration with MESA investigators (N01 HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, and RR-024156)
- Wellcome Trust (064947/Z/01/Z and 081081/Z/06/Z)
- National Institute on Aging (1R01 AG23522-01)
- Intramural Research Program of the National Institute on Aging, NIH, Department of Health and Human Services (Z01 AG000954-06, ISGS (R01 NS42733), (R01 NS39987), Z01 AG000015-50)
- European Commission (QLG1-CT-2002-00896)
- Dutch Kidney Foundation (Grant E033)
- GENECURE (FP-6 LSHM CT 2006 037697)
- NIH (grant LM010098)
- The Netherlands Organisation for Health Research and Development (grant 916.761.70)
- European Union's Seventh Framework Programme (FP7/2007-2013)
- NHLBI (RFP-NHLBI-WH-11-10, HL36310)
- Veni grant Organization for Scientific Research (NWO) (2001.064)
- NIH; National Institute on Aging (AG13196)
- MRC (grant NHLBI 33014)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- IL-6 receptor, tocilizumab, coronary artery disease, primary prevention, C-reactive protein, fibrinogen, rheumatoid arthritis, genetic variants, monoclonal antibodies
- MeSH terms
- Coronary Disease, Gene Frequency, Genotype, Humans, Phenotype, Genetic Variation, Signal Transduction, Randomized Controlled Trials as Topic, Treatment Outcome, Inflammation Mediators, Receptors, Interleukin-6, Polymorphism, Single Nucleotide, Genetic Association Studies, Mendelian Randomization Analysis, Antibodies, Monoclonal, Humanized
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