The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis
Year: 2012
Type: review
Study design: Observational Study
Abstract: 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.
Source: The Lancet
Author: ‡
Institution: University College London
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $7,890
Funders: Wellcome Trust, Cancer Research UK, National Institute for Health and Care Research, British Heart Foundation, European Commission, ZonMw, Nierstichting, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Hjärt-Lungfonden, Karolinska Institutet, Stockholms Läns Landsting, Vetenskapsrådet, National Institutes of Health, Agency for Healthcare Research and Quality, U.S. Public Health Service, World Cancer Research Fund, Agentschap NL, National Institute on Aging, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, U.S. National Library of Medicine, National Center for Research Resources
Awards: G1078500014, RENEWAL: British Regional Heart Study: a prospective investigation of the aetiology and prevention of coronary heart disease, stroke and heart failure among older British men, G1186962729, G1261793039, MESA, G1276754516, G1342751976, G1394812629, G1409423729, G1640378483, G1686417863, Determinants of cardiovascular diseases in Eastern Europe: a multi-centre cohort study., G1907901355, G2130427280, G2144938473, G22458031, G2262782284, G2307454678, MESA, Clinical and Translational Science Award, G2720200114, MESA, G2837638605, G290884426, G291913881, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY--EBCT READING, Siblings With Ischemic Stroke Study (SWISS), G3153998395, G3286339204, G3541910250, Utilising genetic tools to dissect causal pathways in cardiovascular disease: deployment of a 50K high density SNP array in the Whitehall II prospective study, G3647016462, G3663210796, G3687594596, RENEWAL: Dissecting the molecular genetic architecture of plasma lipid traits: identifying functional changes and their use in determining coronary heart disease causality, Integrative Analysis of Genomic Risk Factors in Juvenile Idiopathic Arthritis, CANDIDATE GENE ASSOCIATION RESOURCE (CARE), MESA, G395403786, G399481048, G4157653541, TITLE: MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA), The Baltimore Longitudinal Study Of Aging, G443238052, G4512137732, Health disparities and aging in societies in transition, G4543867954, G4618114702, G4621512325, G4688097470, G4711594299, G4722625316, OPTION 3. 4/1/2014 - 3/31/2015. MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA) - READING CENTER, NHLBI, G4892861650, Programme in Applied and Translational Cardiovascular Genomics (ATCG): the UCL-London-School-Edinburgh-Bristol (UCLEB) consortium of population-based prospective studies, MESA, Genetics Of Stroke, SUBCLINICAL CARDIOVASCULAR DISEASE STUDY-ULTRASOUND, G5231281020, Is human complement factor H a shared risk factor for age-related macular degeneration and atherosclerosis?, G526053842, Bioinformatics Strategies for Genome Wide Association Studies, G5787256936, G587882820, G6095866717, G6128188400, Determinants of cardiovascular diseases in Eastern Europe: Longitudinal follow up of a multi-centre cohort study (The HAPIEE Project)., G6359107525, MESA, G6514094751, G66341962, CHANGES IN HEALTH: SOCIO-ECONOMIC STATUS AND PATHWAYS, Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., Hygiene & British Women’s Heart and Health Study: causes and consequences of cardiovascular disease, GWAS of Hormone Treatment and CVD and Metabolic Outcomes in the WHI, MESA, ISGS: The Ischemic Stroke Genetics Study, G78770644, G7964317829, RENEWAL: Psychosocial and biological factors in the occurrence of cardiovascular disease: the Whitehall II study, Socio-economic status and heterogeneity in aging, Socioeconomic gradient in CHD in early old age, G8732353749, G991334795
OpenAlex ID: W2143727405