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The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis.

- Lancet (2012)

Bottom Line: 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.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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Associations of the minor allele of the IL6R SNP rs7529229 and tocilizumab (8 mg/kg) versus placebo with commonly reported biomarkersConcordance between the drug and genetic variants is shown. Effects are presented as standardised mean difference apart from loge transformed variables (shown by *), for which rs7529229 effects represent the mean difference on the log scale. Estimates for soluble interleukin-6 receptor were not plotted since their substantially greater magnitude would disrupt the scale of the graph: standardised mean differences were 0·75 (95% CI 0·59–0·91) ng/mL per minor allele for rs7529229, and 93·67 (95% CI 90·27–97·06) ng/mL for tocilizumab 8 mg/kg versus placebo. SNP=single nucleotide polymorphism.
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fig2: Associations of the minor allele of the IL6R SNP rs7529229 and tocilizumab (8 mg/kg) versus placebo with commonly reported biomarkersConcordance between the drug and genetic variants is shown. Effects are presented as standardised mean difference apart from loge transformed variables (shown by *), for which rs7529229 effects represent the mean difference on the log scale. Estimates for soluble interleukin-6 receptor were not plotted since their substantially greater magnitude would disrupt the scale of the graph: standardised mean differences were 0·75 (95% CI 0·59–0·91) ng/mL per minor allele for rs7529229, and 93·67 (95% CI 90·27–97·06) ng/mL for tocilizumab 8 mg/kg versus placebo. SNP=single nucleotide polymorphism.

Mentions: The blood markers interleukin 6, soluble IL6R, C-reactive protein, fibrinogen, and total, LDL, and HDL cholesterol were available in both genetic studies and tocilizumab treatment trials allowing a direct comparison of IL6R genotype and IL6R blockade (table). The minor allele of rs7529229 and treatment with tocilizumab showed directionally concordant effects; each was associated with reduced C-reactive protein and fibrinogen and increased interleukin 6 and soluble IL6R (table, figure 2). Tocilizumab treatment increased circulating total, HDL, and LDL cholesterol, and triglycerides, but the IL6R rs7529229 SNP, by contrast, showed no significant association with any of these lipid fractions (table, figure 2). In randomised trials, tocilizumab increased concentrations of albumin and haemoglobin and decreased erythrocyte sedimentation rate (ESR), platelet count, and serum amyloid A (table). The effect of rs7529229 was directionally concordant with that of tocilizumab on albumin, haemoglobin, and platelet count (table, figure 2). Data for ESR were unavailable in the genetic studies, but plasma viscosity (reflected by ESR) was lower in carriers of the rs7529229 minor allele (mean difference per allele −2·16×10−3 mPa.s, 95% CI −3·86×10−4 to −3·94×10−3, p=0·02; five studies, 15 589 individuals). Absence of data for serum amyloid A in the genetic analysis precluded comparison with tocilizumab treatment. In comparison of tocilizumab treatment with the rs7529229 variant, the direction of effect was concordant for nine of the ten biomarkers (table, figure 2), and greater than expected under the hypothesis of no concordance (binomial test, p=0·01).


The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis.

- Lancet (2012)

Associations of the minor allele of the IL6R SNP rs7529229 and tocilizumab (8 mg/kg) versus placebo with commonly reported biomarkersConcordance between the drug and genetic variants is shown. Effects are presented as standardised mean difference apart from loge transformed variables (shown by *), for which rs7529229 effects represent the mean difference on the log scale. Estimates for soluble interleukin-6 receptor were not plotted since their substantially greater magnitude would disrupt the scale of the graph: standardised mean differences were 0·75 (95% CI 0·59–0·91) ng/mL per minor allele for rs7529229, and 93·67 (95% CI 90·27–97·06) ng/mL for tocilizumab 8 mg/kg versus placebo. SNP=single nucleotide polymorphism.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3316968&req=5

fig2: Associations of the minor allele of the IL6R SNP rs7529229 and tocilizumab (8 mg/kg) versus placebo with commonly reported biomarkersConcordance between the drug and genetic variants is shown. Effects are presented as standardised mean difference apart from loge transformed variables (shown by *), for which rs7529229 effects represent the mean difference on the log scale. Estimates for soluble interleukin-6 receptor were not plotted since their substantially greater magnitude would disrupt the scale of the graph: standardised mean differences were 0·75 (95% CI 0·59–0·91) ng/mL per minor allele for rs7529229, and 93·67 (95% CI 90·27–97·06) ng/mL for tocilizumab 8 mg/kg versus placebo. SNP=single nucleotide polymorphism.
Mentions: The blood markers interleukin 6, soluble IL6R, C-reactive protein, fibrinogen, and total, LDL, and HDL cholesterol were available in both genetic studies and tocilizumab treatment trials allowing a direct comparison of IL6R genotype and IL6R blockade (table). The minor allele of rs7529229 and treatment with tocilizumab showed directionally concordant effects; each was associated with reduced C-reactive protein and fibrinogen and increased interleukin 6 and soluble IL6R (table, figure 2). Tocilizumab treatment increased circulating total, HDL, and LDL cholesterol, and triglycerides, but the IL6R rs7529229 SNP, by contrast, showed no significant association with any of these lipid fractions (table, figure 2). In randomised trials, tocilizumab increased concentrations of albumin and haemoglobin and decreased erythrocyte sedimentation rate (ESR), platelet count, and serum amyloid A (table). The effect of rs7529229 was directionally concordant with that of tocilizumab on albumin, haemoglobin, and platelet count (table, figure 2). Data for ESR were unavailable in the genetic studies, but plasma viscosity (reflected by ESR) was lower in carriers of the rs7529229 minor allele (mean difference per allele −2·16×10−3 mPa.s, 95% CI −3·86×10−4 to −3·94×10−3, p=0·02; five studies, 15 589 individuals). Absence of data for serum amyloid A in the genetic analysis precluded comparison with tocilizumab treatment. In comparison of tocilizumab treatment with the rs7529229 variant, the direction of effect was concordant for nine of the ten biomarkers (table, figure 2), and greater than expected under the hypothesis of no concordance (binomial test, p=0·01).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Show MeSH
Related in: MedlinePlus