Interleukin-6 Receptor Pathways in Coronary Heart Disease: A Collaborative Meta-Analysis of 82 Studies
Is genetic variation involving the interleukin-6 receptor (IL6R) related to coronary heart disease (CHD)?
The Asp358Ala (rs2228145) variant in the IL6R was studied in relation to risk factors and inflammation biomarkers in 125,222 participants. The frequency of Asp358Ala was also compared in 51,441 patients with CHD and in 136,226 controls. Effects of Asp358Ala on localized gene expression and to lipopolysaccharide stimulation were also determined.
The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycemia, or smoking. By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34.3% and of IL6 by 14.6%, and mean concentration of C-reactive protein was reduced by 7.5% and of fibrinogen by 1.0%. For every copy of 358Ala inherited, risk of CHD was reduced by 3.4%. Asp358Ala was not related to IL6R mRNA levels or IL6 production in monocytes.
The authors concluded that these data are consistent with a causal association between IL6R-related pathways and CHD.
The functional Asp358Ala IL6R variant is associated with anti-inflammatory effects due to reduced IL6-mediated signaling (the increased IL6 and IL6R levels presumably reflect reduced feedback inhibition). If these anti-inflammatory effects are protective against atherosclerosis, then carriers of this variant should have less coronary artery disease, as this large meta-analysis demonstrates. These data support further studies to determine safety and efficacy of pharmacologic targeting of IL6R signaling pathways in patients at risk of vascular events.
Keywords: Genetic Variation, Inflammation, Coronary Artery Disease, Atherosclerosis, Interleukin-6, Blood Pressure, RNA, Messenger, C-Reactive Protein, Monocytes, Biological Markers, Gene Frequency, Adiposity, Obesity, Fibrinogen, Receptors, Interleukin-6
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