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Interleukin 6 pathway and coronary heart disease

Interleukin 6 pathway and coronary heart disease. Lu Qi, MD, PhD. Assistant Professor of Medicine, BWH and Harvard Medical School Assistant Professor of Nutrition, Harvard School of Public Health. 3/27/2012. IL6 and atherosclerosis. Schuett et al. 2009. Variants in IL6 receptor gene.

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Interleukin 6 pathway and coronary heart disease

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  1. Interleukin 6 pathway and coronary heart disease Lu Qi, MD, PhD Assistant Professor of Medicine, BWH and Harvard Medical School Assistant Professor of Nutrition, Harvard School of Public Health 3/27/2012

  2. IL6 and atherosclerosis Schuett et al. 2009

  3. Variants in IL6 receptor gene IL6 signalling, soluble interleukin 6 activates the membrane-bound receptor in hepatocytes and leucocytes, thereby initiating downstream functional cascades Asp358Ala (rs8192284) variant in IL6R might impair classic IL6 signalling by reducing membrane-bound IL6R levels.

  4. Diabetes. 2007 Asp358Ala with high plasma IL-6 levels Diabetes. 2009 Asp358Ala with low plasma CRP levels

  5. In total 204 930 participants were included Associations of Asp358Ala with several inflammation biomarkers and conventional cardiovascular risk factors in 125 222 participants without a history of cardiovascular disease Assessed Asp358Ala in relation to risk of coronary heart disease in a meta-analysis of 51 441 patients with CHD and 136 226 controls Minor allele frequency of Asp358Ala was 39%

  6. Asp358Ala and cardiovascular risk factors

  7. The pleiotropic effect of Asp358Ala For every minor allele inherited, carriers had a 34.3% increase in soluble IL6R, a 14.6% increase in interleukin 6, a 7.5% reduction in C-reactive protein, and a 1.0% reduction in fibrinogen

  8. Biochemical risk factors and CHD risk

  9. Genetic vs biochemical markers in causal inference Biochemical markers Levels are prone to fluctuation in the circulation One-point measure reflects transient exposure status Confounding and reverse causation Genetic markers Fixed at conception and are indicators of lifelong exposure Not affected by confounding and reverse causation

  10. Asp358Ala and CHD risk Odds Ratio/minor allele=0.966 (95% CI 0.950-0.982; p=0.000045)

  11. Some comments It is necessary to perform comprehensive analysis to demonstrate Whether the genetic effect is pleiotropic The genetic variants may affect multiple molecular risk factors and therefore not suitable for MR analysis Genetic association analysis on the markers with pleiotropic effects may still provide evidence for causal relation, which may involve the combined contribution of multiple risk factors

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