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 (rs ) 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
participants without a history of cardiovascular
disease
Assessed Asp358Ala in relation to risk of coronary heart disease in a meta-analysis of patients with CHD and 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

9. Biochemical risk factors and CHD risk

10. 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

11. Asp358Ala and CHD risk
Odds Ratio/minor allele=0.966 (95% CI ; p= )

13. 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