Interleukin 6 pathway and coronary heart disease

Assistant Professor of Medicine, BWH and Harvard Medical SchoolAssistant Professor of Nutrition, Harvard School of Public Health

Lu Qi, MD, PhD

3/27/2012

IL6 and atherosclerosis

Schuett et al. 2009

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.

Diabetes. 2007

Asp358Ala with high plasma IL-6 levels

Diabetes. 2009

Asp358Ala with low plasma CRP levels

In total 204 930 participants were included

Associations of Asp358Ala with several inflammation biomarkers and conventional cardiovascular risk factors in125 222 participants without a history of cardiovasculardisease

Minor allele frequency of Asp358Ala was 39%

Assessed Asp358Ala in relation to risk of coronary heart disease in a meta-analysis of 51 441 patients with CHD and 136 226 controls

Asp358Ala and cardiovascular risk factors

For every minor allele inherited, carriers had a 34.3% increase insoluble IL6R, a 14.6% increase in interleukin 6, a 7.5% reduction in C-reactive protein, and a 1.0% reduction in fibrinogen

The pleiotropic effect of Asp358Ala

Biochemical risk factors and CHD risk

Genetic vs biochemical markers in causal inference

Levels are prone to fluctuation in the circulation

One-point measure reflects transient exposure status

Confounding and reverse causation

Fixed at conception and are indicators of lifelong exposure

Not affected by confounding and reverse causation

Biochemical markers

Genetic markers

Odds Ratio/minor allele=0.966 (95% CI 0.950-0.982; p=0.000045)

Asp358Ala and CHD risk

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 mayinvolve the combined contribution of multiple risk factors

It is necessary to perform comprehensive analysis to demonstrateWhether the genetic effect is pleiotropic

Some comments