P5505Inflammation implicated in the aetiology of major vascular and non-vascular diseases in East Asians
Authors: Karim M , Lin K , Millwood I Y , Kartsonaki C , Hill M , Guo Y , Bian Z , Yu C , Li L , Clarke R , Chen Z , Walters R G , Holmes M V 
Published: October 2019

Abstract

Background
Mendelian randomisation (MR) studies using genetic variants in the IL6R gene encoding the interleukin-6 (IL-6) receptor have demonstrated that IL-6 plays a causal role in the aetiology of coronary heart disease (CHD) in European populations, with implications for the development of drugs targeting inflammation-related pathways. It is less clear whether IL-6 signalling plays a causal role in vascular disease or major non-vascular diseases in East Asians.

Purpose
Using an MR approach, we investigated associations of altered IL-6 signalling with subtypes of CHD, stroke, cancer and respiratory disease in a large East Asian cohort.

Methods
In approximately 150,000 Chinese adults from the China Kadoorie Biobank, we investigated associations of rs7529229 (in strong linkage disequilibrium, r2=0.99, with the IL6R Asp358Ala variant rs2228145) with blood biomarkers and selected disease events in which inflammation has previously been implicated. First, we used linear regression to quantify the per-allele association of rs7529229 with levels in plasma of log-transformed C-reactive protein (CRP) (n=17,866), fibrinogen (n=9,255), and IL-6 protein (n=633). Second, we used logistic regression to evaluate the association of rs7529229 with incidence of CHD, stroke, cancer, and respiratory disease events. All models were adjusted for age, age-squared, sex (except breast cancer), and case ascertainment (for CRP and fibrinogen), and stratified by recruitment region. We assessed significance at a 5% false discovery rate.

Results
IL6R rs7529229 C-allele was associated with lower log CRP (–0.11 SDs per C-allele; p=4.9x10–25) and log fibrinogen (–0.07 SDs; p=2.2x10–7), and higher log IL-6 (0.15 SDs; p=0.011) (Figure 1), mimicking therapeutic blockade of IL6R. IL6R rs7529229 was associated with a lower risk of acute myocardial infarction (n=4,047 cases; OR: 0.92 [95% CI 0.88–0.96] per C-allele; p=2.8x10–4), with the association similar for fatal and non-fatal cases (Figure 2). There was no evidence of association with ischaemic stroke (n=18,315; OR: 1.00 [0.98–1.03]; p=0.90) or intracerebral haemorrhage (n=7,372; OR: 1.03 [0.99–1.07]; p=0.10). For non-cardiovascular diseases, the IL6R rs7529229 was associated with a lower risk of oesophageal (n=824; OR: 0.88 [0.79–0.97] per C-allele; p=0.013) and colorectal (n=1,151; OR: 0.89 [0.82–0.97]; p=8.3x10–3) cancers, but a higher risk of tuberculosis (n=1,017; OR: 1.15 [1.05–1.26]; p=2.4x10–3).

Conclusion
The results of the present study are consistent with a causal role for the IL-6 signalling pathway in the aetiology of myocardial infarction and some cancers, but not of stroke. These findings provide further genetic support for drug development targeting inflammation in the prevention and treatment of coronary and selected cancer outcomes.

Acknowledgement/Funding
Kadoorie Charitable Foundation, UK Wellcome Trust, Chinese Ministry of Science and Technology, BHF, CRUK, NIHR