Association of interleukin-6 circulating levels with coronary artery disease: A meta-analysis implementing mendelian randomization approach☆

Abstract 

Background

We aim to investigate whether the association between circulating interleukin 6 (IL-6) levels and the risk for coronary artery disease (CAD) is robust and perhaps even causal by a meta-analysis implementing mendelian randomization approach with IL-6 gene G–174C polymorphism as an instrument.

Methods

Data were available from 19 articles encompassing 9417 CAD patients and 15982 controls. A random effects model was applied irrespectively of between-study heterogeneity, and publication bias was examined using a funnel plot and the corresponding statistics.

Results

Overall, comparison of IL-6 gene alleles –174C with –174G had 4% increased risk for CAD (95% confidence interval [95% CI]: 0.97–1.10; P=0.285), accompanying marginal heterogeneity (I²=38.3%; P=0.033). This association was potentiated in dominant model as odds ratio (OR) reached 1.08 (95% CI: 0.96–1.22; P=0.204) and heterogeneity was significant (I²=58.4%; P<0.0005). Subgroup analysis by ethnicity indicated that carriers of –174C allele were associated with a 12% increased risk for CAD in prospective studies involving White populations (OR=1.12; 95% CI: 0.95–1.33; P=0.184), whereas the association in East Asians was remarkably reversed with 37–46% reduced risk. Relative to –174GG homozygotes, carriers of –174C allele had an overall 0.24pg/ml high circulating IL-6 levels (P=0.047). The predicted OR for 1pg/ml elevation in IL-6 levels was 1.60 (95% CI: 1.44–1.72; P<0.01) in prospective studies involving White populations. Publication biases were absent for all comparisons (P>0.1).

Conclusion

Our findings provided strong evidence on the causal association of circulating IL-6 levels with the development of CAD in White populations.

Keywords: Coronary artery disease, Interleukin 6, Polymorphism, Meta-analysis, Mendelian randomization