Circulating interleukin-6 and cancer: A meta-analysis using Mendelian randomization

As a multifactorial cytokine, interleukin-6 (IL-6) is widely believed to play a role in the progression and severity of many forms of cancer. Several observational studies have suggested that circulating IL-6 can explain inter-individual variability in predisposition to cancer. Heikkila and colleagues have written an excellent review, highlighting the involvement of elevated circulating IL-6 in human carcinogenesis1. However, it remains unclear whether the relevance between circulating IL-6 and cancer is causal as the issue of confounding or reverse causation is often unavoidable in observational epidemiology. Ideally, randomized controlled trial of the intervention that alters circulating IL-6 is considered as the gold standard for evaluating this causal relevance, but in some circumstances it is neither practical nor ethical to randomize human beings for such trials. As an alternative, a more promising method termed as ‘Mendelian randomization’ has been developed to exploit the impact of long-term exposure differences on disease risk by using a genetic instrument to account for the potential biases due to confounding and reverse causation2. Like a randomized controlled trial, Mendelian randomization randomizes genotypes at conception according to Mendel’s second law3. This method has been successfully applied to a variety of genetic exposures such as obesity and alcohol consumption in causal susceptibility to cancer4. The most immediate determinant of circulating IL-6 is its encoding gene IL-6. The genomic sequence of IL-6 gene is highly polymorphic and one of the most frequently evaluated variants is -174G/C (rs1800795) in the promoter region5,6. In vitro studies have found the allele-specific impact of -174G/C variant on IL-6 gene promoter activity, with the -174C allele corresponding to lower expression level7. Besides, carriers of the -174G allele had a higher level of circulating IL-6 than those with the -174CC genotype8,9. Based on these observations, we thereby develop a completing hypothesis that the association between circulating IL-6 and cancer is causally related. To test this hypothesis, we employed Mendelian randomization technique to meta-analyze all available published articles in this regard by using IL-6 gene -174G/C variant as an instrument.