Using genetics to create anti-inflammatory drugs

Two large international meta-analyses have discovered convincing new evidence that interleukin-6 receptor (IL6R), a protein that plays a role in inflammatory signaling, has a causal affect on the development of coronary heart disease (CHD). The findings, published Online First in The Lancet, indicate that drugs targeting this IL6R-mediated signaling inflammatory mechanism could potentially also be effective in fighting CHD. Tocilizumab is a similar drug, which is already used frequently for the treatment of rheumatoid arthritis. CHD is caused by atherosclerosis, an accumulation of fatty material in the walls of arteries, and is the leading cause of death worldwide. Until now, researchers have not been able to establish a direct causal link with a specific inflammatory biomarker, despite of scientists' considerable interest on the impact of inflammation in atherosclerosis. Although earlier research demonstrated that there is a link between various blood measures of inflammation and the risk of heart attacks, human genetic studies on the other hand indicate that these links simply reflect on interconnections rather than cause-and-effect relationships. Conversely, the IL6R Genetics Consortium and Emerging Risk Factors Collaboration reported in the first article that the risk of heart disease would be reduced by a genetic variation that is responsible for depressing inflammation. In the study, researchers assessed more than 200,000 people's genetic and biomarker information from 82 studies to evaluate whether a functional genetic variant (Asp358Ala) in the IL6R gene that is known to control IL6R signaling, could have a potential impact on a person's susceptibility to CHD. The findings demonstrated that 358Ala allele was linked to a clear anti-inflammatory effect that was evident by reduced levels of C-reactive protein and fibrinogen in the blood, and by a 3.4% lower CHD risk for each copy of 358Ala inherited. The researchers state: "These results support the inflammation hypothesis in CHD and encourage exploration of modulation of IL6R pathways as a means to prevent CHD." In the second article, researchers of the IL6R Mendelian Randomization Analysis Consortium evaluated data from 40 studies that included nearly 133,500 participants in order to establish whether using a drug to block the IL6 receptor from exerting its pro-inflammatory effects could potentially lower the risk of CHD amongst the general population. They discovered during Mendelian randomization that a single-nucleotide polymorphism (SNP) gene variation in IL6R, i.e. rs7529229, which represents the Asp358Ala variant, had an impact on various inflammatory markers and related pathways. The findings were consistent with results of trials, in which tocilizumab blocked the IL6R in patients with rheumatoid arthritis. The findings were supported by a further meta-analysis that predicted that the same rs7529229 variant was linked to a decreased CHD risk in 25,458 CHD incidents and 100,740 controls. This translates to a reduction rate of 5% in CHD risk for each copy inherited. The researches conclude: "IL6R blockade could provide a novel therapeutic approach to prevention of CHD that warrants testing in suitably powered randomized trials." Matthijs Boekholdt and Erik Stroes from the Academic Medical Center in Amsterdam, the Netherlands says in a linked comment: "Collectively, these large-scale and highly consistent results lend strong support to the concept that inhibition of inflammatory pathways is an attractive strategy to reduce cardiovascular risk."