A two-sample Mendelian randomisation analysis tested 3,213 molecular, physiological and disease traits for causal effects on C-reactive protein and interleukin-6. After Bonferroni correction, 72 traits influenced CRP and nine influenced IL-6. Genetically proxied body mass index and obesity, triglyceride-rich lipoproteins, glycoprotein acetyls and apolipoprotein E raised CRP, while HDL-related cholesterols, polyunsaturated fatty acids and glutamine lowered it. IL-6 responded mainly to adiposity and HDL measures, with smaller effects and weaker sensitivity-analysis support.
The framing matters: most research treats inflammation as a cause of disease, whereas this work positions CRP as a downstream readout of metabolic burden. That fits trial evidence that weight loss and statins lower CRP, and it adds genetic weight to excess adiposity as the dominant modifiable driver. The polyunsaturated fatty acid signal is intriguing but reflects circulating levels, so it cannot be read as proof that supplements or dietary changes would help. Mendelian randomisation estimates lifelong genetic exposures, which rarely translate into the size of effect from an intervention started in midlife, and pleiotropy remains a risk despite the sensitivity checks. The data are also drawn largely from European-ancestry cohorts. This is a preprint and has not been peer reviewed, so findings may shift. For adults, the practical message is confirmatory rather than novel: reducing excess body fat and improving lipid profiles are the most credible levers for lowering systemic inflammation, and a high CRP reading is better treated as a signal of metabolic health than a standalone target.