Background
C-reactive protein (CRP) is a marker of inflammation associated with autoimmune, cardiovascular, and neuropsychiatric disorders. However, it remains unclear whether CRP causally affects these traits or if observed associations result from reverse causation or confounding.
Results
Univariable MR suggests evidence of potential causal effects of CRP on coronary artery disease, high-density lipoprotein (HDL) cholesterol, LDL cholesterol, triglycerides, type 2 diabetes, glycated hemoglobin (HbA1c), rheumatoid arthritis (RA), SCZ and OA at the nominal P < .05 significance level. However, after adjusting for computationally selected heritable confounders, only effects on HDL cholesterol (negative), HbA1c (positive), RA (risk increasing), and SCZ (risk decreasing) remain nominally significant. Using confounder-adjusted MVMR additionally reveals evidence of a protective effect of CRP on bipolar disorder not observed in the univariable analysis.
Conclusion
These results suggest that univariable MR analyses of CRP may be biased by high levels of heritable confounding, though CRP may indeed play a causal role in development of some diseases, potentially mediated by its role in innate immunity. These results also highlight the potential for automatic confounder selection to improve the robustness of MR analyses.
So CRP-lowering intervention might not do much by themselves then?
Personally I think CRP is an indicator of a high level of senescent cells (if you measure it sufficiently frequently to get the back ground level). Hence anything driven by senescence is more likely to occur, but not causally.
Based on the above I don’t see value in measuring CRP.
Alternatively, per the OpenEvidence AI, The American College of Cardiology (ACC), in its 2025 Scientific Statement on Inflammation and Cardiovascular Disease, recommends universal screening of hsCRP in both primary and secondary CVD prevention , recognizing it as a clinically important and independent predictor of cardiovascular events.
Following that, taking action to lower hsCRP would be beneficial.
My first thought based on this abstract (only) is what disappears after heritable confounder adjustment: CAD, LDL, triglycerides, T2D, and knee OA all lose their nominally significant signals. From previous discussions we know that the cardiometabolic literature has long debated whether CRP is causal or merely a downstream readout of upstream inflammatory and adiposity-driven processes. Design-wise, the MVMR analysis essentially reproduces and extends that null. What we know or think we know from the IL-6 axis: trials and MR studies of IL-6R variants show more robust causal signals for ASCVD than CRP variants do. This finding (possibly) lends support to the idea that CRP is the smoke, not the fire, something I personally find dissatisfying but “it is what it is.” There is more to be said about this study but my immediate thought is that it lends support for measuring and managing to a different kind of inflammatory indicator, GlycA being one candidate and the one I have moved to even though hsCRP is bundled with my standard comprehensive screen and GlycA is not.
GlycA “subsumes” other inflammatory metrics. It is not a single protein but a composite nuclear magnetic resonance spectroscopic signal. Because GlycA represents the integrated glycosylation status of multiple high-abundance proteins simultaneously, it offers two advantages for tracking chronic, low-grade metabolic inflammation (inflammaging): It has less analytical noise and shows significantly lower intra-individual variability over time. It effectively “smooths” the acute-phase noise (extreme in CRP, for example), allowing one to monitor the underlying, persistent inflammatory tone. More important, I think, it captures the net result of multiple upstream inflammatory pathways. This makes it a broader, more robust proxy for the cumulative inflammatory burden on the cardiovascular and metabolic systems than any single protein measurement. Finally, more speculation on my part, older people can show blunted CRP metrics such that even multiple readings should not be trusted in someone over, say, 65.
One other point. The mean of GlycA is ~375 mmol/L and the SD is ~82. This is not a healthy mean. A geroprotective goal is likely 325 or less. The distribution has a long right tail.
Report back when you can. So far, my GlycA is slightly discordant with my IL-6 and CRP history, both of which are very low whereas GlycA is around the mean. I’m going to track it down.
Is Rapa reducing your inflammatory markers? What point in the cycle?
Hard to tell from hsCRP only, it varies, but I don’t see a pattern there. On the other hand, some blood markers on my CBC show some reliable changes at the end of a cycle, and some of those values tend to drift back after some months off-cycle. Anyway, I’ll have to get more serious about markers on my next cycle, and will try to look for surrogate markers for the more advanced ones.
Reciprocally, is there any clinical evidence that any CRP-lowering intervention significantly reduces correlated adverse health outcomes? That would be another path to assess correlation vs. causation (especially re: @John_Hemming’s theory of correlation with senescent cells).
I think the only RCTs are for colchicine (but it also affects neutrophils/inflammasome biology) and canakinumab (CANTOS, but in people with prior MI). Otherwise, the MR suggests no strong effects.
The problem here is what you need to do is to reduce the burden of senescence (IMO by getting the cells to function correctly rather than killing them). That will only reduce that part of IL-6 (and hence CRP) production that comes from SASP. If you take a single reading of CRP that will not show what the baseline is as it will also include IL-6 from infection.