Cardiovascular
Does the inflammation marker CRP actually cause disease?
Open access · cc by · source: Europe PMC
People born with gene variants that raise their C-reactive protein were not at higher risk of almost any of 32 diseases linked to high CRP, suggesting CRP is mostly a marker rather than a cause, with a surprising lower risk of schizophrenia.
Study at a glance
- Design
- Mendelian randomisation — Two genetic risk scores for CRP level (4 SNPs in the CRP gene; 18 genome-wide significant CRP SNPs) were applied to published GWAS summary statistics for 32 outcomes using inverse-variance-weighted estimation, with heterogeneity tests and stepwise SNP removal to handle pleiotropy, a Bonferroni threshold, and individual-level replication for schizophrenia.
- N
- No single N: outcome datasets ranged from 1,566 to 184,305 participants of European ancestry; the individual-level schizophrenia follow-up used 25,629 cases and 30,976 controls.
- Population
- Participants of European ancestry in large genome-wide association consortia for 32 autoimmune, cardiovascular, metabolic, neurodegenerative and psychiatric traits.
- Outcome
- Estimated causal effect of genetically raised CRP on risk of each of 32 diseases or traits (e.g., coronary artery disease, type 2 diabetes, Crohn disease, depression, schizophrenia, blood pressure).
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Key findings
For most outcomes genetically higher CRP showed no causal effect. Several nominal signals (including coronary artery disease, Crohn disease and blood pressure) disappeared once pleiotropic variants such as those in IL6R were removed. The one robust finding went in an unexpected direction: higher genetically predicted CRP was linked to lower schizophrenia risk (odds ratio 0.86 per 10% higher CRP), confirmed in individual-level data (odds ratio 0.96 per standard deviation of the score), whereas bipolar disorder showed a nominal increase (odds ratio 1.21) that did not survive correction.
Methodology
The researchers used Mendelian randomisation, treating inherited gene variants that nudge CRP levels as a natural experiment. They built two genetic scores for CRP, one from 4 variants in the CRP gene and one from 18 variants across the genome, and applied them to published genetic association results for 32 conditions ranging from heart disease and diabetes to depression and Alzheimer disease. They tested for pleiotropy (variants affecting disease through routes other than CRP), used a strict multiple-testing threshold, and re-checked schizophrenia using individual-level genetic data.
Limitations
The genetic scores explain only about 2% and 5% of variation in CRP, so small causal effects could still be missed, and the heterogeneity-based removal of variants is an imperfect fix for pleiotropy. All data came from people of European ancestry, results rest largely on summary statistics, and the schizophrenia effect is small and its mechanism speculative. A null MR result speaks to lifelong, modest genetic differences in CRP, not necessarily to short-term large rises during illness or to drugs that lower CRP.
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