Objective We conducted a Mendelian randomization (MR) study to examine causal associations of C-reactive protein (CRP) with (1) spinal pain; (2) extent of multisite chronic pain; and (3) chronic widespread musculoskeletal pain.

Design Two-sample MR study.

Setting/Subjects We used summary statistics from publicly available genome-wide association studies (GWAS) conducted in multiple cohorts and biobanks. Genetic instrumental variables were taken from an exposure GWAS of CRP (n=204,402). Outcome GWASs examined spinal pain (n=1,028,947), extent of multisite chronic pain defined as the number of locations with chronic pain (n=387,649), and chronic widespread pain (n=249,843).

Methods We examined MR evidence for causal associations using inverse-variance weighted (IVW) analysis and sensitivity analyses using other methods. We calculated odds ratios (ORs), 95% confidence intervals (95% CIs), and p-values, using a Bonferroni correction (p<0.0166) to account for 3 primary comparisons.

Results Greater serum CRP (mg/L) was not significantly causally associated with spinal pain (OR=1.04, 95% CI 1.00-1.08; p=0.07) in IVW analysis. Greater serum CRP also showed no significant causal association with extent of multisite chronic pain in IVW analysis (beta coefficient= 0.014, standard error=0.011; p=0.19). CRP also showed no significant causal association with chronic widespread pain in IVW analysis (OR=1.00, 95% CI 1.00-1.00; p=0.75). All secondary and sensitivity analyses also showed no significant associations.

Conclusions This MR study found no causal association of CRP on spinal pain, the extent of chronic pain, or chronic widespread pain. Future studies examining mechanistic biomarkers for pain conditions should consider other candidates besides CRP.

The authors have declared no competing interest.

Drs. Suri and Stanaway are supported by VA I01RX0004291. Dr. Suri is an employee of the VA Puget Sound Health Care System and Director of the Resource Core of the University of Washington Clinical Learning, Evidence and Research (CLEAR) Center, which is funded by NIAMS/NIH P30AR072572. Ms. Elgaeva is supported by the Ministry of Education and Science of the RF via the Institute of Cytology and Genetics (project 0259-2021-0009 / AAAA-A17-117092070032-4). The contents of this work do not represent the views of the US Department of Veterans Affairs, the National Institutes of Health, or the US Government. The study was conducted using publicly available summary data from the studies mentioned above, and we are grateful for the study participants for making such research possible. protocol. FW is supported by Versus Arthritis grant 22467. The authors have no conflicts of interest.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Summary statistics for the four genome-wide association studies used in this analyses were publicly available for download prior to analyses.

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Funding Source: Drs. Suri and Stanaway are supported by VA I01RX0004291. Dr. Suri is an employee of the VA Puget Sound Health Care System and Director of the Resource Core of the University of Washington Clinical Learning, Evidence and Research (CLEAR) Center, which is funded by NIAMS/NIH P30AR072572. Dr. Tsepilov is supported by the Wellcome Sanger Institute and the Russian Foundation for Basic Research (project 19-015-00151). Ms. Elgaeva is supported by the Ministry of Education and Science of the Russian Foundation via the Institute of Cytology and Genetics (project 0259-2021-0009 / AAAA-A17-117092070032-4). The contents of this work are solely the responsibility of the authors and do not represent the views of the US Department of Veterans Affairs, the National Institutes of Health, or the US Government. The study was conducted using publicly available summary data from the studies mentioned above, and we are grateful for the study participants for making such research possible.

Potential Conflicts of Interest: None of the authors has potential conflicts of interest to report.