Genetic impact of blood C-reactive protein levels on chronic spinal & widespread pain

Abstract

Purpose: Causal mechanisms underlying systemic inflammation in spinal & widespread pain remain an intractable experimental challenge. Here we examined whether: (i) associations between blood C-reactive protein (CRP) and chronic back, neck/shoulder & widespread pain can be explained by shared underlying genetic variants; and (ii) higher CRP levels causally contribute to these conditions. Methods: Using genome-wide association studies (GWAS) of chronic back, neck/shoulder & widespread pain (N = 6063–79,089 cases; N = 239,125 controls) and GWAS summary statistics for blood CRP (Pan-UK Biobank N = 400,094 & PAGE consortium N = 28,520), we employed cross-trait bivariate linkage disequilibrium score regression to determine genetic correlations (rG) between these chronic pain phenotypes and CRP levels (FDR < 5%). Latent causal variable (LCV) and generalised summary data-based Mendelian randomisation (GSMR) analyses examined putative causal associations between chronic pain & CRP (FDR < 5%). Results: Higher CRP levels were genetically correlated with chronic back, neck/shoulder & widespread pain (rG range 0.26–0.36; P ≤ 8.07E-9; 3/6 trait pairs). Although genetic causal proportions (GCP) did not explain this finding (GCP range − 0.32–0.08; P ≥ 0.02), GSMR demonstrated putative causal effects of higher CRP levels contributing to each pain type (beta range 0.027–0.166; P ≤ 9.82E-03; 3 trait pairs) as well as neck/shoulder pain effects on CRP levels (beta [S.E.] 0.030 [0.021]; P = 6.97E-04). Conclusion: This genetic evidence for higher CRP levels in chronic spinal (back, neck/shoulder) & widespread pain warrants further large-scale multimodal & prospective longitudinal studies to accelerate the identification of novel translational targets and more effective therapeutic strategies.