High-sensitivity C-reactive protein, low-grade systemic inflammation and type 2 diabetes mellitus: A two-sample...

The role of inflammation in type 2 diabetes mellitus (T2D) remains unclear. We investigated the associations of high sensitivity C-reactive protein (hsCRP) concentration with T2D and glycemic traits using two-sample Mendelian Randomization.

We used publically available summary-statistics data from genome-wide association studies on T2D (DIAGRAM: 12 171 cases; 56 862 controls) and glycemic traits (MAGIC: 46 186 participants without diabetes mellitus). We combined the effects of the genetic instrumental variables through inverse-variance weighting (IVW), and MR-Egger regression and weighted-median estimation as sensitivity analyses which take into account potential violations (e.g., directional pleiotropy) of the assumptions of instrumental variable analyses. Analyses were conducted using 15 known hsCRP genetic instruments among which 6 instruments are hsCRP specific and not involved in inflammatory processes beyond hsCRP concentration regulation. Though we found no association between the combined effect of the genetic instrumental variables for hsCRP and T2D with IVW (odds ratio per 1 ln [hsCRP in mg/L]: 1.15; 95% confidence interval: 0.93, 1.42), we found associations for T2D with MR-Egger regression and weighted-median estimation (odds ratio with 95% confidence interval per 1 ln [hsCRP in mg/L], MR-Egger regression: 1.29; 1.08, 1.49; weighted-median estimator: 1.21; 1.02, 1.39). We found no association with T2D for the combination of hsCRP-specific genetic instruments nor did we found associations with glycemic traits in any of the analyses.

Evidence was provided for a potential causal association between hsCRP and T2D, but only after considering directional pleiotropy. However, hsCRP was not causally associated with glycemic traits.